PHARMACOLOGICAL PRODUCT FOR ENZYME THERAPY FOR THE TREATMENT OF HOMOCYSTRINURIA

Abstract

This description provides formulations for a pharmaceutical product comprising a PEGylated CBS protein having the amino acid sequence SEQ ID NO: 1. Dosages and dosage regimens are provided for the treatment of homocystinuria in a subject in need. In addition, dosages and dosage regimens are also provided for reducing homocysteine ​​(Hcy) levels or increasing cysteine ​​(Cys) and / or cystathionine (Cth) levels in a subject in need.

Description

PHARMACOLOGICAL PRODUCT FOR ENZYME THERAPY FOR THE TREATMENT OF HOMOCYSTINURIA CROSS REFERENCE TO RELATED REQUESTS This application claims priority of 62 / 866,810 filed on June 26, 2019 entitled Drug Product for Enzyme Replacement Therapy for the Treatment of Homocystinuria, and 62 / 983,860 filed on March 2, 2020 entitled Drug Product for Enzyme Therapy for the Treatment of Homocystinuria, the content of each of which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING This application is submitted together with a Sequence Listing in electronic format. The Sequence Listing file, titled 2089_1005PCT_SL.txt, was created on June 26, 2020 and is 18,401 bytes in size. The information in electronic form of the Sequence Listing is incorporated herein by reference in its entirety. FIELD OF DISCLOSURE The disclosure relates to compositions and methods for enzyme therapy for the treatment of homocystinuria using the pharmacological product described herein. DISCLOSURE BACKGROUND Cystathionine β-synthase deficiency homocystinuria (CBSDH), also known as classical homocystinuria (HCU) or HCU type 1, is an orphan disease that affects both children and adults. CBSDH is a rare autosomal recessive metabolic condition characterized by an excess of the compound homocysteine ​​(Hcy) in urine, tissues, and plasma, due to reduced or absent activity of the enzyme cystathionine β-synthase (CBS) (see Kraus et al. al., in: Carmel R, Jacobsen DW, eds. Homocysteine ​​in Health and Disease. Cambridge, UK: Cambridge University Press; 2001: 223-243; Sacharow et al., Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al, eds. GeneReviewsTM [Internet].Seattle (WA): University of Washington, Seattle, 2017; each incorporated by reference in this document in its entirety). The diagnosis of CBSDH can be confirmed by molecular genetic testing of the CBS gene as described by Sacharow et al. CBS is an enzyme in the metabolism of the sulfur amino acid methionine (Met), which is present in dietary proteins (see Maclean et al. J Biol Chem. 2012;287(38):31994-32005, incorporated here by reference in its entirety). Therefore, CBSDH can also be diagnosed by measuring markedly increased concentrations of total methionine in plasma. These findings of elevated amino acids can be corroborated by the detection of reduced activity of the CBS enzyme or by the detection of biallelic pathogenic variants in the gene encoding cystathionine β-synthase (see Picker et al., Homocystinuria Caused by Cystationine BetaSynthase Deficiency. 2004 Jan 15 [Updated November 13, 2014] In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviewsTM [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016, available at: ncb (nlm.nih.gov, which is incorporated herein by reference in its entirety). CBS deficiency also leads to reduced levels of cystathionine (Cth) and cysteine ​​(Cys) (see Veeranki et al. Int J Mol Sel. 2013 Jul 18; 14(7):15074-91, which is incorporated herein by reference in its entirety). CBSDH may be suspected based on the following (Picker et al. 2014): 1) clinical findings including ectopia lentis (detachment of the lens in the eye) and / or severe myopia, asthenic habit (tall and thin), skeletal abnormalities, early onset osteoporosis and / or thromboembolic events, developmental delay / unexplained intellectual disability; 2) detection of hypermethioninemia in newborns or, specifically, a positive family history of CBS deficiency may lead to the identification of presymptomatic patients (see Yap et al. J Inherit Metab Dis 1998; 21:738-47, which is incorporated here for reference in its entirety); and 3) family history. There is considerable variability in all of these clinical signs and the age of symptom onset among patients. Current screening approaches generally fail to detect neonates with less severe CBSDH and only detect a minority of patients with more severe CBSDH (see, Huemer et al. J Inherit Metab Dis. 2015 Nov; 38(6): 1007-19 ; Yap, Orphanet Encyclopedia [online series], 2005, pages 1-13; Schiff etal. Neuropediatrics. 2012 Dec; 43(6):295304; each of which is incorporated herein by reference in its entirety) . It is the most common genetic disorder of sulfur metabolism, with an estimated prevalence of 1:200,000 to 1:335,000 worldwide. In the sulfur metabolism pathway, the essential amino acid L-methionine is metabolized to Hcy, followed by a two-step transsulfuration, first to Cth and finally to Cys. CBS is mainly found in the liver and kidney, which catalyzes Hcy to Cth. Excess Hcy can be re-methylated to methionine by betaine-HCy 5 methyl transferase, also elevating plasma Met levels. Although some patients are diagnosed with the disease shortly after birth, the diagnosis of CBSDH often occurs later in life after classic clinical symptoms have developed (see Huemer et al. J Inherit Metab Dis. 2015 Nov, 38(6):1007-19; Yap, Orphanet Encyclopedia [online series]. 2005, pages 1-13; both incorporated by reference herein in their entirety). CBSDH is characterized by developmental delay / intellectual disability, ectopia lentis and / or severe myopia, skeletal anomalies (excessive limb height and length), and thromboembolism. There is considerable variability in all of these clinical signs between patients. Normal total homocysteine ​​(tHcy) levels vary with age, sex, and nutritional status, but typically range between 4.5 and 11 μmol / L (see Quest D¡aqnostics reference range;questdiaqnost¡cs.com , which is incorporated herein by reference in its entirety). Men tend to have slightly (1 to 2 μmol / L) higher levels of tHcy than women, and an approximate doubling of mean values ​​is seen in patients aged between childhood and 80 years (see Refsum et al. Clin Chem 2004;50:3-32, which is incorporated herein by reference in its entirety). In folate supplemented populations, the upper limit (97.5%) of tHcy levels is approximately 12 μΓηοΙ / L ivia / t / zuzz / u i rao o in adults <65 years and 16 pmol / L in adults over 65 years . Many patients with CBSDH present with severe hyperhomocysteinemia with total tHcy levels greater than 100 pmol / L, while others exhibit elevations ranging from mild to several times normal (see Morris etal. J Inherit Metab D / s 2017;40:4974, which is incorporated herein by reference in its entirety). tHcy levels have been found to be highly correlated with disease severity (see Yap et al. J Inherit Metab Dis 1998;21:738747, which is incorporated herein by reference in its entirety). CBSDH is characterized by ocular conditions (ectopia lentis and / or severe myopia), skeletal system (excessive height, long limbs, scoliosis and pectus excavatum), vascular system (thromboembolism) and central nervous system (CNS) (developmental delay / intellectual disability). There is a variable expression of these clinical signs in patients, where there may be involvement of all systems or just one. Some patients have severe multisystem disease with childhood onset, while those with a less severe presentation of the disease may remain asymptomatic into adulthood. Without treatment, life expectancy is markedly reduced in the most severely ill patients (see Morris et al. J Inherit Metab Dis 2017;40:49-74, which is incorporated herein by reference in its entirety). Studies have shown that a reduction in Hcy levels in patients with CBSDH correlates with less severe manifestations of clinical symptoms (see Yap et al. J Inherit Metab Dis 1998;21:738-747, which is incorporated herein by reference In its whole). The pathways through which Hcy levels cause damage to these systems have been widely described (e.g., Ajith et al. Clin Chim Acta 2015;450:316-321; Sato et al. Bone 2005;36:721- 726; Behera et al. J Cell Physiol 2016, each of which is incorporated herein by reference in its entirety) and has led to studies to also investigate the role of Hcy in the general population. Currently, there are few therapies available for the management of CBSDH. Current therapies target the sulfur metabolism pathway through a combination of one or more of the following: 1) dietary modification to reduce protein and / or Met intake; 2) supplementation with some or all of the following: folate, vitamin B12, vitamin B6; and 3) supplementation with methyl donor betaine to enhance enzymatic remethylation of accumulated Hcy to Met. Although no studies have been published on the quality of life (QoL) of patients with CBSDH, it has been observed that patients and their caregivers suffer from the psychosocial effects of following and managing a highly restricted and socially isolated diet. and are extremely anxious about the long-term medical consequences of the disease. Many patients report that they crave the ability to relax their diets without compromising their long-term prospects. Therefore, there is a long-felt need in the art for a method of treating CBSDH that has greater efficacy and fewer negative effects on patients than present therapies. BRIEF DESCRIPTION OF THE DISCLOSURE Various embodiments of the disclosure provide a pharmacological substance comprising: (a) an isolated cystathionine β-synthase (CBS) protein comprising SEQ ID NO: 1; and (b) a PEG molecule covalently linked to the CBS protein. In certain embodiments of the drug substance described herein, the PEG molecule is ME-200GS. Various embodiments of the disclosure provide a pharmaceutical composition comprising the drug substance and a pharmaceutically acceptable adjuvant, diluent or carrier. In certain embodiments, the formulation is freeze-dried. Various embodiments of the disclosure provide a lyophilized formulation which, upon reconstitution, the reconstituted liquid formulation comprises a ready-to-use drug product in a concentration of between about 20 and 30 mg / ml, or about 25 mg / ml, in buffered saline. with phosphate (PBS); approximately 11.4 mM disodium hydrogen phosphate; about 137 mM sodium chloride; approximately 2.70 mM potassium chloride; and approximately 1.98 mM potassium dihydrogen phosphate. A ready-to-use drug product herein is a liquid pharmaceutical formulation comprising a therapeutically effective amount of the drug product, for example, a unit dose of a pharmaceutical composition that includes the drug substance of a PEGylated human truncated CBS protein with a sequence of amino acids of SEQ ID NO: 1 (for example, 20NHS PEG-CBS). The ready-to-use drug may be provided in a vial or similar container to facilitate administration to a subject. Various embodiments of the disclosure provide a lyophilized formulation which, upon reconstitution, the reconstituted liquid formulation comprises 20-30 mg, or about 25 mg, of the drug substance; 1 mi of water; 2 mg disodium hydrogen phosphate (dihydrate); 8 mg sodium chloride; 0.2 mg potassium chloride; and 0.3 mg of potassium dihydrogen phosphate. Alternatively, a lyophilized formulation may be reconstituted to comprise the drug substance, a buffer and an excipient. In certain embodiments, the buffer is 15 mM potassium phosphate. In certain embodiments, the excipient is 8% (w / v) trehalose. Various embodiments of the disclosure provide a method of treating homocystinuria in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition described herein. In certain embodiments, the therapeutically effective amount is a dosage selected from the range of about 0.25 mg / kg to about 10 mg / kg. For example, the dosage is about 0.33 mg / kg, about 0.66 mg / kg, about 1.0 mg / kg or about 1.5 mg / kg. Alternatively, the dose is approximately 2 mg / kg, approximately 7 mg / kg and approximately 10 mg / kg. For example, the dose may be approximately 0.5 mg / kg. Alternatively, the therapeutically effective amount is a dosage selected from the range of about 5.0 mg / kg to about 50 mg / kg, and about 10.0 mg / kg to about 25 mg / kg. For example, the dosage is selected from the group consisting of: about 0.25mg / kg, about 0.33mg / kg, about 0.66mg / kg, about 1.00mg / kg, about 1.50mg / kg, about 2.00mg / kg, about 3.00mg / kg, ivia / t / zuzz / u i rao or approximately 4.OOmg / kg, approximately 5.00mg / kg, approximately 6.00mg / kg, approximately 7.00mg / kg, approximately 8.OOmg / kg, approximately 9.OOmg / kg, approximately 10.0mg / kg, approximately 11.0mg / kg, approximately 12.0mg / kg, approximately 13.0mg / kg, approximately 14.0mg / kg, approximately 15.0mg / kg, approximately 16.0mg / kg, approximately 17.0mg / kg , approximately 18.0mg / kg, approximately 19.0mg / kg, approximately 20.0mg / kg, approximately 21.0mg / kg, approximately 22.0mg / kg, approximately 23.0mg / kg, approximately 24.0mg / kg, approximately 25.0mg / kg, approximately 26.0mg / kg, approximately 27.0mg / kg, approximately 28.0mg / kg, approximately 29.0mg / kg, approximately 30.0mg / kg, approximately 31.0mg / kg, approximately 32.0mg / kg, approximately 33.0mg / kg, approximately 34.0mg / kg, approximately 35.0mg / kg, approximately 36.0mg / kg, approximately 37.0mg / kg, approximately 38.0mg / kg, approximately 39.0mg / kg, approximately 40.0mg / kg, approximately 41.0mg / kg, approximately ivia / t / zuzz / u i rao o 42.0mg / kg, approximately 43.0mg / kg, approximately 44.0mg / kg, approximately 45.0mg / kg, approximately 46.0mg / kg, approximately 47.0mg / kg, approximately 48.0mg / kg, approximately 49.0mg / kg, and approximately 50.0mg / kg. In certain embodiments, the method further comprises administering to the subject at least one selected from the group consisting of: pyridoxine, vitamin B6 and betaine. In certain embodiments, the subject follows a methionine (Met) restricted diet. In certain embodiments, the method further comprises the administration of an antiplatelet agent. In certain embodiments, the antiplatelet agent is an anticoagulant or a warfarin-based anticoagulant. In certain embodiments, the administration step occurs approximately once every 3 days. In certain embodiments, the administration step occurs approximately once a day. In certain embodiments, the administration step occurs approximately once per week. In certain embodiments, the administration step is repeated over approximately weeks. In certain embodiments, the administration step is repeated for approximately 3 months. In certain embodiments, the administration step is repeated for approximately 6 months. In certain embodiments, the administration step is repeated for more than 6 months. In certain embodiments, the administration step is repeated for the remainder of the subject's life. Various embodiments of the disclosure provide a method of decreasing the level of homocysteine ​​(Hcy) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition described herein. In certain embodiments, the Hcy level is less than about 80 μΜ after the administration step. In certain embodiments, the Hcy level is reduced by up to 10% after the administration step. In certain embodiments, the Hcy level is reduced by up to 20% after the administration step. administration. administration. administration. administration. administration. In certain embodiments, the Hcy level is reduced by up to 30% after passage of In certain embodiments, the Hcy level is reduced by up to 40% after passage of In certain embodiments, the Hcy level is reduced by up to 50% after the passage of In certain embodiments, the Hcy level is reduced by up to 60% after passage of In certain embodiments, the Hcy level is reduced by up to 70% after passage of In certain embodiments, the Hcy level is reduced by up to 80% after the administration step. In certain embodiments, the Hcy level is reduced by up to 90% after the administration step. In certain embodiments, the Hcy level is within the range of about 10 μΜ to about 20 μΜ after the administration step. In certain embodiments, the Hcy level is less than 10 μΜ after the administration step. In certain embodiments, the Hcy level is approximately 55 μΜ after the administration step. In certain embodiments, the therapeutically effective amount is a dosage selected from the range of about 0.25 mg / kg to about 10 mg / kg. For example, the dose may be about 0.33 mg / kg, about 0.66 mg / kg, about 1.0 mg / kg, about 1.50 mg / kg, about 2.0 mg / kg, about 7.0 mg / kg, or about 10 mg / kg. In certain embodiments, the dosage is less than 10 mg / kg. In certain embodiments, the method further comprises administering to the subject at least one selected from the group consisting of: pyridoxine, vitamin B6 and betaine. In certain embodiments, the subject follows a methionine (Met) restricted diet. In certain embodiments, the method further comprises the administration of an antiplatelet agent. In certain embodiments, the antiplatelet agent is an anticoagulant or a warfarin-based anticoagulant. In certain embodiments, the administration step occurs approximately once every 3 days. In certain embodiments, the administration step occurs approximately once a day. In certain embodiments, the administration step occurs approximately once per week. In certain embodiments, the administration step is repeated for approximately 6 weeks. In certain embodiments, the administration step is repeated for approximately 3 months. In certain embodiments, the administration step is repeated for approximately 6 months. In certain embodiments, the administration step is repeated for more than 6 months. In some embodiments, the administration step is repeated for the remainder of the subject's life. Various embodiments of the disclosure provide a method of increasing the level of cysteine ​​(Cys) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition described herein. Various embodiments of the disclosure provide a method of increasing the level of cystathionine (Cth) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition described herein. Various embodiments of the disclosure provide a method of treating, alleviating or preventing negative clinical outcomes associated with the ocular system, skeletal system, vascular system and / or central nervous system of a subject, the method comprising: administering to the subject a substance therapeutically effective formulation of the pharmaceutical composition described herein. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects, features and advantages will be apparent from the following description of particular embodiments of the disclosure, as illustrated in the accompanying drawings. ivia / t / zuzz / u i rao o The drawings are not necessarily to scale; Instead, emphasis is placed on illustrating the principles of various dissemination modalities. Figure 1 provides a flow chart of the PEGylation process used in certain embodiments described herein. Figure 2 is a diagram of the input conditions in the puzzle box test for each trial over the three-day testing period. Figure 3 shows the results of the preclinical study in a mouse model of homocystinuria employing long-term continuous treatment with 20NHS PEG-CBS (denoted “PEG CBS C15S” in the figure) on a variable diet background (standard methionine diet (“STD”), high methionine diet (“HMD”), and / or low or restricted methionine diet (“MRD”)). DETAILED DESCRIPTION INTRODUCTION Cystathionine beta synthase deficiency (CBSDH) homocystinuria is characterized by elevated levels of plasma homocysteine ​​(Hcy), along with elevated Met levels and reduced cysteine ​​(Cys) concentrations (see Yap S. Homocystinuria due to cystathionine beta-synthase deficiency . Orphanet Encyclopaedia. Orphanet Encyclopaedia [online series] 2005; Morris et al. al. J Inherit Metab Dis 2017;40:49-74; NORD, Kraus JP. Homocystinuria due to cystathionine beta-synthase deficiency. NORD. NORD [series online] 2017; each of which is incorporated herein by reference in its entirety). To date, more than 180 different mutations of the CBS gene associated with CBSDH have been identified (see Human Genome Mutation Database. 2017. Ref Type .: Online Source. Available at hgmd.cf.ac.uk / ac / index.php, which is incorporated herein by reference in its entirety). Homocysteine ​​(Hcy) is a naturally occurring amino acid that, along with serine, serves as a substrate for the CBS enzyme. CBS governs the unidirectional flow of sulfur from methionine (Met) to cysteine ​​(Cys) operating at the intersection of transmethylation, transsulfuration and remethylation pathways (see Maclean et al. J Biol Chem. 2012;287(38):31994 -32005, which is incorporated herein by reference in its entirety). Native CBS is activated by binding of the allosteric activator Sadenosylmethionine (SAM) and catalyzes a β-replacement reaction where serine is condensed with Hcy in a pyridoxal-5'-phosphate (pyridoxine or vitamin B6)-dependent manner to form cystathionine. (Cth). Cystathionine γ-lyase (CGL), which operates downstream of CBS, uses Cth as a substrate to generate Cys. Therefore, proper function of CBS is important for the regulation of Hcy, Met, and Cys metabolism. The severity and presentation of signs and symptoms of CBSDH vary widely among patients (see Karaca et al. Gene 2014; 534:197-203; Trondle et al. Acta Med Austríaca 2001; 28:145-151; Kluijtmans et al. Am J Hum Genet 1999;65:59-67; each of which is incorporated herein by reference in its entirety). Many patients present with severe hyperhomocysteinemia with total homocysteine ​​(tHcy) levels greater than 100pmol / L, while others exhibit tHcy elevations ranging from mild to several times normal (see Morris et al. J Inherit Metab Dis 2017; 40:49 -74, which is incorporated herein by reference in its entirety). Significantly elevated tHcy levels generally correlate with a more severe presentation, while lower levels generally correlate with a milder ivia / t / zuzz / u i rao form of the disease. Normal tHcy levels vary with age and nutritional status, but generally range between 10 and 15pmol / L. CBSDH is commonly classified according to whether the affected individual responds to total homocysteine ​​(tHcy)-lowering treatment with pyridoxine (vitamin B6), a cofactor of the CBS enzyme required for normal CBS function (see Mudd et al. Am J Hum Genet 1985;37:1-31;Abbott et al. Am J Med Genet 1987;26:959-969;which are incorporated herein by reference in their entirety). In general, patients who respond to pyridoxine have lower tHcy levels, resulting in a milder form of the disorder. These patients may present later in life with only one or a few symptoms of CBSDH, and many remain undiagnosed. Consequently, patients who respond very well to pyridoxine are believed to be underrepresented in most studies. Retrospective studies show that patients with the highest tHcy levels (treated or untreated) have more severe and younger symptoms (see Yap et al. J Inherit Metab Dis 1998; 21:738-747; Mudd et al. Am J Hum Genet 1985;37:1-31, both incorporated herein by reference in their entirety). Untreated individuals with elevated tHcy levels typically present with growth retardation, thromboembolism, severe myopia with posterior dislocation of the optic lens, osteoporosis-like fractures, marfanoid habitus (particularly elongation of the long bones), and psychiatric abnormalities, including learning disabilities (see Yap S. Homocystinuria due to cystathionine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005; Morris et al. J Inherit Metab Dis 2017; 40:49-74; NORD, Kraus JP. Homocystinuria due to deficiency of cystathionine beta-synthase. NORD [online series] 2017, each of which is incorporated herein by reference in its entirety). Some patients with elevated tHcy levels have severe childhood-onset multisystem disease. Without treatment, life expectancy is markedly reduced in the most severely ill patients (see Morris et al. J Inherit Metab Dis 2017; 40:49-74, which is incorporated herein by reference in its entirety). Normal human plasma contains less than 16 mM of Hcy-derived compounds, measured as tHcy and consisting of thiol-free homocysteine ​​(Hcy-SH or fHcy), disulfides (such as homocysteine-cysteine ​​and homocysteine), and protein-bound homocysteine ​​(see Ueland; Nord Med 1989; 104:293-298; Mudd et al. N Engl J Med 1995; 333:325; Mudd et al. Arterioscler Thromb Vaso Biol 2000; 20:1704-1706; each of which is incorporated herein by reference in its entirety). The distinction between the sulfhydryl form (homocysteine; Hcy) and the disulfide form (homocysteine) (see Yap S. Homocystinuria due to cystationine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005, which is incorporated herein by reference in its entirety) is important because many of the pathophysiological effects depend on the presence of the sulfhydryl group in Hcy (see Yap S. Homocystinuria due to cystathionine betasynthase deficiency. Orphanet Encyclopaedia [online series] 2005; Ueland et al. Nord Med 1989; 104:293298; Mudd et al. N Engl J Med 1995;333:325; each of which is incorporated herein by reference in its entirety). CBS is primarily expressed in the liver, pancreas, kidney, and brain (see Morris et al. J Inherit Metab D / s2017; 40:49-74, which is incorporated herein by reference in its entirety). The catalytic domain binds ΜΛ / t / ZUZZ / U I ÍVÓO to pyridoxal 5'-phosphate (the cofactor also known as pyridoxine or vitamin B6) and the regulatory domain binds to SAM (an allosteric activator). Insufficient levels of CBS enzymatic activity block the transsulfuration pathway in the first step, resulting in the accumulation of Hcy, elevated levels of SAH and Met, and reduced levels of Cth and Cys. As the clinical evidence of these dysregulated Met metabolites reviewed herein demonstrates that elevated Hcy (most often measured clinically as plasma tHcy) is more strongly implicated in the pathophysiology of CBSDH. Higher than normal Hcy levels modify sulfhydryl groups in proteins, preventing proper protein cross-linking and leading to structural abnormalities in multiple body systems. Elevated Hcy levels also alter intracellular signaling, leading to endothelial dysfunction and ultimately thromboembolism and vascular disease. In CBSDH, Hcy accumulation leads to ocular, skeletal, vascular, and psychological manifestations. The diagnosis of CBSDH is sometimes confirmed by molecular genetic testing of the CBS gene (see Sacharow et al. Homocystinuria Caused by Cystationine Beta-Synthase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al, editors. GeneReviewsTM [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017, which is incorporated herein by reference in its entirety). Current screening approaches generally fail to detect neonates with less severe CBSDH and only detect a minority of patients with more severe CBSDH (see Huemer et al. J Inherit Metab Dis. 2015 Nov;38(6): 1007-19; Yap, Orphanet Encyclopaedia [online series], 2005, pages 1-13; Schiff et al. Neuropediatrics. December 2012; 43(6):295-304). The measurement of choice for determining Hcy levels in clinical samples is tHcy, which includes both free Hcy and Hcy bound to proteins or in the form of disulfides. Normal tHcy levels vary with age, sex, and nutritional status, but generally range between 4.5 and 11 μΜ (QUEST DIAGNOSTICS™ reference range). Many patients with CBSDH present with severe hyperhomocystinuria with total tHcy levels greater than 100 μΜ, while others have elevations ranging from mild to several times normal (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1): 49-74, which is incorporated herein by reference in its entirety). tHcy levels are highly correlated with disease severity (see Yap et al. J Inherit Metab Dis 1998;21:738-47). Studies have shown that a reduction in Hcy levels in patients with CBSDH correlates with less severe manifestations of clinical symptoms (see Yap et al. J Inherit Metab Dis 1998; 21: 738-47; Yap et al. Arterioscler Thromb Vasc Biol. 2001 Dec;21 (12): 2080-5; both incorporated herein by reference). The pathways through which homocysteine ​​levels damage these systems have been widely described (see Ajith et al. Clin Chim Acta 2015;450:316-321; Behera et al. J Cell Physiol 99999:1-6, 2016; Saha et al. FASEB J 2016;30:441-456; which are incorporated herein by reference in their entirety) and have led to studies investigating the role of Hcy in the general population, which have exposed the significant pathogenic role of Hcy in the disease. An objective of treatment with the drug described herein is to increase the activity of the CBS enzyme in circulation, resulting in better metabolic control, thereby improving IVIA / t / ZUZZ / U I ÍVÓO the clinical manifestations of the disease and slowing down or preventing further deterioration. High molecular weight compounds, such as enzymes, have limited tissue penetration capacity and are therefore mainly present in plasma. These proteins generally remain in the circulation for a short period of time as they are removed from the bloodstream by various mechanisms (see Vugmeyster et al. World J Biol Chem. 2012;3(4):73-92, included herein), incorporated by reference in its entirety). Ideally, administered CBS would maintain high activity in plasma for long enough to have a sustained effect on sulfur amino acid metabolism. This goal can be achieved by PEGylation, the addition of PEG moieties onto the surface of the protein. Protein PEGylation is a strategy that has become widely accepted and has been shown to minimize proteolysis, immune response, and antigenicity, while increasing protein stability and size and reducing renal excretion (see Kang et al. 2009;14(2):363- 380, which is incorporated herein by reference in its entirety). The drug product described herein is a PEGylated htCBS C15S enzyme formulated for administration to a subject and designed for prolonged systemic exposure. A. Clinical manifestation of homocystinuria There is significant evidence indicating the causal effect of elevated tHcy levels and negative clinical outcomes on the four systems commonly affected in patients with CBSDH (ocular, skeletal, cardiovascular, and neurological). These data are complemented by studies in the general population that demonstrate a strong relationship between slightly elevated tHcy levels and negative outcomes. 1. Eyes Abnormalities involving the eyes may be an early clinical sign of CBSDH. Many people develop a displacement of the eye lenses away from the center of the eyeball (ectopia lentis). Affected people also often develop severe nearsightedness (nearsightedness or nearsightedness) and iridodonesis (tremor of the colored part of the eye). Ectopia lens and myopia generally develop after the first year of life and, in untreated individuals, before ten years of age (see Mudd et al. Am J Hum Genet 1985; 37: 1-31, which incorporated here by reference in its entirety). Other eye abnormalities that occur less frequently include cataracts, optic nerve degeneration, and glaucoma. Some people may have retinal detachment, which can cause blurred vision or the appearance of “floaters” in the field of vision (see Burke et al. BrJ Ophthalmol, 1989;73(6): 42731, which is incorporated in the present by reference in its entirety). Elevated Hcy levels are a strong and independent risk factor for ocular complications, particularly lens dislocation, in patients with CBSDH and in the general population (see Mudd et al. Am J Hum Genet 1985;37:1- 31; Ajith et al. Clin ChimActa 2015;450:316-321; Mulvihill et al. J AAPOS 2001;5:311-315; which are incorporated herein by reference in their entirety). Even with prescribed dietary and pharmacological interventions, most patients with CBSDH eventually develop ocular complications. It has been observed that reducing Hcy levels delays and perhaps IVIA / t / ZUZZ / U I ÍVÓO prevents lens dislocation in patients with CBSDH (see Yap et al. J Inherit Metab Dis 1998; 21: 738-47, which is incorporated herein by reference in its entirety). 2. Central nervous system Developmental delays and learning problems, such as mental retardation, may also be early signs of CBSDH that occur between one and three years of age (see Screening, Technology and Research in Genetics (STAR-G) Project. 2016 Homocystinuria. Available in Newborn Screening Information; National Institutes of Health (NIH), U.S. National Library of Medicine, Genetics Home Reference. Homocystinuria. 2016. qhr.nlm.nih.gov; incorporated here by reference in its entirety). The intelligence quotient (IQ) in people with CBSDH has been reported to range between 10 and 138. Patients with the highest tHcy levels are more likely to have a lower IQ (with a mean IQ of 57 if untreated) compared to less affected patients (with a mean IQ of 79) (see Sacharow et al., Homocystinuria Caused by Cystathionine BetaSynthase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al, editors. GeneReviewsTM [Internet].Seattle (WA): University of Washington, Seattle; 1993-2017, which is incorporated herein by reference in its entirety). Seizures occur in approximately 20% of individuals not treated with CBSDH (see Mudd et al. Am J Hum Genet 1985;37:1-31, which is incorporated herein by reference in its entirety). Many people have psychiatric problems including personality disorder, anxiety, depression, obsessive-compulsive behavior, and psychotic episodes (see Sacharow et al. 2017). Extrapyramidal signs such as dystonia may also occur (see Screening, Technology and Research in Genetics (STAR-G) Project. 2016. Homocystinuria. Available at newbornscreening.info, which is incorporated herein by reference in its entirety). Studies have shown that early decreases in Hcy levels, induced by a low-Met diet, folic acid / vitamin B supplements, and / or pyridoxine and betaine therapy, can delay and sometimes prevent or reverse the progression of several neurological disorders and allow normal development of IQ in patients with CBSDH (see El Bashir et al. JIMD Rep 2015;21:89-95; Yap et al. J Inherit Metab Dis 2001 ;24:437-447; incorporated herein by reference in their entirety). Associations between elevated Hcy levels and central nervous system (CNS) symptoms, including mental retardation, neurodegenerative diseases, seizures, dystonia, psychosis, cognitive impairment, dementia, and depression, are well documented in patients with CBSDH and in the general population ( see Abbott et al. al. Am J Med Genet 1987;26:959-969;Schimke et al. JAMA 1965;193:711-719; Herrmann et al. Clin Chem Lab Med 2011 ;49:435-441; incorporated herein by reference in their entirety). 3. Skeletal system People with CBSDH frequently develop a variety of skeletal abnormalities. Affected people are usually tall and thin with a “marfanoid” habit, which includes thinning and lengthening of the long bones (dolichostenomelia), knees bent inward to ivia / t / zuzz / u i rao or touching when the legs are straight (“hollow knees” or genu valgum), a highly arched foot (pies cavus), an abnormal lateral curvature of the spine (scoliosis), an abnormally protruding chest (pectus carinatum), or an abnormally sunken chest (pectus excavatum). By adolescence, 50% of people show signs of osteoporosis (see Screening, Technology and Research in Genetics (STAR-G) Project. 2016. Homocystinuria. Available at newbornscreening.info, which is incorporated herein by reference in its entirety ). In a study of 25 Irish patients with CBSDH followed for 25 years, the risk of skeletal abnormalities was found to be considerably lower in patients with good compliance to Hcy-lowering treatment compared with patients who were noncompliant (see Yap et al. J Inherit Metab Dis 1998;21:738-47, which is incorporated herein by reference in its entirety). 4. Cardiovascular system The relationship between CBSDH and vascular disease was first demonstrated in 1985 in an epidemiological study in patients with moderately to severely elevated Hcy levels due to homozygous CBSDH (see Mudd et al. Am J Hum Genet 1985;37:1- 31, attached below), incorporated by reference in its entirety). Thromboembolism is the most serious, often life-threatening, complication of CBSDH and can affect any vessel. It is the leading cause of morbidity and premature death in patients with CBSDH (see Yap et al. Arteríoscler Thromb Vasc Biol. 2001 Dec;21 (12):2080-5, which is incorporated herein by reference in its entirety). The risk of thromboembolic events was approximately 25% at age 16 years and 50% at age 29 years. Several reports described how treatments that lower tHcy levels significantly reduced the incidence of vascular events, the main cause of morbidity, in patients with CBSDH (see Wilcken et al. J Inherit Metab Dis 1997; 20:295-300; Yap et al. al. Arteríoscler Thromb Vasc Biol. 2001 Dec; 21(12):2080-5, which are incorporated herein by reference in their entirety). Since then, several other studies have demonstrated an increased risk of vascular events, particularly venous thrombosis, in patients with CBSDH (see Kelly et al. Neurology 2003;60:275-279; Magner et al. J Inherit Metab Dis 2011;34: 33-37; which are incorporated herein by reference in their entirety). 5. Additional Manifestations Although less common, several additional findings have been reported in patients with CBSDH including extremely thin and fragile skin, brittle hair, skin discoloration (hypopigmentation), and cheek rashes (malar flushing). Some people may develop fatty changes in the liver, protrusion of part of the intestines through a tear in the abdominal wall (inguinal hernia), or inflammation of the pancreas. Abnormal anteroposterior curvature of the spine (kyphosis) and collapsed lung (spontaneous pneumothorax) have also been reported in people with CBSDH (see Yap; Orphanet Encyclopedia [online series]. 2005, pages 1-13, included herein incorporated by reference in its entirety). ivia / t / zuzz / u i rao o In summary, MRD alone is effective in correcting multiple symptoms of HCU despite failing to reduce plasma Hcy concentration below the recommended level and causing increased anxiety and reduced bone mineralization. On the other hand, enzyme therapy with 20NHS PEG-CBS, as described herein, reduced plasma Hcy concentrations below the suggested threshold of 100 μΜ and corrected all monitored symptoms of HCU. Furthermore, 20NHS PEGCBS retains its efficacy under Met restriction, resulting in a fully normalized plasma biochemical profile. By extrapolating these data to human patients, our results establish that 20NHS PEG-CBS as a single lifetime therapy could be effective in preventing and correcting the clinical symptoms of HCU. Furthermore, treatment with 20NHS PEG-CBS should allow elimination of Met / diet restriction and therefore, in turn, substantially improve the quality of life of HCU patients and their families. II. COMPOSITIONS A. Native human CBS enzyme The complete native CBS enzyme is a tetramer with four identical monomers, where each monomer (size 63 kDa) is organized into three functional domains. The first is an N-terminal region of approximately 70 amino acids that binds heme and is thought to function in redox sensing and / or enzyme folding. The second is a central domain that contains the catalytic core and shows the folding of PLP (pyridoxal-5'-phosphate)-dependent enzymes of the type II family. The PLP coenzyme is deeply buried in a cleft between the N- and C-terminal domains. The third region is the C-terminal regulatory domain, which consists of a tandem pair of CBS motifs that upon binding to S-adenosylmethionine (SAM) activate the enzyme. Removal of the regulatory region generates an enzyme that is constitutively active (see Miles et al. J Biol Chem. 2004 Jul 16;279(29):29871-4, The pyridoxal-5'-phosphate (PLP)-dependent enzymatic fold contains a heme group. It catalyzes the PLP-dependent beta replacement reaction where it condenses L-homocysteine ​​with L-serine to form L-cystathionine. It is allosterically regulated by the binding of S-adenosyl-L-methionine (Ado-Met) to the C-terminal regulatory domains, resulting in a conformational rearrangement of these domains and the release of an autoinhibitory block. Activation of CBS can also be achieved by complete removal of the C-terminal regulatory domains, generating a dimeric form of the enzyme that is constitutively active (see Miles et al. J Biol Chem. 2004 Jul 16;279(29): 29871-4; ErenoOrbea et al., Proc Nati Acad Sci USA 111(37), E3845-3852 (2014), each of which is incorporated herein by reference in its entirety). The drug substance in the drug product described herein is a recombinant human truncated CBS protein with a cysteine ​​to serine substitution at amino acid position 15 of the protein (htCBS C15S) compared to the amino acid sequence of SEQ ID NO: 2 in the present sequence listing and SEQ ID NO: 2 of WO 2017 / 083327 (which is incorporated herein by reference in its entirety), which represents a native CBS protein, which has been modified by ivia / t / zuzz / u ι rao or addition of polyethylene glycol (PEG). The enzyme is also known as htCBS C15S. In certain embodiments, the drug substance htCBS C15S has the amino acid sequence of SEQ ID NO: 1. This form of the enzyme has a high tendency to aggregate, which poses a major limitation in the manufacturing and production of human CBS (hCBS). PEGylated C15S htCBS (including “20NHS PEG-CBS” as defined herein) has been designed to form dimers rather than tetramers, which are less susceptible to aggregation. High molecular weight compounds, such as enzymes, are removed from the circulation by degradation by proteolysis and various elimination mechanisms (see Vugmeysteretal. World J Biol Chem. 2012;3(4):73-92, incorporated herein for reference in its entirety). PEGylation is known to minimize proteolysis and immunogenicity, while increasing protein stability and reducing renal excretion (see Kang et al. 2009; 14(2):363-380, which is incorporated herein by reference In its whole). These structural modifications make the pharmaceutical product described herein comprising PEGylated C15S htCBS a more suitable candidate than native hCBS as an enzyme therapy (ET) for CBSDH. Native CBS is an intracellular enzyme and there is no known mechanism for the uptake of the enzyme from the extracellular environment to its primary intracellular site of action, while C15S PEGylated htCBS acts extracellularly. Unlike native endogenous CBS, PEGylated C15S htCBS corrects metabolic abnormalities by operating directly in the circulation and indirectly in tissues and does so without requiring SAM for activation. The native hCBS enzyme is activated in cells upon binding of Sadenosyl methionine (SAM) to its C-terminal regulatory domain. However, circulating SAM levels in both patients and healthy individuals are well below the levels required for CBS activation (see Stabler et al. Metabolism, 2002. 51(8): p. 981-8, which is incorporated herein by reference in its entirety). Therefore, delivering native CBS to the circulation would be ineffective, as CBS would not be activated. PEGylated C15S htCBS, although it remains in circulation and does not enter cells, has been designed to circumvent the need for SAM activation by removing the Cterminal regulatory domain of CBS that renders the enzyme constitutively active. B. Enzyme therapy (ET) PEGylated C15S htCBS is a truncated and PEGylated hCBS with a cysteine ​​to serine substitution at position 15 for ET for the treatment of CBSDH. This modification optimizes the enzyme to form dimers instead of tetramers and is constitutively active. PEGylated C15S htCBS complements deficient CBS activity, reducing homocysteine ​​(Hcy) and methionine (Met) levels in plasma, urine and tissues, increasing cystathionine (Cth) levels, and normalizing cysteine ​​(Cys) levels in patients with CBSDH. Reduction of total Hcy (tHcy) levels is the goal of current treatment (see, Morris et al. J Inherít Metab Dis. 2017 Jan;40(1):49-74, which is incorporated herein by reference in its entirety ) and is strongly correlated with improved clinical outcomes (ocular, skeletal, vascular, and neurological) (Yap; Orphanet Encyclopedia [online series]. 2005, pages 1-13, which is incorporated herein by reference in its entirety) . Μλ / t / ZUZZ / UI ÍVÓO PEGylated C15S htCBS is a recombinant form of the native human CBS enzyme, which is produced in the E. coli bacteria. The native human CBS DNA sequence (SEQ ID NO: 3 in the present sequence listing and SEQ ID NO: 1 of WO 2017 / 083327, which is incorporated herein by reference in its entirety) was genetically modified to eliminate the regulator C-terminaL region (amino acids 414551) (SEQ ID NO: 4 in the present sequence listing and SEQ ID NO: 3 of WO 2017 / 083327), forming the truncated human CBS. The human truncated CBS DNA sequence was further modified to introduce a point mutation of T—>A at position 43 of the DNA coding region, resulting in a cysteine ​​to serine substitution at position 15 of the protein. translated, generating the truncated human CBS C15S. (htCBS C15S) (SEQ ID NO: 5 in this sequence listing and SEQ ID NO: 13 of WO 2017 / 083327). This change reduces aggregation and allows for batch-to-batch consistency compared to native hCBS. The enzyme is further modified in E. coli bacteria during expression, resulting in the removal of the first Met from the protein as shown in SEQ ID NO: 1. After its purification, the htCBS C15S enzyme is modified further by PEGylation with N-20 kDa PEG moieties functionalized with hydroxylsuccinimide ester, which react with primary amines on the protein surface. An approximate average of 5.1 PEG molecules are attached to each monomeric unit of the enzyme giving a heterogeneous dimeric product with an average molecular weight of 290 kDa. C. PEGylation of htCBS C15S to produce 20NHS PEG-CBS ME-200GS (also known as methoxy-PEG-CO(CH2)3COO-NHS) is used here to PEGylate htCBS C15S: O0 0 CH3O—(CH?Cn?O)n—CCHZCHZCH?CO-N ] EITHER ME-200GS has a molecular weight of 20 kDa and a chemical name of assuccin¡míd¡lox¡glutar¡l-ω-methoxy¡, polyoxyethylene. ME-200GS targets free amines on the surface of htCBS C15S. An amide bond is formed between PEG and the lysine residue in htCBS C15S. The resulting molecule is referred to throughout the disclosure as "20NHS PEG-CBS", and is a PEGylated human cystathionine beta synthase molecule that is truncated and has a C15S mutation, as indicated in SEQ ID NO: 1. Tangential flow filtration (TFF) with a molecular weight cutoff of 100 kDa and 15 volume exchanges is used to deplete free PEG and other PEGylation impurities and subsequently used for formulation against PBS buffer. All process-related substances, including ammonium and other ions, imidazole, Triton large cutoff TFF diafiltration. PEG ME-200GS is manufactured by NOF Corporation under cGMP conditions according to the process flow diagram provided in Figure 1. All raw materials used in the manufacturing of the ME-200GS product are synthetic or inorganic in nature. Impurities that could potentially be present in the PEG ME-200GS raw material are small molecules. D. Post-translation modifications Posttranslational modifications may require additional bioprocessing steps to separate modified and unmodified polypeptides, increasing costs and reducing the efficiency of biologics production. Accordingly, in some embodiments, the production of a polypeptide agent in a cell is enhanced by modulating the expression of a target gene that encodes a protein that affects post-translational modification. In additional embodiments, the production of biological products is improved by modulating the expression of a first target gene that encodes a protein that affects a first post-translational modification and modulating the expression of a second target gene that encodes a protein that affects a second post-translation modification. Furthermore, proteins expressed in prokaryotic or eukaryotic cells may undergo various post-translational modifications that may affect the production and / or structure, biological activity, stability, homogeneity and / or other properties of the biological product. Many of these modifications occur spontaneously during cell growth and polypeptide expression and can occur at various sites, including the peptide backbone, amino acid side chains, and the amino and / or carboxyl termini of a given polypeptide. Furthermore, a given polypeptide may comprise several different types of modifications. For example, proteins expressed in bacterial cells, such as E. coü, may be subject to acetylation, histone trimming, carboxylation and / or deamidation (see Yang et al., PNAS 111 (52) E5633-E5642 (2014), which is incorporated herein by reference in its entirety). For example, proteins expressed in avian and mammalian cells, such as Chinese hamster ovary (CHO) cells, may be subject to acetylation, carboxylation, gamma-carboxylation, histone trimming, deamidation, cyclization, and N-glutamine deamidation. terminal and deamidation of asparagine. In some embodiments, protein production is enhanced by modulating the expression of a target gene that encodes a protein involved in protein deamidation. Proteins can be deamidated through several pathways, including N-terminal glutamine cyclization and deamidation and asparagine deamidation. Therefore, in one embodiment, the protein involved in protein deamidation is N-terminal asparagine amidohydrolase. Protein deamidation can result in altered structural properties, reduced potency, reduced biological activity, reduced efficacy, increased immunogenicity, and / or other undesirable properties and can be measured by various methods, including, but not limited to, charge-based protein separations. by, for example, ion exchange chromatography, HPLC, isoelectric focusing, capillary electrophoresis, native gel electrophoresis, reverse phase chromatography, hydrophobic interaction chromatography, affinity chromatography, mass spectrometry or the use of L-isoaspartyl methyltransferase. ivia / t / zuzz / u i rao o In some embodiments, the protein that affects protein secretion is a molecular chaperone selected from the group consisting of: Hsp40, HSP47 (also called serpin peptidase inhibitor, H-cyano; heat shock protein 47), HSP60, Hsp70, HSP90, HSP100, protein disulfide isomerase, peptidyl prolyl isomerase, calnexin, Erp57 (protein disulfide isomerase family A, member 3) and BAG 1. In some embodiments, the protein that affects protein secretion is selected from the group consisting of γ-secretase, p115, a signal recognition particle (SRP) protein, secretin, and a kinase (e.g., MEK). It is contemplated that further optimization could be achieved by systematically adding or removing nucleotides to generate longer or shorter sequences and testing those generated sequences by running a window of the longest or shortest size up or down the target RNA from that point. Combining this approach to generate new candidate targets with efficacy testing of RNA effector molecules based on those target sequences in an inhibition assay as known in the art or as described herein may lead to further improvements in the efficacy of the inhibition. Still further, such optimized sequences may be adjusted, for example, by introducing modified nucleotides as described herein or as known in the art, adding or changing the overhang, or other modifications known in the art and / or or discussed herein to further optimize the molecule (e.g., increase serum stability or circulating half-life, increase thermal stability, improve transmembrane delivery, target a particular location or cell type, increase interaction with the enzymes of the silencing pathway, increase the release of endosomes, etc.) as an inhibitor of expression. E. Stability The drug substance or drug product is stable at a variety of temperatures and storage conditions. In some embodiments, the drug substance or drug product is stable when stored at -65°C and -20°C. Alternatively, the drug substance or drug product may be stable when stored at a temperature in a range of about 2°C to about 8°C. Alternatively, the drug substance or drug product may be stable when stored at a temperature in the range of 25°C±2°C. For example, the drug substance or drug product remains stable between 20°C and 25°C. In certain embodiments, the drug substance or drug product is stable under reducing conditions. In certain embodiments, the drug substance or drug product is stable under non-reducing conditions. In some embodiments, the drug substance or drug product remains stable for at least 2 days, at least 7 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or at least 12 months. For example, the drug substance or drug product remains stable during storage for about 2 days. For example, the drug substance or drug product remains stable during storage for about 7 days. For example, the drug substance or drug product remains stable during storage for about 1 month. For example, ivia / t / zuzz / u ι ζυο or the drug substance or the drug product remains stable during storage for about 2 months. For example, the drug substance or drug product remains stable during storage for about 3 months. For example, the drug substance or drug product remains stable during storage for about 6 months. For example, the drug substance or drug product remains stable during storage for approximately 12 months. For example, the drug substance or drug product remains stable during storage for about 18 months. In some embodiments, the drug substance or drug product remains stable for storage at -65°C for up to 18 months. In some embodiments, the drug substance or drug product remains stable for storage between about 2°C and about 8°C for up to 3 months. In some embodiments, the drug substance or drug product remains stable for storage at 25°C ± 2°C for up to 1 month. In some embodiments, the drug substance or drug product remains stable for at least 3 freeze-thaw cycles. In some embodiments, the drug substance or drug product remains stable for up to 6 freeze-thaw cycles. For example, the drug substance or drug product remains stable for 5 freeze-thaw cycles. In certain embodiments, the drug product is stable after ejection of a syringe. III. PHARMACEUTICAL COMPOSITIONS The drug described herein comprising PEGylated C15S htCBS is intended to restore metabolic control and improve clinical manifestations of the disease by reducing homocysteine ​​levels and normalizing cysteine ​​levels in patients with CBSDH. htCBS C15S is manufactured by recombinant technology using E. coli BL21 (DE3) and formulated as a sterile drug product in phosphate-buffered saline. The drug product is intended for administration by subcutaneous (SC) injection. The activity of PEGylated C15S htCBS in circulation also improved or even completely normalized metabolite profiles in tissues (see WO 2017 / 083327, which is incorporated herein by reference in its entirety). Therefore, the drug product does not necessarily need to be delivered into its native intracellular milieu. The pharmacological product reduces the accumulation of toxic Hcy in the circulation, urine and tissues of CBSDH patients; normalizes Cys levels in circulation and tissues; increases Cth levels in circulation and tissues; and / or prevents, delays and / or reverses the onset of CBSDH manifestations. The drug product achieves at least one of these benefits while allowing patients to enjoy a normal diet. In fact, it has been observed that increased Cth activity even with ivia / t / zuzz / u ι rao or a regular diet (e.g., 4.0 g / kg MET) is evidence of increased activity of the product pharmacological and / or a decrease in renal elimination. The 20NHS PEG-CBS drug was formulated at a concentration of between 20 and 30 mg / ml, or approximately 25 mg / ml, in phosphate-buffered saline (PBS) containing disodium hydrogen phosphate (dihydrate) (11.4 mM), sodium chloride (137 mM), potassium chloride (2.7 mM) and potassium dihydrogen phosphate (1.98 mM), prepared with water for injection (WFI). The drug substance was freely soluble in aqueous solution. The molecular weight of the drug calculated from isotopically averaged molecular weight from SEC / UV / MS is 45.290 kDa for the monomer and 90.58 kDa for the dimer. All batches were a clear liquid that was virtually free of visible particles and dark red in color. Furthermore, SDS-PAGE was performed under both reducing and non-reducing conditions and an Immunoblot provided mutually consistent results for each batch. A distinctive, uniform, and consistent pattern of PEGylation variant was demonstrated using each of these methods. Concomitant medications, including anticoagulants, vitamin and mineral supplements, betaine, antidepressants, may also be combined with the drug product described herein to improve the effectiveness of the pharmaceutical composition. IV. FORMULATIONS For the therapeutic uses mentioned above, the dose administered will vary with the compound used, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the disclosure, if inhaled, may be in the range of 0.05 micrograms per kilogram of body weight (pg / kg) to 100 micrograms per kilogram of body weight (pg / kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range of 0.01 micrograms per kilogram of body weight (pg / kg) to 100 milligrams per kilogram of body weight (mg / kg ). The protein having an amino acid sequence SEQ ID NO: 1, which is PEGylated to form the drug substance described herein, can be used alone, but will generally be administered in the form of a pharmaceutical composition in association with an adjuvant, diluent or pharmaceutically acceptable carrier. Therefore, the present disclosure further provides a pharmaceutical composition comprising the drug substance described herein in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Pharmaceutically acceptable adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the disclosure are those conventionally employed in the field of pharmaceutical formulation and include, among others, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerin, sorbic acid, potassium sorbate, partial mixtures of glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, ivia / t / zuzz / u ι rao or magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, block polymers of polyethylene-polyoxypropylene, polyethylene glycol and wool grease (lanolin). The pharmaceutical compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In one embodiment, the pharmaceutical composition can be administered orally. In one embodiment, the pharmaceutical composition can be administered subcutaneously. The pharmaceutical compositions of the disclosure may contain any conventional non-toxic pharmaceutically acceptable adjuvant, diluent or carrier. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic adjuvant, diluent or carrier, for example, as a solution in 1,3-butanediol. Among the acceptable adjuvants, diluents and carriers that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any soft fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant. The pharmaceutical compositions of this disclosure may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules and suspensions and aqueous solutions. These dosage forms are prepared according to techniques well known in the field of pharmaceutical formulation. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added. The pharmaceutical compositions of the disclosure may also be formulated in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at room temperature but liquid at ivia / t / zuzz / u i rao or rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this disclosure can be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other solubilizing agents. or dispersants known in the art. The pharmaceutical compositions herein may be in a form for administration through the circulatory system as shown in WO 2015 / 153102, WO 2016 / 183482 and WO 2018 / 009838, which are incorporated in their entirety by reference. The CBS protein may be encoded by a recombinant nucleic acid expressed by enucleated hematopoietic cells (EHC), including erythrodroid or thromboid cells. For example, erythroid cells are red blood cells, erythrocytes, or reticulocytes. For example, thromboid cells are platelets. In certain embodiments, the encoded CBS protein is fused to a translated membrane-anchored polypeptide. In certain embodiments, the CBS protein is located on the surface of the EHC. The CBS protein can be cleaved for activation of the enzyme in the extracellular space. Alternatively, the internally localized CBS protein may be released into the extracellular space by lysis of the EHC. Alternatively, the enzymatic target of the CBS protein may enter the EHC and then exit through the membrane after disruption. In certain embodiments, the CBS protein has an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 5 in the present sequence listing or SEQ ID NO: 2, 3 , or 13 of WO 2017 / 083327 (which is incorporated herein by reference in its entirety). Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99%w (weight percentage), more specifically from 0.05 to 80%w, even more specifically from 0.10 to 70%w, and even more specifically from 0.10 to 80% p, and even more specifically from 0.10 to 50% p, of active ingredient, all percentages by weight being based on the total composition. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceutics-The Science of Dosage Form Design", ME Aulton, Churchill Livingstone, 1988, which is incorporated herein by reference in its entirety. The buffer solution of disodium hydrogen phosphate (dihydrate), sodium chloride, potassium chloride and potassium dihydrogen phosphate are introduced into the drug substance by diafiltration. The drug product is formulated at a target concentration of 20-30 mg / mL, or approximately 25 mg / mL, in PBS (pH = 7.4±0.2). PBS buffer contains disodium hydrogen phosphate (dihydrate) (11.4 mM), sodium chloride (137 mM), potassium chloride (2.7 mM), and potassium dihydrogen phosphate (1.98 mM). Table 1 provides the details of the formulation. Table 1. Formulation of the pharmacological product ivia / t / zuzz / u i rao o Component Quantity (g) per lot Drug substance 25 mg / mL (range 20 - 30 mg / mL) Water for injection (WFI) Sufficient amount to volume Di-sodium hydrogen phosphate (dihydrate) 11.4 mM Sodium chloride 137 mM Potassium chloride 2.7 mM Potassium dihydrogen phosphate 1.98 mM ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Table 2 provides an example unit dose composition of the drug product described herein. Table 2. Unit dose of the pharmacological product Component Single dose quantity (1 ml / vial) Function Pharmacological substance 25 mg Active ingredient; Enzyme Water for injection (WFI) 1mL Solvent Di-sodium hydrogen phosphate (dihydrate) 2.0 mg Buffer component Sodium chloride 8.0 mg Excipient Potassium chloride 0.2 mg Excipient Potassium dihydrogen phosphate 0.3 mg Buffer component In certain embodiments, the drug product is formulated for an exposure of approximately 50 mU / pL in a subject. A lyophilized formulation may be used for administration to humans after reconstitution. A. Freeze drying The pharmaceutical compositions may be in a lyophilized formulation. In some embodiments, the lyophilized formulation comprises the drug substance, a buffer, and an excipient. In certain embodiments, upon reconstitution of the lyophilized formulation in a suitable reconstitution buffer, water or any other pharmaceutically acceptable adjuvant, diluent or carrier, the concentration of the drug is between about 20 and 30 mg / ml. In some embodiments, the concentration of the drug substance is about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 26 mg / ml, about 27 mg / ml, about 28 mg / ml, about 29 mg / ml or about 30 mg / mL. In some embodiments, the concentration of the drug is about 25.4 mg / ml. In certain embodiments, upon reconstitution of the lyophilized formulation in a suitable reconstitution buffer, water or any other pharmaceutically acceptable adjuvant, diluent or carrier, the buffer is potassium phosphate at a concentration of 15 mM. In certain embodiments, the excipient is trehalose at a concentration of 8% (w / v). In some embodiments, the formulation comprises sucrose such that, upon reconstitution of the lyophilized formulation in a suitable reconstitution buffer, water or pharmaceutically acceptable adjuvant, diluent or carrier, the concentration of sucrose is 5%. In some embodiments, the collapse onset temperature (Tc,on) determined by freeze-drying microscopy is -21°C. In some embodiments, the formulation has a pH of 7.5. In some embodiments, the freeze-drying process can be carried out in 48 hours or less without melting the crystalline structure of the cake. The lyophilization process may be optimized to adjust one or more of the following parameters or properties such as, but not limited to, (i) reduced reconstitution time of the lyophilized formulation (e.g., less than 1 minute), (ii) reduced viscosity for allow a more concentrated drug product, (iii) incorporation of an isotonic buffer to minimize patient pain, and / or (iv) reduction of dePEGylation. The lyophilized formulation can be prepared using the following protocol. Three days before preparation of the formulation, the drug (stored at -80°C) at 20-30 mg / ml or approximately 25 mg / ml is thawed for 72 hours at 2-8°C in a refrigerator. After thawing, the drug substance is homogenized by gentle stirring. Dialysis is performed under controlled conditions at 2-8°C for 24 hours. Dialysis cassettes with a cutoff of 20 kDa are used and the buffer is changed three times at a volume ratio greater than or equal to 1:50 each time. The buffer is changed after 3 and 6 hours of total dialysis time. The last step of dialysis is done overnight. After dialysis, the formulation is recovered from the dialysis cassettes and filtered using a 0.22 pm polyvinylidene difluoride (PVDF) filter. After filtration, the vials are filled with a fill volume of 1.0 under laminar airflow conditions. Freeze drying is performed in an Epsilon 2-12D pilot scale freeze dryer (Martin Christ, Osterode, Germany). The chamber pressure is controlled by a capacitance meter and regulated by a vacuum pump and a controlled nitrogen dosage. After equilibrating the vials at 5°C, the vials are frozen at -45°C and equilibrated for an additional 5 hours at -45°C. The shelf temperature is set at -15°C for 31 hours in primary drying. Secondary drying is carried out at a shelf temperature of 40°C for 2.5 hours. At the end of the lyophilization process, the chamber is aerated with nitrogen at 800 mbar and the vials are capped by lifting the shelves. After capping, the chamber is aerated to atmospheric pressure with nitrogen. Table 3 shows the parameters of the freeze-drying process after cycle optimization. __________________ Table 3. Parameters of the freeze-drying process_____________________ ivia / t / zuzz / u i rao o # Step Time [hh:mm:ss] Temperature [°C] Pressure [mbar] Total time [hours] Ramp [°C / min] 1 Load 0:00:00 5 1.00 0 0.0 2 Balanced at 5°C 1:00:00 5 1.00 0 1.0 3 Freezing 1:40:00 45 1.00 0 2.7 0.50 4 Freezing 5:00:00 45 1.00 0 6.7 5 Primary drying 0:30:00 45 0.1 7.2 6 Primary drying 1:00:00 15 0.1 8.2 0.50 7 Primary drying 31:00:0 0 15 0.1 39. 2 8 Secondary drying 3:00:00 40 0.1 42. 2 0.31 9 Secondary drying 2:30:00 40 0.1 44. 7 10 Aeration 0:30:00 40 800 45. 2 11 Plugging 0:01:00 40 800 45. 2 12 Storage 0:30:00 5 1.00 0 45. 7 During the freeze-drying process, product temperature, shelf temperature, condenser temperature and chamber pressure (capacitance and Piran!) gauge are monitored. Product temperature is monitored by Pt100 sensors (OMEGATM). V. TREATMENTS OF DISEASES, DISORDERS OR CONDITIONS People with CBSDH are usually asymptomatic at birth and, unless treated, symptoms appear in these people over time, some as early as infancy, many in childhood, and, since it is a spectrum disease, in In some patients, symptoms appear only in adulthood (see Yap, 2005; Mudd etal. Am J Hum Genet 1985; 37:1-31; Morris etal. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis 2017; 40:49-74; Mudd et al. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Diseases. 7 ed. New York: McGraw Hill; 2001 ;1279- 1327, each of which is incorporated by reference in its entirety). Four major organ systems are typically involved, the ocular, skeletal, and vascular systems, as well as the CNS. Other organs, such as the liver, pancreas, gastrointestinal tract, and skin, including hair follicles, may also be involved (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Morris et al. J Inherit Metab Dis 2017; 40:49-74; Muacevic-Katanec et al. CollAntropol 2011; 35:181-185; Suri etal. JNeurol Sel 2014; 347:305-309, each of which is incorporated herein by reference in its whole). Accumulating data show that reduction in Hcy levels can serve as an indicator of successful application of enzyme therapy (ET) in CBSDH. It is consistent with the NIH-FDA Biomarker Working Group definition (see FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration ( FDA USA); 2016-, Reasonably Likely Surrogate Endpoint. 2017 Sep 25. Co-published by National Institutes of Health (US), Bethesda (MD). ncbi.nlm.nih.gov / books / NBK326791 / , which is incorporated into the present by reference in its entirety) of a “pharmacodynamic / response biomarker, the level of which changes in response to exposure to a medical product…” and, even more, of a closely linked marker, in the case of a ET for CBSDH , to the drug's mechanism of action. Therefore, Hcy in blood or plasma is not only a useful marker for pharmacodynamic studies, but has also been previously recognized as a “reasonably likely surrogate end point” for homocystinuria (HCU). In infants and children with CBSDH, the priority is to prevent complications associated with CBSDH and ensure adequate growth and development of normal intelligence (see Morris et al. J Inherit Metab Dis 2017;40:49-74, incorporated herein as reference in its entirety). In patients diagnosed later in life, the goals of treatment should be to prevent life-threatening thromboembolism and minimize the progression of already established complications. To address these goals, the biochemical abnormalities associated with CBSDH should be improved and, if possible, normalized (see Morris et al. J Inherit Metab Dis 2017; 40:49-74, which is incorporated herein by reference in its entirety). According to the 2016 Guidelines for the Diagnosis and Management of CBSDH, Hcy levels should be kept as close to normal as possible (at or below 10 to 15 pmol / L). This is generally not possible in patients with CBSDH given the available treatments, so aspirational targets are suggested, below 50pmol / L in patients with pyridoxine-sensitive CBSDH and below 100pmol / L in non-responsive patients. to pyridoxine (see Morris et al. J Inherit Metab Dis 2017; 40:4974, which is incorporated herein by reference in its entirety). As noted above, patients who do not respond to pyridoxine tend to have higher Hcy levels than those who respond to pyridoxine. Although two goals are recommended for patients with the same disease, these goals were designed to be achievable, rather than optimized, to minimize complications. In general, the effectiveness of long-term treatments needed to control CBSDH, especially as they most often rely on dietary restrictions and supplementation, is subject to poor or inconsistent lifelong compliance. An ET for CBSDH would avoid many of these pitfalls. By compensating for the metabolic defect in CBSDH through a mechanism that should not require severe Met restriction or Cys supplementation, an ET would be expected to achieve a more consistent reduction in Hcy, without dangerously elevating Met levels, and also allowing the liberalization or normalization of the diet. There is currently no cure for CBSDH that corrects the underlying genetic causes of the condition, but the generally accepted therapeutic goal is to reduce tHcy levels as much as possible (see Morris et al. J Inherit Metab Dis. 2017 Jan;40( 1) :49-74, which is incorporated herein by reference in its entirety). Consequently, current therapy is aimed at correcting biochemical abnormalities, thereby reducing the risk of adverse clinical manifestations of the disease. Hcy levels rarely completely normalize with currently available treatments for patients with CBSDH. A combination of strategies is required to achieve treatment goals in most patients. These treatment strategies include: 1) increasing residual CBS activity by administering pharmacologic doses of pyridoxine (vitamin B6, a cofactor of CBS, along with folic acid) to pyridoxine-sensitive patients (see Yap et al. Arterioscler Thromb Vaso Bioi. 2001 Dec;21 (12): 2080-5, which is incorporated herein by reference in its entirety); 2) decrease methionine load through severe dietary / protein restriction, while supplementing the diet with products beyond metabolic blockade, and 3) improve alternative metabolic pathways to counteract the effects of CBS deficiency, e.g. administer betaine (a methyl donor) to enhance the remethylation of Hcy to Met. In ΜΛ / Ε / ζυζζ / υΊ rao or certain modalities, folate supplements and (if necessary) vitamin B12 supplements are provided (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74, which is incorporated herein by reference in its entirety). A. Current Therapies for CBSDH In some embodiments, patients with CBSDH should receive adequate folate supplements and (if necessary) vitamin B12 supplements (see Morris et al. J Inherit Metab Dis 2017;40:4974, which is incorporated herein by reference in its entirety). . Additionally, patients should be treated with pyridoxine therapy (if responsive), a Met-restricted diet, supplemented with Cys, and / or betaine therapy. A combination of strategies is required to achieve treatment goals in most patients. The most common prescribed treatment was a combination of diet and betaine, followed by betaine alone and diet alone (see Adam et al. Mol Genet Metab 2013; 110:454-459, which is incorporated herein by reference in its entirety). As patients get older than 16 years, they are more frequently prescribed betaine alone without diet, in recognition of adult patients' poor compliance with the Met-restricted diet. However, compliance with betaine in adults is also poor. Median protein intake varied widely among patients and increased dramatically with age. Consistent with these findings, a recent report indicated that only four adult patients among 24 patients who were prescribed a low-protein diet with specific amino acid supplementation appropriate for CBSDH followed this treatment (see Lorenzini et al. J Inherit Metab Dis . 2017 Oct. 4, which is hereby incorporated by reference in its entirety). Multiple CBSDH experts have described similarly wide variability in the United States (Orphan Technology Scientific Advisory Board composed of physicians who are U.S. CBSDH experts). A study comparing tHcy values ​​of untreated versus treated patients ( 25 and 93 patients, respectively) concluded that there were no significant differences between these two groups (tHcy range from 15.7 to 281.4 and from 4.8 to 312). μmol / L, respectively; mean values ​​125.0 and 119.0pmol / L, respectively) although the study did not provide details on the patients' treatment regimens (see Stabler et al. JIMD Rep 2013; 11:149-163, which is incorporated herein by reference in its entirety ). These results suggest all or a combination of the following conclusions: that patients had a heterogeneous disease presentation, that standard treatments were ineffective, and / or that treatment compliance was poor. 1. Pyridoxine After diagnosis, patients are tested for responsiveness to pyridoxine, a CBS cofactor. Administration of pyridoxine (vitamin B6) at pharmacological doses increases residual CBS activity in people who have been shown to be sensitive to pyridoxine. The definition of pyridoxine responsiveness varies widely from site to site, although the 2016 guideline, written ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO as part of the European Network and Registry of Homocystinuria and Methylation Defects (EHOD), defined pyridoxine responsiveness as a 20% reduction in tHcy levels within 6 weeks of exposure to pyridoxine. Patients with severely elevated tHcy levels and patients with mildly or moderately elevated tHcy levels can be defined as sensitive despite having very different tHcy levels. Furthermore, different treatment centers define response to pyridoxine differently, and therefore classification of patients by tHcy levels, rather than by pyridoxine responsiveness, is more appropriate and rigorous. . In general, patients who respond to pyridoxine have some residual CBS activity and therefore lower tHcy levels, resulting in a less severe presentation. Pyridoxine is generally considered safe in patients with CBSDH (see Yap; Orphanet Encyclopedia [online series], 2005, pages 1-13, which is incorporated herein by reference in its entirety). Its most frequently reported adverse effects include peripheral neuropathy in patients treated with high doses defined as greater than 900 mg / day (see Schaumburg et al. N Engl J Med 1983;309:445-448; Ludolph et al. Eur J Pediatr 1993 ; 152:271; which are incorporated herein by reference in their entirety), apnea and unresponsiveness in neonates receiving 500 mg / day of pyridoxine (Mudd et al. Am J Hum Genet 1985; 37: 1-31, which incorporated herein by reference in its entirety), and rhabdomyolysis (see Shoji et al. J Inherit Metab Dis 1998;21:439-440, which is incorporated herein by reference in its entirety). While pyridoxine treatment is widely used, it provides a modest decrease in tHcy levels, and most patients who are defined as sensitive cannot significantly reduce, let alone normalize, tHcy levels with pyridoxine alone, as that their initial levels are many times higher than normal (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74, which is incorporated herein by reference in its entirety). In addition to long-term pyridoxine treatment, it is recommended that pyridoxine-sensitive CBSDH patients also receive folate and, as needed, vitamin B12 supplements. 2. Dietary restriction Lifelong dietary restrictions have previously been recommended for all patients with CBSDH (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74; Walter et al. Eur J Pediatr. 1998 Apr;157 Suppl. 2: S71-6; which are incorporated herein by reference in their entirety). The recommended diet is extremely limited and aims to reduce Met intake by restricting protein content. The mainstay of current therapy for patients with CBSDH is a lifelong low-protein diet that includes as little as 5 g of natural protein per day (www.hcunetworkamerica.org) supplemented with Met-free L amino acids and, in many cases, Additional Cys (Yap et al. J Inherit Metab Dis 1998; 21: 738-47; Morris et al. J Inherit Metab Dis. 2017 Jan; 40(1):49-74; incorporated herein by reference in their entirety) , to complement the diet. The severely restricted diet consists of low-methionine grain-based foods, low-methionine fruits and vegetables, low-methionine medicinal foods, oils, and sugar. Foods such as meat, chicken, fish, eggs, milk, yogurt, cheese, ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO soy products, nuts, legumes, and many fruits and vegetables that contain moderate amounts of Met. Since native CBS is a key enzyme in Met metabolism, ingestion of Met, an essential amino acid found in many foods, results in elevated plasma concentrations of tHcy and reduced concentrations of the downstream metabolites Cth and Cys. Prepared foods, baked goods, and packaged foods should be highly restricted, as they often contain milk, eggs, or flour. The amount of protein each CBSDH patient needs and tolerates is different and is likely to vary over time. This amount is adjusted according to tHcy levels that are monitored in frequent blood tests (ASIEM Low Protein Handbook for Homocystinuria). Most patients on dietary therapy also require daily consumption of a foul-tasting Met-free synthetic amino acid formula to prevent secondary malnutrition and for adequate growth in children, and in adults for adequate nutrition (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74; which is incorporated herein by reference in its entirety). Although dietary modifications with the combination of vitamin supplements can decrease tHcy levels to some extent in people who are fully compliant with the highly restrictive diet, the tHcy levels of most patients with CBSDH are maintained several times in orders of magnitude above normal. For most people, it is very challenging to achieve full lifelong compliance with dietary modifications, and the resulting periods of poor metabolic control have cumulative deleterious effects (see Morris et al. J Inherit Metab Dis. 2017 Jan;40( 1):49-74; which is incorporated herein by reference in its entirety). Diet compliance is often poor and generally deteriorates further during adolescence and adulthood (see Walter et al. Eur J Pediatr. 1998 Apr;157 Suppl. 2:S71-6; Schiff et al. Neuropediatrics. 2012 Dec;43(6):295-304, Garland et al. Paediatr Child Health. 1999 Nov;4(8):557-62; incorporated herein by reference in their entirety). Additionally, eating foods high in Met does not cause an immediate negative physical reaction, further compounding the difficulty with diet compliance (www.hcunetworkamerica.org). Met restriction is even more challenging in children due to the need to ensure sufficient Met to facilitate growth and development. Most patients on dietary treatment also require a Met-free, Cys-enriched L-amino acid supplement for adequate growth in children, and in adults for adequate nutrition (see Morris et al. JInheritMetab Dis 2017;40: 49-74, which is incorporated herein by reference in its entirety). A recent report indicated that only four adult patients among 24 patients who were prescribed a low-protein diet with specific amino acid supplements appropriate for CBSDH followed this treatment (see Lorenzini et al. J Inherit Metab Dis. (2018) 41: 109-115, which is hereby incorporated by reference in its entirety). Multiple CBSDH experts have described similarly wide variability in the United States. 3. Betaine supplementation The problems associated with largely diet-based therapies have necessitated other approaches to lowering Hcy, most notably betaine supplementation (Ν,Ν,Ν-tñmethylglycine, ivia / t / zuzz / u ι rao or marketed as CYSTADANE ™) administered at least twice a day. Betaine is rarely effective as monotherapy (Sakamoto et al. Pediatr Int 2003;45:333-338, which is incorporated herein by reference in its entirety), and is typically used as an adjunct to pyridoxine and / or a restricted diet in met. (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74; which is incorporated herein by reference in its entirety). Betaine does not address the underlying CBS deficiency but rather induces an alternative pathway, resulting in remethylation of Hcy back to Met and correcting the partial misfolding of CBS mutants (see Kopecka et al. J Inherit Metab Dis 2011;34:39-48, which is incorporated herein by reference in its entirety). In the presence of betaine, the enzyme betaine homocysteine ​​methyltransferase (BHMT) remethylates Hcy to Met (Singh et al. Genet Med 2004;6:90-95, which is incorporated in its entirety by reference), thereby partially reducing Hcy levels while increases the already very high levels of Met. CBS downstream metabolites are not improved by betaine administration and Cys supplementation may be necessary. Furthermore, betaine treatment has been associated with abnormalities in cerebral white matter, a sign of vascular damage in the brain (Prins et al. Nat Rev Neurol 2015;11:157-165, which is fully incorporated herein as reference), in patients with (Devlin et al. J Pediatr 2004, 144:545-548, Yaghmai et al. Am J Med Genet 2002;10857-63; incorporated herein by reference in their entirety) and without (Vatanavicharn et al. J Inherit Metab Dis 2008;31 Supl 3:477-481; Brenton et al. J Child Neurol 2014;29:88-92; Sasai et al. Tohoku J Exp Med 2015;237:323-327; incorporated here by reference in their entirety) acute cerebral edema. Betaine may be unpleasant (Walter et al. Eur J Pediatr. 1998 Apr;157 Suppl. 2:S71-6, which is incorporated herein by reference in its entirety) and cause an unpleasant fishy body odor and / or breath (see Manning et al. JIMD Rep 2012;5:71-75, which is incorporated herein by reference in its entirety). Both effects potentially exacerbated by the requirement for high doses (greater than 6 g / day in adult and pediatric patients). Consequently, compliance is generally poor (see Adam et al. Mol Genet Metab. 2013 Dec.;110(4):454-9; Walter et al. Eur J Pediatr. 1998 Apr;157 Suppl. 2:S71-6 ; Sakamoto et al.. Pediatr Int 2003;45:333-338; which are incorporated herein by reference in their entirety). The pharmaceutical formulation of betaine, CYSTADANE™, was approved by the FDA in 2006 and is indicated to decrease elevated blood Hcy levels in homocystinuria disorders, including CBS deficiency, 5,10-methylenetetrahydrofolate reductase deficiency ( MTHFR) and cobalamin cofactor (cbl) metabolism defects. (see Recordati. Product Information CYSTADANE™ (Pl). 2017. Reference Type: Online Source, which is incorporated herein by reference in its entirety.) The largest survey to date of dietary practices among pyridoxine-unresponsive patients CBSDH indicated that betaine was a common treatment option, particularly in late-diagnosed patients, adolescents, and adults. The use of betaine as primary therapy in 34% of non-diet patients is thought to be due to lack of dietary compliance, as there are no controlled studies examining the long-term effectiveness of betaine when given without diet. diet (see Adam et al. Mol Genet Metab 2013;110:454-459, which is incorporated herein by reference in its entirety). In fact, a study in a CBSDH mouse model found that the ability of betaine treatment to significantly reduce tHcy decreased over time (see Maclean KN. Betaine treatment of cystathionine b-synthase-deficient homocystinuria; does it work and can it be improved? Dove Press 2012; 2:23-33, which is incorporated herein by reference in its entirety). 4. Antiplatelet therapies In addition to Hcy-lowering therapies, patients with poorly controlled Hcy levels and / or those who have additional risk factors for thrombosis (e.g., Factor V Leiden, prior thrombosis, and pregnancy), may benefit from treatment with antiplatelet agents. (e.g., aspirin, dipyridamole, or clopidogrel) (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74; which is incorporated herein by reference in its entirety). COUMADIN™ anticoagulants may also be used in patients with prior venous thrombosis. However, anticoagulant agents are associated with an increased risk of cerebral hemorrhage and their use should be determined by the individual patient (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74; which is incorporated by reference in its entirety). 5. Clinical results with current therapies The manifestations of CBSDH continue to progress with classic clinical symptoms reaching varying degrees of disability and impact on the quality of life of affected individuals. Regardless of the individual's age of onset, loss of biochemical control at any age is associated with the development of serious, potentially life-threatening complications (see Walter et al. Eur J Pediatr. 1998 Apr;157 Suppl. 2: S71-6, which is incorporated herein by reference in its entirety). Treatment should be continued throughout life, as periods of poor metabolic control have cumulative deleterious effects that can lead to serious complications and premature death (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49 -74, which is incorporated herein by reference in its entirety). Without treatment, the prognosis of pyridoxine-unresponsive CBSDH is poor and the life expectancy of patients is markedly reduced. No randomized controlled trials of dietary or other therapy for CBSDH have been conducted since the disease was first described in 1962 (see Carson et al. Arch Dis Child. 1969 Jun;44(235):387-92; Gerritsen et al. Biochem Biophys Res Commun., December 19, 1962; 9:493-6, which are incorporated herein by reference in their entirety). However, several observational studies have been published. An international study documenting the natural history of 629 untreated CBS patients showed that the risk of complications increases with age (see Mudd et al. Am J Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety). Treatment (pyridoxine, Met-restricted diet) was observed to reduce plasma tHcy levels and markedly reduce the risk of thromboembolic events and lens dislocation, although compliance with the restricted diet was noted to be poor. Yap et al. (Arterioscler Thromb Vasc Biol. 2001 Dec.;21(12):2080-5) conducted an international multicenter study in 158 treated patients. The incidence of cardiovascular events was markedly reduced in this treated group compared with historical control data from Mudd et al. (Am J IVIA / t / ZUZZ / U I ÍVÓO Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety). This apparent benefit was correlated with lower (but not normalized) plasma tHcy levels in treated patients. It was noted that consistent compliance with the required regime was very difficult. In general, although several CBSDH treatment strategies are available, they cannot restore most patients to near-normal tHcy levels. Furthermore, its long-term effectiveness is subject to poor or inconsistent lifelong compliance. Therefore, it is difficult to maintain a constant reduction of Hcy in patients with CBSDH. Treatment with the drug product described herein aims to avoid many of these pitfalls. By compensating for the metabolic defect in CBSDH through a mechanism that should not require severe Met restriction or Cys supplementation, enzyme therapy (ET) is expected to achieve a more consistent reduction in Hcy, without dangerously elevating Hcy levels. Met. SAW. DOSAGE AND ADMINISTRATION In certain embodiments, the drug product may be administered to a subject by subcutaneous (SC), intravenous (IV), or intraperitoneal (IP) injection. In one embodiment, the drug product can be administered to a subject 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times. In another embodiment, the drug product is administered more than 20 times. In another embodiment, the drug product is administered more than 100 times. Alternatively, the drug product may be administered for the remainder of the subject's life. In certain embodiments, administration of the drug product may be repeated every 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, daily, 2 days, 3 days, 4 days, 5 days, 6 days, week, 2 weeks, 3 weeks and month. In certain embodiments, administration of the drug product is performed once every 3 days, once every 2 days, or once daily. In certain embodiments, administration of the drug product may be a series of doses separated by minutes, hours, days or weeks. For example, the number of doses in a series may be 1, 2, 3, 4, 5 or 6. As a non-limiting example, 3 doses are administered to a subject 24 hours apart. As another non-limiting example, a subject is administered 5 doses 12 hours apart. The subject may be a human being. In certain embodiments, administration of the drug product may follow a dosing schedule of a series of doses having a range between the first series of doses and the second series of doses. The range between doses can be 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, day, 2 days, 3 days, 4 days, 5 days, 6 days, a week, 2 weeks, 3 weeks, monthly, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months. The number of doses in a series may be 2, 3, 4, 5 or 6. As a non-limiting example, a subject may be administered a first series of 5 doses 12 hours apart and then 14 days after the first dose to a subject ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO may be given a second series of 5 doses 12 hours apart. As another non-limiting example, a subject is administered two series of doses over a period of 8 weeks, where the first series is a dose twice a week for two weeks and the second series of doses is three times a week for 6 weeks. weeks. In certain embodiments, the drug product may be administered at least once after betaine has been administered to a subject. The time between administration of betaine and administration of the drug product may be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, week, 2 weeks, 3 weeks, monthly, 2 months, quarterly, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months , 15 months, 16 months, 17 months or 18 months. As a non-limiting example, the drug product can be administered 14 days after Betaine was administered to the subject. As another non-limiting example, a subject may be administered the drug product two doses after Betaine has been administered to the subject. As another non-limiting example, the drug product can be administered 14 or 15 days after administration of betaine. In certain embodiments, the drug product may be administered in combination with betaine to a subject. The combination may be administered at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15. In certain embodiments, the drug product may be administered in combination with betaine plus 15 times. Additional combination therapies that may be administered to a patient include the drug product and at least one treatment to reduce tHcy levels, such as a very low protein / Met diet and / or vitamins / supplements. In one embodiment, the dose of the drug product administered to a subject may be between about 0.25 mg / kg and about 10 mg / kg. For example, the dose is about 0.33 mg / kg, about 0.66 mg / kg, 1.0 mg / kg or 1.5 mg / kg. Alternatively, the dose is approximately 2 mg / kg, approximately 7 mg / kg and approximately 10 mg / kg. For example, the dose may be approximately 0.5 mg / kg. Alternatively, the therapeutically effective amount is a dosage selected from the range of about 5.0 mg / kg to about 50 mg / kg, and about 10.0 mg / kg to about 25 mg / kg. For example, the dose is selected from the group consisting of: about 0.25mg / kg, about 0.33mg / kg, about 0.66mg / kg, about 1.00mg / kg, about 1.10mg / kg, about 1.20mg / kg, about 1.30mg / kg, approximately 1.40mg / kg, approximately 1.50mg / kg, approximately 1.60mg / kg, approximately 1.70mg / kg, approximately 1.80mg / kg, approximately 1.90mg / kg, approximately 2.00mg / kg, approximately 3.00mg / kg, approximately 4.00mg / kg, approximately 5.00mg / kg, approximately 6.00mg / kg, approximately 7.00mg / kg, approximately 8.00mg / kg, approximately 9.00mg / kg, approximately 10.0mg / kg, approximately 11.0mg / kg ivia / t / zuzz / u i rao o approximately 20.Omg / kg, approximately 21.0mg / kg, approximately 22.0mg / kg, approximately 23.0mg / kg, approximately 24.0mg / kg, approximately 25.0mg / kg, approximately 26.0mg / kg , approximately 27.Omg / kg, approximately 28.0mg / kg, approximately 29.0mg / kg, approximately 30.0mg / kg, approximately 31.0mg / kg, approximately 32.0mg / kg, approximately 33.0mg / kg, approximately 34.Omg / kg , approximately 35.0mg / kg, approximately 36.0mg / kg, approximately 37.0mg / kg, approximately 38.0mg / kg, approximately 39.0mg / kg, approximately 40.0mg / kg, approximately 41.0mg / kg, approximately 42.0mg / kg, approximately 43.0mg / kg, approximately 44.0mg / kg, approximately 45.Omg / kg, approximately 46.Omg / kg, approximately 47.Omg / kg, approximately 48.Omg / kg, approximately 49.Omg / kg, and approximately 50.0 mg / kg. In certain embodiments, the drug product is administered to a subject on a methionine-restricted diet. Alternatively, the drug product is administered to a subject who is not on a methionine-restricted diet. In certain embodiments, the drug product can be co-administered with another therapeutic agent to treat CBSDH. As used herein, “coadministered” means the administration of two or more components. These components for coadministration include, but are not limited to, betaine or vitamin B6. Coadministration refers to the administration of two or more components simultaneously or with a time lapse between administration of 1 second, 5 seconds, 10 seconds, 15 seconds, 30 seconds, 45 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes , 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 36 minutes, 37 minutes, 38 minutes, 39 minutes, 40 minutes, 41 minutes, 42 minutes,43 minutes, 44 minutes, 45 minutes, 46 minutes, 47 minutes, 48 ​​minutes, 49 minutes, 50 minutes, 51 minutes,52 minutes, 53 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58 minutes, 59 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours , 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 1.5 days, 2 days or 3 days. In certain modalities, the time lapse between the administration of two or more components is greater than 3 days. In certain embodiments, the drug product may be used as a parenteral agent, to be administered to patients chronically via subcutaneous (SC) injection at an initial dosage range once a week. For example, weekly dosage of medications for 6 doses. In certain embodiments, the subject may be within an age range of 18 to 65 years. In certain embodiments, a subject as young as 16 years of age may receive similar treatment. In certain embodiments, administration occurs over the course of 1 day, 2 days, 3 days, 4 days, 5 days or 6 days. In certain embodiments, administration occurs over the course of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks. , 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, ΜΛ / Ε / ΖυΖΖ / υΊ fVÓO weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks , 41 weeks, weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, weeks, 51 weeks or 52 weeks. In certain embodiments, the drug product is administered as a combination therapy with pyridoxine (also called vitamin B6) and / or an antiplatelet therapy. VIII. PATIENT STRATIFICATION In certain embodiments, individuals eligible for effective enzyme therapy using the drug product described herein include patients who have a diagnosis of CBSDH, based on confirmation of CBS-deficient genetic homocystinuria by CBS gene mutation analysis and a plasma level. of tHcy greater than or equal to 80 μΜ. B. Clinical presentation According to the CBSDH Guidelines for Diagnosis and Management, the disease should be suspected in children who present with severe or rapidly progressive myopathy, lens dislocation, and / or developmental delays (see Morris et al. Guidelines for the diagnosis and management of cystathionine betasynthase deficiency. J Inherít Metab Dís 2017;40:49-74, which is incorporated herein by reference in its entirety). Testing is also warranted in adults who present with thromboembolism and / or lens dislocation but without other symptoms and in those with multisystem disease, including ocular, connective tissue, neuropsychiatric, and vascular complications (see Mudd et al. Am J Hum Genet 1985 37 :131; Morris et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis 2017; 40:49-74; Kelly et al. Neurology 2003;60:275-279, each of which is incorporated herein by reference in its entirety). C. Biochemical analysis Plasma tHcy levels are determined using the sum of all free and bound homocysteine ​​species after treating the plasma with a reducing agent. In healthy individuals with stable dietary habits, tHcy levels remain relatively constant over time (see Refsum et al. Clin Chem 2004; 50:3-32; McKinley et al. Clin Chem 2001;47:1430-1436; each of which is incorporated by reference in its entirety). However, consumption of a high-protein meal can increase tHcy levels by approximately 10% over a period of several hours (see Verhoef et al. Am J Clin Nutr 2005; 82:553-558, incorporated herein for reference in its entirety). A study in individuals with hyperhomocysteinemia (tHcy >40pmol / L) found that intra-individual tHcy levels varied by up to 25% over a period of 4 to 8 months. However, information on the variability of diets, test methods and sampling times was not provided, which hampered the ability to interpret the data (see Refsum H, Smith AD, Ueland PM et al. Facts and recommendations about total homocysteine ​​determinations: an expert opinion. Clin Chem 2004; 50:3-32, which is incorporated herein by reference in its entirety). In folate-unsupplemented populations, the corresponding upper reference limits are approximately 15 and 20 pmol / L, respectively. To support a diagnosis of CBS in a newborn, plasma tHcy is expected to be between 50 and more than 100pmol / L and plasma Met is expected to be between 200 and 1500 μηηοΙ / L (i.e., 3-23 mg / dL) (see Sacharow et al. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. GeneReviews 2017, which is incorporated herein by reference in its entirety). To support a diagnosis of CBS in an untreated older individual, plasma tHcy is expected to be greater than 100 pmol / L and plasma Met is expected to be greater than 50μmol / L (i.e., greater than 0.7 mg / L). dL). A control neonate or an older individual would be expected to have plasma tHcy of less than 15pmol / L and Met between 10 to 40 pmol / L (0.2 - 0.6 mg / dL). High to high normal Met levels (reference ranges are typically 40 to 45 and 12 to 15 μmol / L, respectively) in combination with low to low normal Cth levels (reference range 0.05 to 0.08 and 0.35 to 0.5 pmol / L, respectively) may be useful in distinguishing CBSDH from HCU caused by genetic and nutritional disorders of Hcy remethylation (see Morris et al. J Inherit Metab Dis2017; 40:49-74; Stabler et al. JIMD Rep 2013;11:149-163; Bartl et al. Clin Chim Acta 2014;437:211 217, each of which is incorporated herein by reference in its entirety). Another useful test determines the production of Cth from Hcy and serine in cultured fibroblasts, using radioactive or deuterium-labeled substrates (see Morris et al. J Inherit Metab Dis 2017; 40:49-74; Kraus JP. Methods Enzymol 1987; 143:388394, Smith et al., J Chromatogr B Anaiyt Technol Biomed Life Sci 2012, 911:186-191, each of which is hereby incorporated by reference in its entirety). However, enzyme analysis cannot always distinguish between individuals who respond to pyridoxine and those who do not respond, and enzyme activity may be normal in mild cases (see Alcaide et al. Clin Chim Acta 2015;438:261- 265, which is incorporated herein by reference in its entirety). More recently, rapid stable isotope assays measuring the activity of CBS released from organs into plasma showed 100% sensitivity in pyridoxine non-responders, but only 86% sensitivity in pyridoxine responders. pyridoxine (see Alcaide et al. Clin Chim Acta 2015;438:261- 265; Krijt et al. J Inherit Metab Dis 2011 ;34:49-55, all of which are hereby incorporated by reference). D. Molecular Diagnosis Molecular genetic testing, the gold standard diagnostic test for CBSDH, can be performed using single-gene testing or using a multigene panel (see Yap S. Homocystinuria due to cystationine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005 ; Sacharow SJ, Picker JD, Levy HL. Homocvstinuria Caused bv Cystathionine Beta-Svnthase Deficiency. GeneReviews 2017: Morris et al. J Inherit Metab Dis 2017; 40:49-74; Katsanis et al. Nat Rev Genet 2013; 14: 415 -426; each of which is hereby incorporated by reference in its entirety). People at high risk for having a particular CBS mutation should undergo single-gene screening. However, this ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO is only useful in selected populations with a common CBS mutation (for example, 93% of people with CBSDH in Qatar carry the p.Arg336Cys; c.1006C>T mutation) and in people from families with a known pathogenic variant. In other patients, the CBS gene can be sequenced and deletion / duplication analysis targeting the gene can be performed only if one or no pathogenic variant is found. Alternatively, simultaneous molecular testing of multiple genes can be performed using a multigene panel. Methods used may include sequence analysis, deletion / duplication analysis, and other non-sequence-based tests (see Morris et al. J Inherit Metab Dis 2017;40:49-74, which is incorporated herein by reference in its entirety). In general, molecular genetic testing is reserved for high-risk populations with a limited number of prevalent mutations (see Morris et al. J Inherit Metab Dis 2017; 40:49-74; Huemeret al. J Inherit Metab Dis 2015;38: 1007-101, each of which is incorporated herein by reference in its entirety). E. Pyridoxine response tests Pyridoxine response testing is used in the clinic to determine whether pyridoxine supplements should be prescribed to patients with CBSDH. Because different treatment centers have defined pyridoxine responsiveness differently (see Morris et al. J Inherit Metab Dis 2017;40:49-74, which is incorporated herein by reference in its entirety), the classification of patients by tHcy levels, rather than by their pyridoxine responsiveness, is more rigorous. Pyridoxine responsiveness is not a measure of metabolic control, but rather an indication that some residual CBS activity remains. F. Newborn Screening (NBS) Generally, NBS testing for CBSDH deficiency is performed by analyzing dried blood spots to determine Met levels. Alternatively, assessment of tHcy rather than Met levels in dried blood spots for NBS is available in some centers worldwide. It is used as a second-tier test to reduce NBS false-positive rates in individuals with high Met levels (see Turgeon et al. Clin Chem 2010;56:1686-1695, which is incorporated herein by reference in its entirety). and is not used to improve sensitivity or reduce false negative rates. VIII. PHENOTYPIC RESULTS Retrospective studies show a proportional relationship between tHcy levels and outcomes. Patients with the highest tHcy levels (treated or untreated) have more severe symptoms at an earlier age, while patients with lower tHcy levels have fewer symptoms and progress less rapidly (see Yap S. Homocystinuria due to to cystathionine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005; Mudd et al. AmJHum Genet 1985; 37:1-31, each of which is incorporated herein by reference in its entirety). People with high tHcy levels often present with delayed growth, thromboembolism, severe myopia with subsequent dislocation of the ΜΛ / Ε / ζυζζ / υΊ rao O optical lens, osteoporosis-type fractures, marfanoid habit (in particular, elongation of the long bones) and / or psychiatric abnormalities such as learning difficulties, (see Yap S. Homocystinuria due to cystathionine beta- synthase deficiency. Orphanet Encyclopaedia [online series] 2005; Morris et al. J Heredar Metab Dis 2017; 40:49-74; NORD, Kraus JP. Homocystinuria due to cystathionine beta-synthase deficiency. NORD [online series] 2017, each of which is incorporated herein by reference in its entirety). Reflecting the spectrum of CBS deficiency, some patients have severe childhood-onset multisystem disease, while those with less elevated Hcy levels may not be diagnosed until adulthood (see Morris et al. J Inherit Metab Dis 2017; 40:49-74, which is hereby incorporated by reference in its entirety). Life expectancy is markedly reduced in patients with very elevated Hcy levels, although even patients with moderately elevated tHcy levels suffer multiple negative clinical outcomes. Orphanet Encyclopaedia [online series] 2005; Morris et al. J Inherit Metab Dis 2017; 40:49-74; NORD, Kraus JP. Homocystinuria due to cystathionine beta-synthase deficiency. NORD [online series] 2017, each of which is incorporated herein by reference in its entirety). Reflecting the spectrum of CBS deficiency, some patients have severe childhood-onset multisystem disease, while those with less elevated Hcy levels may not be diagnosed until adulthood (see Morris et al. J Inherit Metab Dis 2017; 40:49-74, which is hereby incorporated by reference in its entirety). Life expectancy is markedly reduced in patients with very elevated Hcy levels, although even patients with moderately elevated tHcy levels suffer multiple negative clinical outcomes. Significant evidence has been observed indicating the causal effect of elevated tHcy levels and negative clinical outcomes in the four systems commonly affected in patients with CBSDH (ocular, skeletal, cardiovascular, and neurological). In the ocular system, frequently observed phenotypic outcomes include: ectopia lentis, iridodonesis, myopia, and less frequently observed phenotypic outcomes include: glaucoma, optic atrophy, retinal degeneration, retinal detachment, cataracts, and corneal anomalies. In the skeletal system, frequently observed phenotypic outcomes include: osteoporosis, biconcave vertebrae, scoliosis, increased length of long bones, irregularly widened metaphyses, metaphyseal spicules, abnormal size / shape of epiphyses, growth arrest lines, pes cavus and high arched palate, and less frequently observed phenotypic findings include: arachnodactyly, enlarged carpal bones, abnormal bone age, pectus carinatum / excavatum, genu valgum, kyphosis, and short fourth metacarpal. In the vascular system, frequently observed phenotypic findings include: vascular occlusions, malar blush, and livedo reticularis. In the central nervous system, frequently observed phenotypic findings include: mental retardation, psychiatric disorders, and extrapyramidal signs, and less frequently observed phenotypic findings include: seizures and abnormal electroencephalogram. In additional body systems, the following phenotypic findings are frequently observed: light, brittle hair, thin skin, fatty changes in the liver, inguinal hernia, myopathy, endocrine abnormalities, reduced clotting factors, and spontaneous intestinal perforation. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO A strong relationship has been observed between mildly elevated tHcy levels and negative outcomes, but data have also indicated that reducing tHcy levels has a positive impact on clinical manifestations. The CBSDH literature suffers from the rarity of the disease and smaller subsequent studies, but benefits from magnification of clinical outcomes in a population with severely elevated Hcy levels. In contrast, studies in the broader population benefit from large sample sizes but smaller elevations in tHcy levels. Taken together, these studies consistently demonstrate that elevated tHcy levels are strongly predictive of negative clinical outcomes and that pharmacological intervention to reduce those levels is beneficial. A potential outcome of treatment of CBSDH with the drug product described herein is to reduce the plasma tHcy concentration to the lowest possible levels while maintaining a more relaxed diet, which includes higher concentrations of Met than those provided in other therapies for CBSDH and other essential amino acids. In infants and children with CBSDH, the priority is to prevent complications associated with CBSDH and ensure adequate growth and development of normal intelligence (see Morris et al. J Inherit Metab Dis. 2017 Jan;40(1):49-74, which is incorporated herein by reference in its entirety). In patients diagnosed later in life, the priority may be to prevent life-threatening thromboembolism and minimize the progression of already established complications. To address these goals, the biochemical abnormalities associated with CBSDH can be improved and, if possible, normalized (see Morris etal. J Inherit Metab Dis. 2017 Jan;40(1):49-74, which is incorporated herein by reference in its whole). A survey comparing dietary management practices for patients with CBSDH in 29 centers in 8 European countries found that there was little consensus across treatment centers on target ranges for plasma tHcy levels, with the recommended median target being less than 55 μΜ and within a range of less than 20 to 100 μΜ among the 29 centers (see Adam et al. Mol Genet Metab. 2013 Dec;110(4):454-9, which is hereby incorporated in its entirety by reference ). The cutoff value greater than or equal to 80 μΜ for tHcy levels for treatment eligibility was chosen herein to avoid exclusion of patients with prior plasma tHcy levels of approximately 100 μΜ given within-person variability. of 25% in plasma tHcy levels analyzed over several months apart (see Refsum et al. Clin Chem 2004;50:3-32; Guttormsen et al, J Clin Invest. 1996,98(9):2174-83 ; each of which is incorporated herein by reference in its entirety) to provide levels high enough to detect clinically significant reductions in a small number of patients. The 25% within-person variability in plasma tHcy levels was tested several months apart (see Refsum et al. Clin Chem 2004;50:3-32; Guttormsen et al., J Clin Invest. 1996, 98(9):2174- 83; each of which is incorporated herein by reference in its entirety) may be partially due to changes in diet, medications, or supplements in patients with CBSDH over time. If left untreated, the prognosis for patients with pyridoxine-unresponsive CBSDH is dismal (see Morris et al. J Inherit Metab Dis 2017;40:49-74, which is incorporated herein by reference in its entirety). In 1985, an international retrospective study that documented the natural history of CBSDH in 629 MA / IZ / ZUZZ / UI ÍVÓO patients, using time-to-event analysis before treatment, showed that 70% of patients experienced lens dislocation by age 10 years, and 85% developed symptoms by age 12 years (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Mudd et al., Skovby F. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Diseases, 7th edition, New York: McGraw Hill, 2001, 1279-1327, both hereby incorporated by reference in their entirety). Overall, 50% of affected individuals had radiographically detected spinal osteoporosis by the age of 15 years and 23% of patients who did not respond to pyridoxine (4% of responders) died by the age of 30 years. (see Mudd et al. Am J Hum Genet 1985; 37:131, which is incorporated herein by reference in its entirety). Taken as a whole, the available evidence indicates that current approaches to the treatment of CBSDH, including restrictive diet and the use of dietary supplements, are ineffective in halting disease progression in most patients. Consequently, there is a substantial unmet medical need to identify well-tolerated therapies that will improve or normalize the metabolic abnormalities of CBSDH and slow or arrest the progression of the clinical manifestations of the disease. A causal effect between increased Hcy levels and key clinical outcomes associated with CBSDH, including ocular complications (particularly lens dislocation), skeletal outcomes (particularly osteoporosis), vascular events (particularly in particular, stroke and small blood vessel disease) and various CNS disorders. results (particularly cognitive function), has been observed. The relationship between elevated tHcy levels and negative clinical outcomes and, conversely, reduced Hcy levels and improved clinical outcomes, is further strengthened by multiple studies in the general population. Overall, these clinical findings highlight the need for early diagnosis of CBSDH and immediate treatment to lower Hcy levels as close to normal as possible. Although no studies have been published on the quality of life (QoL) of patients with CBSDH, unpublished reports indicate that patients and their caregivers suffer the psychosocial effects of following and managing a highly restricted and socially isolated diet and are extremely anxious. due to the long-term medical consequences of the disease. Not surprisingly, patients long to be able to relax their diets without compromising their long-term prospects. The strong relationship between tHcy levels and key clinical outcomes in patients with CBSDH shows that change in tHcy levels is a reliable surrogate marker for a combination of clinical endpoints in CBSDH. Therefore, changes in tHcy levels are useful for (i) monitoring patient progress in the clinic and (i) predicting the clinical benefits of new treatments in a clinical trial and (i) predicting the efficacy of a therapy. For example, the drug product normalizes or increases the flexibility of the femoral artery in a subject compared to before administration of the drug product to the subject. For example, I278T mice have significantly reduced femoral artery flexibility compared to wild-type mice. A diet restricted in Met can, in fact, result in a diameter of the ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO smaller femoral artery in I278T mice compared to a regular diet in both drug-treated and non-drug-treated mice. Studies previously performed in 3 murine models of the disease have shown that htCBS C15S is effective after systemic administration as described in WO 2017 / 083327, which is incorporated herein by reference in its entirety. These studies showed a decrease of up to 90% in intracellular Hcy and plasma levels of extracellular Hcy in tissues, such as the brain. Administration of the drug product was observed to result in a concentration gradient, with Hcy flowing from higher concentrations in the intracellular space to lower concentrations in the extracellular space where it can be further processed by the drug product. The extracellular PEGylated C15S htCBS serves as a “sink” for Hcy. In summary, the drug product restored control of the Met metabolic pathway in animal models of CBSDH. These studies have also shown that SC dosing of PEGylated C15S htCBS in murine models of CBSDH corrected metabolite levels, including elevation of Cth levels and normalization of Cys levels. Furthermore, PEGylated C15S htCBS positively affected disease phenotypic expression in mice, including facial alopecia, liver histology, osteoporosis, body composition, diabetic retinopathy (possibly secondary to kidney disease), and macular and optic atrophy due to retinal vascular occlusion or not. . -arteritic ischemic optic neuropathy, cytokines and lipid levels. PEGylated C15S htCBS also rescued CBS knockout (KO) mice from premature death (see Looker et al. Diabetologia 2003;46:766-772; Pusparajah et al. Front Physiol 2016;7:200; Gerth et al. J AAPOS 2008;12 :591-596, Stanger et al. Clin Chem Lab Med 2005, 43:1020-1025, Cahill et al. Am J Ophthalmol 2003; 136:1136-1150; Minniti et al. EurJ Ophthalmol 2014;24: 735-743; each of which is incorporated herein by reference in its entirety). PEGylated C15S htCBS was also observed to be well tolerated and no toxicological effects were observed with chronic dosing in animal models of the disease. PEGylated C15S htCBS acts in the extracellular space and is predicted to reduce plasma tHcy concentrations regardless of patients' genetics, concurrent therapy, or baseline tHcy level. Therefore, the eligible study population should include patients who respond and do not respond to pyridoxine. In healthy individuals, tHcy levels are in the range of approximately 5 to 15 pM (OECD Environmental Health and Safety Publications. Series in Principles of Good Laboratory Practice and Compliance Monitoring. No. 1 ENV / MC / CHEM(98)17 Principies of Good Laboratory Practice (revised 1997), which is incorporated herein by reference in its entirety), 98% of which is in the form of disulfides or bound to proteins. Only 2% of tHcy exists as an unbound compound, free and reduced aminothiol that can serve as a substrate for the enzyme (see EMA: Guideline on bioanalytical method validation, EMEA / CHMP / EWP / 192217 / 2009, ev. 1, 21 July 2011; ATL-15-1419 Atlanbio Study Report “LC-MS / MS determination of cystathionine-D4 as product of the cystathionine β-synthase activity in monkey plasma samples collected during the study 529736; both are incorporated herein by reference in their entirety ). Patients with CBSDH, on the other hand, not only present plasma levels that can reach 400 μΜ IVIA / t / ZUZZ / U I ÍVÓO and more, but also have a drastically altered balance, with free homocysteine ​​reaching 10-25% of tHcy values. In mouse models, administration of C15S PEGylated htCBS resulted in up to a 90% reduction in tHcy levels. Therefore, the initial levels of free homocysteine ​​available for the enzyme (10%-25% of the total) cannot solely explain the significant decrease in tHcy levels that were recorded, and additional reserves must be available for the enzyme. For example, as free Hcy becomes scarce as a result of PEG htCBS activity, the balance between free Hcy and Hcy adducts (in the form of protein-bound Hcy or disulfides) in the plasma changes to favor the generation of free Hcy, which can be processed by the enzyme. A. Ocular Complications Elevated Hcy levels are an important and independent risk factor for ocular complications, in particular, lens dislocation, in patients with CBSDH and in the general population. Even with prescribed dietary and pharmacological interventions, most patients with CBSDH eventually develop ocular complications. Reducing Hcy levels has been shown to delay and perhaps prevent lens dislocation in patients with CBSDH (see Yap S. Homocystinuria due to cystathionine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005; Mudd et al. Am J Hum Genet 1985;37:1-31; Martinez-Gutierrez etal. Int Ophthalmol (2011) 31:227-232; Ajith et al. Clin Chim Acta 2015;450:316-321; Mulvihill et al. J AAPOS 2001 ; 5:311-315; Marti-Carvajal et al. Cochrane Database Syst Rev 2015;1:CD006612; Sweetser et al. N Engl J Med 2016, 375:1879-1890; Sadiq etal. Semin Ophthalmol2013; 28:313-320 ; Wright etal. Homocysteine, folates, and the eye. Eye (Lond) 2008; 22:989-993; Lieberman et al. Am J Ophthalmol 1966, 61:252-255; Harrison et al. Ophthalmology 1998, 105:1886-1890 ; Ramsey et al. Am J Ophthalmol 1972; 74:377-385; Couser et al. Ophthalmic Genet 2017, 38:91-94; Ghorbanihaghjo et al. Mol Vis 2008, 14:1692-1697; Javadzadeh et al. Mol Vis 2010;16:2578-2584;Seddon et al. Am J Ophthalmol 2006; 141:201-203; Coral et al. Eye (London) 2006; 20:203-207; Axer-Siegel et al. Am J Ophthalmol 2004, 137:84-89; Heuberger et al. Am J Clin Nutr 2002; 76:897-902; Huang et al. SciRep 2015; 5:10585; Sen et al. Indian J Clin Biochem 2008; 23:255-257; Yousefi et al. Protein Pept Lett 2013; 20:932-941; Gerth et al. J AAPOS 2008; 12:591-596; Stanger et al. Clin Chem Lab Med 2005, 43:1020-1025; Cahill et al. Am J Ophthalmol 2003, 136:1136-1150; Minniti et al. Eur J Ophthalmol 2014, 24:735-743; Turkcu et al. Medicine (Kaunas) 2013,49:214-218; Vessani et al. Am J Ophthalmol 2003; 136:41-46; Leibovitch et al. J Glaucoma 2003, 12:36-39; Leibovitzh et al. Medicine (Baltimore) 2016;95:e4858; Micheal et al. Mol Vis 2009; 15:2268-2278; Clement et al. J Glaucoma 2009; 18:73-78; Cumurcu et al. BMC Ophthalmol 2006; 6:6; Bleich et al. J Neural Transm (Vienna) 2002;109:1499-1504; Lee et al. Curr Eye Res 2017;1-6; Wang et al. Am J Ophthalmol 2004; 137:401-406; Ganapathy et al. Invest Ophthalmol Vis Sci 2009; 50:4460-4470, each of which is incorporated herein by reference in its entirety). Even with prescribed dietary and pharmacological interventions, most patients with CBSDH eventually develop ocular complications. Reducing Hcy levels has been shown to delay and perhaps prevent dislocation ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO of the lens in patients with CBSDH (see Yap et al. J Inherit Metab Dis 1998; 21:738-747, which is incorporated herein by reference in its entirety). One of the earliest and most consistently present manifestations of CBSDH is ectopia lentis (dislocation of the lens) (see Mulvihill et al. JAAPOS 2001; 5:311-315, which is incorporated herein by reference in its entirety). This usually occurs after two years of age and is present in approximately 50% of untreated patients who do not respond to pyridoxine by the age of six years and in 50% of untreated patients who respond to pyridoxine. at the age of 10 years (see Mudd et al. al. Am J Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety). The dislocation can be partial (subluxation) or complete and, although it can occur inferiorly or nasally, it is usually bilateral (see Mulvihill et al. JAAPOS 2001; 5:311-315; Sweetser et al. N Engl J Med 2016;375 :1879 -1890, both hereby incorporated by reference in their entirety). Lens dislocation often follows a period of rapidly progressing myopia, which can lead to marked astigmatism, monocular diplopia, and decreased best-corrected acuity (see Sadiq et al. Semin Ophthalmol 2013;28:313-320, which is discussed below). incorporated here by reference in its entirety). In general, myopia (greater than 1 diopter [D]) is thought to affect approximately 85% of patients with CBSDH, with very high myopia (greater than 5D) affecting 50 to 76% of patients. Iridodonesis (tremor of the iris after moving the eyeball) affects approximately 56% of patients and spherophakia (a small, spherical lens that tends to subluxate) affects 50% of patients (see Yap S. Homocystinuria due to cystathionine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005, Mulvihill et al. J AAPOS 2001, 5:311-315, each of which is incorporated herein by reference in its entirety). Additional complications associated with CBSDH include cataract formation, chronic vitritis (inflammation of the vitreous humor) and chorioretinal inflammation, pupillary block with acute and / or chronic angle-closure glaucoma and (in children), amblyopia (lazy eye) (see Sadiq et al. al. Semin Ophthalmol 2013;28:313-320, which is incorporated herein by reference in its entirety). Evidence from a long-term retrospective study in 25 patients under 24 years of age with CBSDH suggests that lens dislocation can be prevented, or at least significantly reduced and delayed, in patients whose tHcy levels are consistently reduced from an early age ( see Yap et al., J Inherit Metab Dis 1998;21:738-747, which is hereby incorporated by reference in its entirety). Early treatment to lower Hcy was also associated with a lower risk of overall ocular complications, including worsening myopia. Supporting evidence is derived from a case-control study in 32 patients with CBSDH and 25 sibling controls, in which early treatment to lower Hcy was associated with a significant reduction in ocular complications compared to patients who were treated later in life or who were not fully compliant with treatment (see El Bashir et al. JIMD Rep 2015; 21:89-95, which is incorporated herein by reference in its entirety). The largest and longest longitudinal study to date of the ocular outcomes of 25 patients with cobalamin C deficiency, which is similarly characterized by elevated levels of ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO tHcy, found that macular degeneration, optic nerve pallor, nystagmus, strabismus, and vascular changes were all present in the majority of patients. Numerous studies in patients with CBSDH and in the general population have demonstrated relationships between elevated Hcy levels and a variety of ocular disorders (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Ajith, Clin Chim Acta 2015; 450 :316-321; Mulvihill et al. J AAPOS 2001;5:311-315; Wright et al. Eye (Lond) 2008;22:989-993, each of which is incorporated herein by reference in its entirety ), including myopia and lens dislocation (see Yap S. Homocystinuria due to cystathionine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005; Mudd et al. Am J Hum Genet 1985; 37:1-31; Martinez- Gutierrez et al. Int Ophthalmol 2011;31:227-232, Suri et al. J Neurol Sci 2014, 347:305-309, Mulvihill et al. J AAPOS 2001,5:311-315, Lieberman et al. Am J Ophthalmol 1966, 61:252-255;Harrison et al. Ophthalmology 1998;105:1886-1890;Ramsey et al. Am J Ophthalmol 1972;74:377-385;Couser et al. Ophthalmic Genet 2017;38:91-94; each of which is incorporated herein by reference in its entirety), iridodonesis (see Mulvihill et al. J AAPOS 2001; 5:311-315, which is incorporated herein by reference in its entirety), retinal arteriosclerosis (see Ghorbanihaghjo et al. Mol Vis 2008; 14:1692-1697, which is incorporated herein by reference in its entirety), macular degeneration related to age (see Javadzadeh et al. Mol Vis 2010; 16:2578-2584; Seddon et al. Am J Ophthalmol 2006; 141:201-203; Coral etal. Eye (Lond) 2006; 20:203-207; Axer- Siegel et al. Am J Ophthalmol 2004;137:84-89, each of which is incorporated herein by reference in its entirety), age-related maculopathy (AMD) (see Heuberger et al. Am J Clin Nutr 2002; 76:897-902; Huang et al. Sci Rep 2015; 5:10585, both incorporated herein by reference in their entirety), cataracts (see Sen et al., Indian J Clin Biochem 2008; 23:255-257; Yousefi et al. Protein Pept Lett 2013; 20:932-941, both incorporated herein by reference in their entirety), diabetic retinopathy (possibly secondary to disease) (see Looker et al. Diabetologia 2003; 46:766-772; Pusparajah et al. Front Physiol 2016; 7:200, both incorporated herein by reference in their entirety) and macular and optic atrophy due to retinal vascular occlusion or nonarteritic ischemic optic neuropathy (see Gerth et al. J AAPOS 2008; 12:591-596; Stanger et al. Clin Chem Lab Med 2005; 43:1020-1025; Cahill et al. Am J Ophthalmol2003; 136:1136 -1150; Minniti et al. EurJ Ophthalmol 2014; 24:735-743; each of which is incorporated herein by reference in its entirety). A retrospective study of 629 patients with CBSDH found that lens dislocation usually occurs after the age of two years and is present in approximately 50% of untreated patients who do not respond to pyridoxine by the age of six years and in 50% of patients not treated with pyridoxine. sensitive patients at the age of 10 years (see Mudd et al. Am J Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety). The largest and longest longitudinal study to date of the ocular outcomes of 25 patients with cobalamin C deficiency, which is similarly characterized by elevated tHcy levels, found that macular degeneration, optic nerve pallor, nystagmus , strabismus, and vascular changes were all present in the majority of patients (see Brooks et al. Ophthalmology. 2016 Mar; 123(3):571-82, which is hereby incorporated in its entirety by reference). ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Numerous studies in both patients with CBSDH and the general population have demonstrated relationships between elevated Hcy levels and a variety of ocular disorders (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Ajith TA, Ranimenon. Clin Chim Acta 2015;450:316-321; Mulvihill et al. J AAPOS 2001;5:311-315; Wright et al. Eye (Lond) 2008;22:989-993, each of which is incorporated herein by reference in its entirety), including myopia and lens dislocation (see Yap S. Homocystinuria due to cystathionine beta-synthase deficiency. Orphanet Encyclopaedia [online series] 2005; Mudd et al. Am J Hum Genet 1985; 37: 1-31; Martinez-Gutierrez et al. Int Ophthalmol 2011; 31:227-232; Mulvihill et al. J AAPOS 2001; 5:311-315; Sadiq et al. Semin Ophthalmol 2013; 28:313-320; Lieberman etal Am J Ophthalmol 1966;61:252-255; Harrison etal. Ophthalmology 1998;105:1886-1890; Ramsey etal. Am J Ophthalmol 1972;74:377-385; Couser etal. Ophthalmic Genet2017;38:91-94, each of which is incorporated by reference in its entirety), iridodonesis (see Mulvihill et al. J AAPOS 2001;5:311-315, which is incorporated herein by reference in its entirety), retinal arteriosclerosis (see Ghorbanihaghjo et al. Mol Vis 2008; 14:16921697, which is incorporated herein by reference in its entirety ), age-related macular degeneration (see Javadzadeh etal. Mol Vis 2010; 16:2578-2584; Seddon et al. Am J Ophthalmol 2006; 141:201203; Coral et al. Eye (Lond) 2006; 20:203- 207; Axer-Siegel et al. Am J Ophthalmol2004;137:84-89; each of which is incorporated herein by reference in its entirety), age-related maculopathy (AMD) (see Heuberger et al. Am J Clin Nutr 2002;76:897-902; Huang et al. Sci Rep 2015;5:10585, both incorporated herein by reference in their entirety), cataracts (see Sen et al. Indian J Clin Biochem 2008;23:255- 257; Yousefi et al. Protein Pept Lett 2013;20:932-941, both incorporated herein by reference in their entirety), diabetic retinopathy (possibly secondary to kidney disease) (see Looker et al. Diabetologia 2003; 46:766 -77 2; Pusparajah et al. Front Physiol 2016; 7:200, both incorporated herein by reference in their entirety) and macular and optic atrophy due to retinal vascular occlusion or nonarteritic ischemic optic neuropathy (see Gerth etal. J AAPOS 2008; 12:591-596; Stangeretal. Clin Chem Lab Med 2005 ; 43:1020-1025; Cahill et al. Am J Ophthalmol 2003; 136:1136-1150; Minniti et al. Eur J Ophthalmol 2014; 24:735-743; each of which is incorporated by reference in its entirety) . Studies investigating associations between Hcy levels and glaucoma provided inconsistent results. Some showed a positive relationship between Hcy levels and normal tension glaucoma, pseudoexfoliative glaucoma (PEXG) and primary open angle glaucoma (POAG), while others did not (see Lieberman et al. Am J Ophthalmol 1966;61 :252-255; Turkcu et al. Medicine (Kaunas) 2013;49:214-218; Vessan¡ et al. Am J Ophthalmol 2003;136:41-46; Leibovitch et al. J Glaucoma 2003;12:36-39 ; Leibovitzh et al. Relationship between homocysteine ​​and intraocular pressure in men and women: A population-based study. Medicine (Baltimore) 2016;95:e4858; Micheal et al. Mol Vis 2009;15:2268-2278; Clement et al. J Glaucoma 2009;18:73-78; Cumurcu et al. BMC Ophthalmol 2006;6:6; Bleich et al. J Neural Transm (Vienna) 2002;109:1499-1504; Lee et al. Curr Eye Res 2017;1 -6; Wang et al. Am J Ophthalmol 2004;137:401-406; each of which is incorporated herein by reference in its entirety). However, loss of retinal ganglion cells (RGCs), a common observation in people with glaucoma, was demonstrated in mice with endogenously elevated Hcy levels caused by deletion of the CBS gene, suggesting a probable link between glaucoma and elevated ivia / t / zuzz / u ι ι tHcy levels in patients with CBSDH (see Ganapathy et al., Invest Ophthalmol Vis Sci 2009;50:44604470, which is incorporated herein by reference in its entirety). 2. Mechanism Several mechanisms have been proposed to explain the effects of elevated Hcy levels on ocular health (see Ajith TA, Ranimenon; Clin Chim Acta 2015;450:316-321, which is incorporated herein by reference in its entirety). Mechanisms explaining the effects of elevated tHcy include altered vascular endothelial function, retinal ganglion cell apoptosis, extracellular matrix alterations, decreased lysyl oxidase activity and oxidative stress, as well as cytotoxic and proinflammatory effects. direct effects of Hcy, which appear to contribute to opacification of the lens and damage to the optic nerve. Potential mechanisms also include activation of the N-methyl-D-aspartate (NMDA) receptor, leading to cellular influx of calcium and increased production of reactive oxygen species (ROS), which contribute to cataract formation. These changes, together with the direct cytotoxic effects of Hcy, can cause endothelial injury, initiating thrombogenesis and apoptosis of RGCs, leading to retinopathy and glaucoma. Elevated levels of Hcy have also been shown to increase levels of asymmetric dimethylarginine (AMDA) and block the activity of nitric oxide synthase (NOS), causing vasoconstriction and optic nerve atrophy by decreasing nitric oxide (NO) levels. ). Finally, an accumulation of homocysteinylated proteins in the vascular wall can trigger the production of anti-Hcy antibodies and inflammatory responses, leading to phagocytosis, oxidative stress, RGC apoptosis, and alterations of the extracellular matrix (ECM). Together, these changes damage the vasculature, lens proteins, and optic nerve, ultimately leading to visual dysfunction. In patients with CBSDH, lens dislocation is considered to be mainly caused by degenerative changes in zonular fibers, in particular Cys-rich multidomain ECM proteins such as fibrillinal (see Sadiq et al. Semin Ophthalmol 2013; 28:313-320 ; Hubmacher et al. Biochemistry 2011; 50:5322-5332; Hubmacher et al. J Biol Chem 2005; 280:34946-34955; Hubmacher et al. J Biol Chem 2010; 285:1188-1198; each of which is incorporated here by reference in its entirety). In healthy individuals, the formation of numerous disulfide bonds within the domain within fibrillin-1 allows for precise protein folding, essential for structural integrity and function. Fibrillin-1 chains can then form interchain disulfide bonds, leading to the assembly of high molecular weight multiprotein assemblies known as microfibrils (see Kinsey et al. J Cell Sci 2008; 121: 2696-2704; Hubmacher et al. Proc Nati Acad Sci USA 2008;105:6548-6553, both incorporated herein by reference in their entirety). This process is largely dependent on interactions between fibrillin-1 and fibronectin (see Hubmacher et al. Biochemistry 2011; 50:5322-5332, which is incorporated herein by reference in its entirety). Microfibrils form a scaffold for the deposition of tropoelastin, an essential step in the formation of elastic fibers such as those found in the skin, lungs, blood vessels / arteries, ligaments, and the eye (see Hubmacher et al. J Biol Chem 2010; 285:1188- 1198, which is ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO incorporated herein by reference in its entirety). The importance of fibrillin-1 is illustrated by patients with Marfan syndrome, a condition caused by mutations in the fibrillin-1 gene, where connective tissue dysfunction is associated with symptoms such as lens dislocation, organ prolapse , osteoporosis and joint hypermobility (see Suk et al., J Biol Chem 2004, 279:51258-51265; Collod-Beroud et al. Hummutat 2003; 22:199-208, both incorporated herein by reference in their entirety). In vitro studies showed that the addition of Hcy to fibrillin-1 disrupted the formation of disulfide bonds, which in turn led to abnormal protein folding, increased susceptibility to proteolytic degradation, and abnormal ECM and fiber formation. elastic (see Hubmacher et al. J Biol Chem 2010; 285: 1188-1198, Whiteman et al., Antioxid Redox Signal 2006, 8:338346, both incorporated herein by reference in their entirety). The addition of Hcy to human dermal fibroblasts was also associated with reduced forms of fibronectin that bound fibrillin-1 suboptimally, thus preventing microfibril formation (see Hubmacher et al. Biochemistry 2011; 50:5322-5332; Hubmacher et al J Biol Chem 2010; 285:1188-1198, both incorporated herein by reference in their entirety). In addition to lens dislocation, degeneration of zonular fibers in patients with CBSDH can lead to increased lens curvature, lenticular myopia, astigmatism, retinal detachment, strabismus, cataract and iridodonesis (see Sadiq et al. Semin Ophthalmol 2013; 28:313-320, which is incorporated herein in its entirety by reference). If left untreated, anterior lens dislocation can cause acute pupillary block glaucoma. In extreme cases, complete dislocation of the lens is associated with increased ocular axial length, possibly a compensatory reaction to blurred vision (see Mulvihill et al. J AAPOS 2001; 5:311-315, which is incorporated herein by reference in its whole). A retrospective study of 25 cases of CBSDH detected in Ireland between 1971 and 1996, either by the national NBS program or by clinical presentation, was conducted to examine the effects of Hcy-lowering therapies on clinical outcomes (see Yap et al. al. J Inherit Metab Dis 1998; 21:738-747, which is incorporated herein by reference in its entirety). The majority of cases (24 / 25) did not respond to pyridoxine. Consequently, treatment for most patients consisted of a Met-free diet, supplemented with Cys, with vitamin B12 and folate supplementation, if necessary. Treatment was started before 6 weeks of age for the patients and was compared with a different group where treatment started at the time of diagnosis and a control patient who was never treated. The mean follow-up period was 14.3 years (range 2.5 to 23.4) in the groups treated before 6 weeks of age and 14.7 years (range 11.7 to 18.8) for the rest of the groups. patients, resulting in a total of 365.7 patient years of treatment. Of the 21 patients detected by NBS, 18 remained free of complications during treatment. Of these individuals, 15 / 18 had 20:20 vision and 3 / 18 had had increasing myopia over the previous two years. Consistent with the findings of Mudd et al. (see Mudd et al. Am J Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety), lens dislocation in late-diagnosed individuals occurred around two years of age. Lens dislocation was not reported in ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO none of the people treated early who complied well with therapy. Three of the early-treated patients (those with the highest fHcy levels) had worsening myopia without lens dislocation, which was likely due to the relatively high fHcy levels in this small group of patients. This led the authors to suggest that progressive myopia could be the first sign, before lens dislocation, of poor dietary compliance, despite the patient's insistence to the contrary. The worsening of myopia in these patients highlights how tenuous the balance between neutral and negative clinical outcomes is for these patients. All patients detected late developed ectopia lentis. This suggests that the treatment may delay the onset of lens dislocation, rather than prevent it. Median lifetime plasma fHcy levels were higher in patients with myopia than in those without myopia (18, 18, and 48 μmol / L vs. 11 μηποΙ / L, respectively). Of the three patients identified by NBS who developed complications in the group where treatment was started after diagnosis, all did not comply with their diets. Overall, 6 / 24 patients had lens dislocation; of these, two had an early diagnosis but did not adhere to their diets and four had a late diagnosis, including the only patient who was never treated. Consistent with the findings of Mudd et al. (see Mudd etal. Am J Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety), lens dislocation in individuals with late diagnosis (i.e., patients who had complications after 2 years ) occurred at approximately two years of age. At the time the study was published, none of the early-treated people with good compliance had reported lens dislocation. Compliant patients maintained their fHcy levels at equivalent tHcy levels largely below 120 μίτιοΙ / ί. However, all patients were under 24 years of age at the time of publication and many were still pediatric patients. Compliance with a protein-restricted diet has been shown to decline rapidly from adolescence to adulthood. The delicate balance described above suggests that the modest reduction in tHcy levels that these patients achieved may delay the onset of symptoms rather than prevent them as these patients age. These results (see Yap et al. J Inherit Metab Dis 1998; 21:738-747; Mudd et al. Am J Hum Genet 1985; 37:1-31; each of which is incorporated herein by reference in its entirety) were supported by those from a similar case-control study, conducted in Qatar, reporting outcomes, including vision disorders, in 32 CBSDH cases and 25 sibling controls (see El Bashir et al. JIMD Rep 2015; 21:89-95, which is incorporated herein by reference in its entirety). The mean age of the subjects was 11.2 years, (range 0.6 to 29) and 56% were men. Overall, 9 / 32 cases (28%) were diagnosed by NBS and treated in the first month of life. The rest were diagnosed between 14 and 240 months of age. tHcy and Met levels were significantly lower among those diagnosed through NBS compared to those diagnosed clinically. This was possibly attributed to better compliance with diet and medications early in life. None of the 9 cases identified by NBS had vision problems at the time the study was published, compared IVIA / t / ZUZZ / U I ÍVÓO with 18 (78%) in the group with late diagnosis (p <0.001 between groups). However, similar to the Irish study of 25 patients described above, patients in this study ranged in age from 0.6 to 29 years, and long-term complications are not yet known. A comparison of data from Yap and Naughten (see Yap et al. J Inherit Metab Dis 1998; 21:738747, which is incorporated herein by reference in its entirety) with the Kaplan-Meier curves produced by Mudd et al. showed that the proportion of patients with lens dislocation and osteoporosis who were compliant with treatment and 'treated early' was significantly lower than expected for untreated CBSDH patients (p<0.001). Therefore, an elevated Hcy level is considered an important and independent risk factor for ocular complications, in particular, lens dislocation, in patients with CBSDH and in the general population (e.g., as shown in Yap et al. and Mudd et al.). This highlights the need for early diagnosis and treatment of CBSDH, as well as patient compliance with treatment. B. Skeletal complications CBSDH is associated with an increased risk of osteoporotic fractures that may be attributed in part to low bone mineral density (see Mudd et al. and Weber et al. Mol Genet Metab 2016;117:351-354; each is incorporated herein by reference in its entirety). A retrospective review of data from 19 patients with CBSDH over 8 years found that low bone mineral density (BMD) was common among pediatric and adult patients with CBSDH (see Weber et al.). This study suggested that bone mass accumulation during childhood and adolescence, a critical period for skeletal growth, is deficient in CBSDH and may have a negative impact on the achievement of maximum bone mass. This study also highlighted how even diet-compliant patients with moderately elevated tHcy levels of only 5 times above the normal range already suffer from poor skeletal clinical outcomes in childhood. According to Mudd et al., 80% of patients with CBSDH develop osteoporosis before the age of 30. Furthermore, elevated Hcy levels are associated with an increased risk of osteoporotic fractures, even in patients without CBSDH (see Sato et al. Bone 2005,36:721-726; van Meurs et al. N Engl J Med 2004; 350: 2033-2041; McLean et al. N Engl J Med 2004; 350: 2042-2049; each of which is incorporated herein by reference in its entirety). A retrospective review of data from 19 subjects (9 men, 3.5 to 49.2 years of age) who underwent clinical DXA bone densitometry between 2002 and 2010 found that low BMD was common among pediatric and adult patients with CBSDH ( see Weber et al. Mol Genet Metab 2016;117:351-354, which is incorporated herein by reference in its entirety). At the time of the first DXA scan, the mean lumbar spine (LS) BMD Z score was -1.2 ±1.3, and the total hip BMD Z score was -0.89 ± 0.4; both were significantly less than 0 (the expected mean Z score in the general population) with p=0.002 and 0.02, respectively. The LC BMD Z score at diagnosis was -1.26 ± 1.4 in patients <21 years of age and -1.06 ± 1.1 in adults. 38% of patients ΜΛ / Ε / ΖυΖΖ / υΊ fVÓO had low BMD for age (defined by a Z score <-2). tHcy and Met levels were positively associated with LS BMD Z score in multiple linear regression models (see Weber et al Mol Genet Metab 2016; 117:351-354, which is incorporated herein by reference in its entirety) . The mean tHcy levels for these 19 individuals were only 59.2pmol / L, and the majority of the 19 patients were pediatric. This study suggests that the accumulation of bone mass during childhood and adolescence, a critical period for skeletal growth, is deficient in CBSDH and may have a negative impact on achieving maximum bone mass. This study also highlights how patients compliant with the diet with moderately elevated tHcy levels of only 5 times above the normal range already suffer poor skeletal clinical outcomes in childhood. Previous studies have demonstrated clear relationships between Hcy levels and fracture risk in elderly populations (see Sato et al. Bone 2005,36:721-726; van Meurs et al. N Engl J Med 2004;350:2033 -2041; McLean et al. N Engl J Med 2004;350:2042-2049; each of which is incorporated herein by reference in its entirety). Results from two prospective population-based studies, including 2406 subjects aged 55 years or older, showed that age- and sex-adjusted fracture risks increased by 30% for each one SD increase in tHcy level ( see van Meurs et al. N Engl J Med 2004;350:2033-2041; which is incorporated herein by reference in its entirety). A homocysteine ​​level in the highest age-specific quartile was associated with a factor of 1.9 increase in fracture risk. Associations between homocysteine ​​levels and fracture risk appeared to be independent of bone mineral density and other potential fracture risk factors. An elevated homocysteine ​​level was a significant and independent risk factor for osteoporotic fractures in older men and women in the general population, of similar magnitude to established risk factors for fractures and cardiovascular diseases (see van Meurs et al. N Engl J Med 2004;350:2033-2041; which is incorporated herein by reference in its entirety). Furthermore, a prospective study from the U.S. of 825 men and 1174 women (substudy of the HOPE-2 trial) found that a serum tHcy level in the highest quartile was associated with a 1.9-fold increased risk of hip fractures among women and a four-fold increased risk of hip fractures. hip among women, higher risk among men, compared with serum tHcy levels in the lowest quartile (see Sawka et al. Arch Intern Med. 2007 Oct 22;167(19):2136-9, which is incorporated herein by reference in its entirety). Associations between tHcy levels and fracture risk were independent of BMD and other potential fracture risk factors (see van Meurs et al. N Engl J Med 2004;350:2033-2041; McLean et al. N Engl J Med 2004,350: 2042-2049; Sawka et al. Arch Intern Med. 2007 Oct 22;167(19):2136-9; each of which is incorporated herein by reference in its entirety). Consistent with these results, a study in 433 stroke patients, older than 65 years, found that age-adjusted incidence rates per 1000 person-years for hip fractures increased almost linearly from 2.89 in the lowest quartiles of Hcy levels to 27.87 in the highest quartiles (see Sato et al. Bone 2005; 36:721-726, which is incorporated herein by reference in its entirety). Together, these results suggest that elevated Hcy levels are an important and independent risk factor for osteoporotic fractures in older men and women. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Skeletal abnormalities are not present at birth and are unusual in infants and very young children (see Mudd et al. Am J Hum Genet 1985;37:1-31, which is incorporated herein by reference in its entirety). The first signs of skeletal involvement are usually sergenu valgum and pes cavus, with elongation of the long bones, a typical feature of Marfan syndrome, which often develops around puberty (see Morris et al. J Inherit Metab Dis 2017;40 :49-74; which is incorporated herein by reference in its entirety). Osteoporosis, especially of the vertebrae and long bones, is common in patients with CBSDH and can lead to scoliosis / kyphosis and / or vertebral collapse (see Mudd et al. Am J Hum Genet 1985;37:1-31; Weber et al. Mol Genet Metab 2016;117:351-354; each of which is incorporated herein by reference in its entirety). Other skeletal manifestations may include marfanoid facial features caused by prominent upper teeth and high palate and anterior chest wall deformities, such as pectus excavatum or carinatum (see Morris et al. J Inherit Metab Dis 2017;40:49-74; Sweetser et al N Engl J Med 2016;375:1879-1890; Brenton et al. J Bone Joint Surg Br 1972;54:277-298; each of which is incorporated herein by reference in its entirety). Because of these shared skeletal features between Marfan syndrome and CBSDH, patients with CBSDH are sometimes mischaracterized as Marfan patients. J Bone Joint Surg Br 1972;54:277-298; each of which is incorporated herein by reference in its entirety). Because of these shared skeletal features between Marfan syndrome and CBSDH, patients with CBSDH are sometimes mischaracterized as Marfan patients. A study in 25 Irish patients with CBSDH followed for 25 years found that the risk of osteoporosis was significantly lower in patients identified through newborn screening with good compliance with Hcy-lowering treatment (diet, vitamins and / or betaine), compared with non-compliant patients or in those with a late diagnosis (see Yap et al. J Inherit Metab Dis 1998;21:738-747). Supporting evidence for these results came from a small Korean study in five CBSDH patients with good long-term metabolic control. In this study, patients who received early Hcy-lowering therapy had fewer skeletal abnormalities than those with a later diagnosis (see Lim et al. Osteoporos Int 2013, 24:2535-2538, which is incorporated herein by reference in its entirety). . Finally, in a study using a murine model for CBSDH, normalization of tHcy levels by treatment with CBS ET was associated with prevention of osteoporosis (see Majtan et al. Enzyme replacement prevents neonatal death, liver damage and osteoporosis in murine homocystinuria, FASEB J 2017, which is incorporated herein by reference in its entirety). The precise mechanisms leading to low BMD and skeletal fragility in patients with CBSDH are not fully understood (see Weber et al. Mol Genet Metab 2016; 117:351-354; Lim JS, Lee DH. Changes in bone mineral density and body composition of children with well-controlled homocystinuria caused by CBS deficiency (Osteoporos Int 2013; 24:2535-2538, all of which are hereby incorporated by reference). However, many of the connective tissue disorders in Patients with CBSDH resemble those seen in Marfan syndrome, a connective tissue disorder caused by mutations in the fibrillin-1 gene and characterized by features including ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO elongation of long bones and osteoporosis-type fractures (see Hubmacher et al., Biochemistry 2011; 50:5322-5332; Hubmacher et al. J Biol Chem 2010; 285:1188-1198, the which are hereby incorporated by reference in their entirety). Elevated levels of Hcy are thought to lead to bone fragility and fractures through two distinct pathways (see Behera et al. J Cell Physiol 2016, which is incorporated herein as reference in its entirety). The former results in reduced bone mass accumulation during childhood and adolescence through impaired fibrillin assemblies. The second pathway leads to impaired bone remodeling, resulting in brittle bones through decreased collagen cross-linking (see Behera et al. J Cell Physiol 2016; Kang et al. J Clin Invest 1973; 52 :2571-2578, both incorporated herein by reference in their entirety). Together, these data suggest that bone mass accumulation during childhood and adolescence, a critical period for skeletal growth, is deficient in patients with CBSDH and that this negatively affects the achievement of maximum bone mass. Furthermore, there is a strong relationship between Hcy levels and fracture risk in elderly populations (see Sato et al. Bone 2005; 36:721-726; van Meurs et al. N Engl J Med 2004; 350:2033 -2041; McLean et al., N Engl J Med 2004, 350:2042-2049, each of which is incorporated herein by reference in its entirety). Results from two international prospective population-based studies, including 2406 subjects aged 55 years or older, showed that a homocysteine ​​level in the highest age-specific quartile was associated with an increase of one factor. 1.9 in fracture risk (see van Meurs et al., N Engl J Med2004, 350:2033-2041, which is incorporated herein by reference in its entirety). An elevated homocysteine ​​level was a strong and independent risk factor for osteoporotic fractures in older men and women in the general population, similar in magnitude to that of established risk factors for fractures (low bone mineral density, cognitive impairment, recent falls ) and for cardiovascular disease (see van Meurs et al. N Engl J Med 2004;350:2033-2041, which is incorporated herein by reference in its entirety). Furthermore, a prospective study from the U.S. of 1,999 subjects (substudy of the HOPE-2 trial) found that a serum tHcy level in the highest quartile was associated with a 1.9-fold increased risk of hip fractures among women and a four-fold increased risk among women, men, compared to serum tHcy levels in the lowest quartile (see Sawka et al. Arch Intern Med. 2007 Oct 22;167(19):2136-9, which is incorporated herein by reference in its entirety) . Associations between tHcy levels and fracture risk were independent of BMD and other potential fracture risk factors (see van Meurs et al. N Engl J Med 2004; 350:2033-2041; MacLean et al. N Engl J Med 2004;350:2042-2049; Sawka et al. Arch Intern Med. 2007 Oct 22;167(19):2136-9, each of which is incorporated herein by reference in its entirety). Consistent with these results, a study in 433 stroke patients, older than 65 years, found that age-adjusted incidence rates per 1000 person-years for hip fractures increased almost linearly from 2.89 in the older quartiles. low Hcy levels to 27.87 in the highest quartiles (see Sato et al. Bone 2005; 36:721-726, which is incorporated herein by reference in its entirety). Together, these results suggest that elevated Hcy levels are an important and independent risk factor for osteoporotic fractures in older men and women. 167 (19): 2136-9, ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO each of which is incorporated herein by reference in its entirety). Consistent with these results, a study in 433 stroke patients, older than 65 years, found that age-adjusted incidence rates per 1000 person-years for hip fractures increased almost linearly from 2.89 in the lowest quartiles of Hcy levels to 27.87 in the highest quartiles (see Sato et al. Bone 2005; 36:721-726, which is incorporated herein by reference in its entirety). Together, these results suggest that elevated Hcy levels are an important and independent risk factor for osteoporotic fractures in older men and women. The precise mechanisms leading to low BMD and skeletal fragility in patients with CBSDH are not fully understood (see Weber et al. Mol Genet Metab 2016; 117:351-354; Lim JS, Lee DH. Changes in bone mineral density and body composition of children with well-controlled homocystinuria caused by CBS deficiency (Osteoporos Int 2013; 24:2535-2538, all of which are hereby incorporated by reference). However, many of the connective tissue disorders in Patients with CBSDH resemble those seen in Marfan syndrome, a connective tissue disorder caused by mutations in the fibrillin-1 gene and characterized by features including elongation of long bones and osteoporosis-like fractures (see Brenton et al. al., J Bone Joint Surg Br 1972;54:277-298;Hubmacher et al. Biochemistry 2011;50:5322-5332;Hubmacher et al. J Biol Chem 2010;285:1188-1198, each of which is incorporated herein by reference in its entirety). In healthy individuals, fibrillin-1, together with collagen and elastin polymers, assembles to form the ECM, the architectural scaffolds for bone formation, homeostasis, and repair (see Olivieri et al. Fibrogenesis Tissue Repair 2010; 3:24 , which is incorporated herein by reference in its entirety). Studies show that elevated tHcy levels can lead to structural modifications of fibrillin-1 fragments, preventing multimerization and leading to fibrillin-1 degradation (see Hubmacher et al. J Biol Chem 2005;280: 34946-34955; Hubmacher et al. J Biol Chem 2010; 285:1188-1198, both incorporated herein by reference in their entirety). This process is further affected by homocysteinylation of fibronectin, which prevents the formation of fibronectin-fibrillin complexes necessary for multimerization of fibrillin-1 (see Hubmacher et al. Biochemistry 2011; 50:5322-5332, which incorporated here by reference in its entirety). Such findings suggest that elevated levels of Hcy have a detrimental effect on ECM formation. In healthy individuals, fibrillin bundles (i.e., microfibrils) play an important role in bone mineralization, through the storage and activation of transforming growth factor beta (TGF-beta) and bone morphogenetic proteins (BMPs) ( see Nistala et al. Ann NY Acad Sci 2010;1192:253-256; Nistala et al. J Biol Chem 2010;285:34126-34133, both incorporated herein by reference in their entirety). Impaired activation of TGF-beta and BMP could potentially contribute to the skeletal phenotype observed in both Marfan syndrome and CBSDH and could also decrease bone mineral content, as observed in mild forms of CBSDH (see Herrmann et al. Clin Chem 2005; 51:2348-2353, which is incorporated herein by reference in its entirety). Furthermore, there is evidence in vivo and in vitro that Hcy can weaken bone strength through the formation of decreased collagen cross-links (see Kang et al. J Clin Invest 1973; 52:2571-2578, which is incorporated herein IVIA / t / ZUZZ / U I ÍVÓO for reference in its entirety). Together, these data suggest that bone mass accumulation during childhood and adolescence, a critical period for skeletal growth, is deficient in patients with CBSDH and that this may have a negative impact on the achievement of maximal bone mass. In addition to its effects on bone deposition, elevated Hcy levels increase the rate of bone remodeling by increasing osteoclast (OC) activity and decreasing osteoblast (OB) activity (see Behera et al. J Cell Physiol 2016 ; Herrmann et al. Clin Chem 2005; 51:2348-2353; Vacek et al. Clin Chem Lab Med 2013; 51:579-590; Vijayan et al. J Endocrinol 2017; 233:243-255, each of which is incorporated herein by reference in its entirety). An imbalance between the activities of OB and OC can lead to brittle bones and a higher incidence of fractures. Mechanisms leading to Hcy-mediated decreases in OB activity are thought to include decreased bone blood flow (a consequence of decreased NO availability) (see Tyagi et al. Vasc Health Risk Manag 2011;7: 31-35, which is incorporated herein by reference), in its entirety) and increased rates of OB apoptosis (Figure 2 and Tables 14) (see Behera et al. J Cell Physiol 2016; Kim et al. Bone 2006; 39: 582590, both incorporated herein by reference in their entirety). Mechanisms leading to increased OC activity are thought to include increased levels of intracellular ROS, which enhance both OC differentiation and OC activity through increased matrix metalloproteinase (MMP) activity (see Vacek et al. . Clin Chem Lab Med 2013;51:579-590, which is incorporated herein by reference in its entirety) and suppression of OC apoptosis (see Behera et al. J Cell Physiol 2016; Herrmann et al. Clin Chem 2005; 51:2348-2353; Koh et al. J Bone Miner Res 2006; 21:1003-1011, each of which is incorporated herein by reference in its entirety). Indeed, a recent study in CD1 mice fed a high-Hcy diet showed that short-term (7 days) Hcy administration was associated with a loss of tissue mineral density (TMD) and an increase in the number of OCs, while that long-term (30 days) Hcy administration led to OC reprogramming, apoptosis, and mineralization, which restored TMD but compromised tissue biomechanical properties (see Vijayan et al. J Endocrinol 2017;233:243 -255, which is incorporated herein by reference in its entirety). Therefore, elevated Hcy levels can lead to bone fragility and fractures through two distinct pathways (see Behera et al. J Cell Physiol 2016, which is incorporated herein by reference in its entirety). The former results in reduced bone mass accumulation during childhood and adolescence, through impaired ECM formation and suppressed activation of TGF-beta and BMP associated with fibrillin-1. The second pathway leads to impaired bone remodeling, resulting in brittle bones, through an increase in OC and a decrease in OB activities. Elevated Hcy levels are associated with increased oxidative stress in the bone microenvironment. Increased ROS induces osteoblast apoptosis, which decreases osteoblast genesis. This increased oxidative stress further reduces NO availability through the production of superoxide anions, which could also decrease bone blood flow and angiogenesis. The ROS generated by this process activate osteoclast genesis through monocyte fusion, which further contributes to the loss of BMD, leading to osteoporosis. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO A recent study in neonatal CBS knockout (KO) mice, maintained on standard rodent chow without Met restriction, found that subcutaneous administration of a CBS ET, using recombinant PEGylated human truncated CBS (PEG-CBS) for 5 months , prevented the reduction of bone mass, mineral density in these animals, and could also normalize these values ​​in animals that were treated later in life (see Majtan et al. Enzyme replaces prevents neonatal death, liver harm, and osteoporosis in murine homocystinuria. FASEB J 2017, which is hereby incorporated by reference in its entirety). In this study, changes in body composition that characterize both the KO model and CBSDH patients were prevented. In both plasma and tissues, tHcy and Cys levels normalized, Cth levels increased, and SAM / SAH ratios improved. Supporting evidence for the effects of Hcy reduction on skeletal outcomes is derived from a 25-year survey of 25 Irish patients with CBSDH (see Yap et al. J Inherit Metab Dis 1998; 21:738-747, which incorporated here by reference in its entirety). In this study, osteoporosis (diagnosed by radiological examination, rather than DXA) was present in one of three non-adherent patients identified by NBS and in one of four patients with a late diagnosis (at two years old). None of the 18 patients who complied with early treatment (from 6 weeks of age) showed signs of osteoporosis. A small study was conducted in Korea on five patients with CBSDH (3 boys and 3 girls), all diagnosed at a young age (3 during NBS and 2 at 7 years), with good metabolic control for 3.4 years (see Lim et al. Osteoporos Int 2013;24:2535-2538, which is attached below), incorporated by reference in its entirety). The mean plasma tHcy level at diagnosis was 34.3 ± 52.6 (13 to 78.6)pmol / L. plasma Met was 716 ±1347.6 (24.3 to 1566)pmol / L and treatment consisted of a low Met diet with pyridoxine, betaine and folic acid supplements. Body composition measurements and BMD of all patients were within normal ranges for the Korean population, and no significant changes in skeletal morphology were observed over time. Three patients (60%) had mild TL spinal scoliosis (Cobb angles 7.3°, 7.6°, and 10.3°), and fractures were reported four times in three patients. Of these, two were caused by a sports injury and one by a traffic accident. Two cases of mild compression fracture of the lumbar spine were detected by radiography and a history of severe back pain was documented. Patients who received an early diagnosis showed fewer skeletal abnormalities than those with a late diagnosis. However, this study showed that even patients diagnosed early by NBS, who were compliant with dietary treatment and had mild to moderately elevated tHcy levels, already had skeletal abnormalities and multiple fractures as children. Together, these findings suggest a beneficial effect of early Hcy-lowering treatment on skeletal outcomes in patients with CBSDH. It should be noted that in patients who were compliant with treatment, tHcy levels were reduced, but not normalized, and although there were fewer skeletal abnormalities in these patients, significant negative clinical outcomes (osteoporosis and fractures) were observed in this group of patients. mostly young people. IVIA / t / ZUZZ / U I ÍVÓO C. Vascular complications The relationship between CBSDH and vascular disease was first demonstrated in 1985 in an epidemiological study in patients with moderately to severely elevated Hcy levels due to homozygous CBSDH (see Mudd et al. Am J Hum Genet 1985; 37:1- 31, attached below), incorporated by reference in its entirety). Thromboembolism is the main cause of morbidity and premature death in patients with CBSDH (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Karaca et al. Gene 2014; 534:197-203; Yap S. J Inherit Metab Dis 2003;26:259-265, each of which is incorporated herein by reference in its entirety). The overall rate of thromboembolic events in patients with untreated CBSDH is approximately 10% per year (see Cattaneo M. Semin Thromb Hemost 2006; 32:716-723, which is incorporated herein by reference in its entirety), and the risk increases after surgery and during or immediately after pregnancy (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Novy et al. Thromb Haemost 2010; 103:871-873, both incorporated herein by reference in their whole). Thromboembolism can affect any blood vessel, but venous thrombosis (particularly CSVT) is more common than arterial thrombosis in patients with CBSDH (see Mudd et aL Am J Hum Genet 1985; 37: 1-31; Karaca et al. Gene 2014;534:197203;Eslamiyeh et al., Iran J Child Neurol 2015;9:53-57;Sabou et al. J Child Neurol 2015;30:107-112, each of which is incorporated herein by reference in its entirety). Strokes, especially CSVT, have been described in infants (see Mahale et al. J Pediatr Neurosci. 2017 AprJun; 12(2):206-207, which is incorporated herein by reference in its entirety), although they occur more typically in young adults (see Yap et al. Arterioscler Thromb Vasc Biol 2001; 21:2080-2085, which is hereby incorporated in its entirety by reference). The risk of thromboembolic events was approximately 25% at age 16 years and 50% at age 29 years. In 1999, Hankey et al. reported that all three genetic causes of HCU (CBSDH, MTHFR deficiency, and vitamin B12 deficiency) were associated with a high risk of premature cardiovascular (CV) disease, affecting half of all homozygotes by the age of 30 years ( see Hankey et al. Lancet 1999;354:407-413, which is incorporated herein by reference in its entirety). The only biochemical change common to all three disorders is elevated serum Hcy levels (often greater than 100pmol / L) (see Faeh et al. Swiss Med Wkly 2006; 136:745-756, which is incorporated herein by reference in its whole). Several reports described how treatments that lower tHcy levels significantly reduced the incidence of vascular events, the main cause of morbidity, in patients with CBSDH (see Yap et al. J Inherit Metab Dis 2001; 24:437-447; Wilcken DE , Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment (J Inherit Metab Dis 1997; 20:295-300, both incorporated herein by reference in their entirety). Since then, several other studies have demonstrated a increased risk of vascular events, particularly venous thrombosis, in patients with CBSDH (see Karaca et al. Gene 2014; 534:197-203; Kelly et al. Neurology 2003; 60:275-279, Lussana et al., Thromb Res 2013,132:681-684, Magner et al. J Inherit Metab Dis 2011;34:33-37, each of which is incorporated herein by reference in its entirety). ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO An elevated plasma level of tHCy is a risk factor for vascular disease and a strong predictor of mortality in patients with coronary artery disease, with and without CBSDH (see Mudd et al. Am J Hum Genet 1985; 37:1-31 ; Karaca et al. Gene 2014; 534:197-203; Kelly et al. Neurology 2003; 60:275-279; Faeh et al. Swiss Med Wkly 2006; 136:745-756; Boushey et al. JAMA 1995; 274 :1049-1057; Clarke R etal. JAMA 2002; 288:2015-2022; Hankey etal. Lancet 1999; 354:407-413; Khan et al. Stroke 2008; 39:2943-2949; Graham et al. The European Concerted Action Project. JAMA 1997;277:1775-1781; Clarke et al. N Engl J Med 1991; 324:1149-1155; Clarke et al. Ir J Med Sci 1992; 161:61-65; Woodward et al. Blood Coagul Fibrinolysis 2006;17:1-5;Refsum et al. Annu Rev Med 1998;49:31-62;Yoo et al. Stroke 1998;29:2478-2483;Selhub etal. N Engl J Med 1995;332:286- 291; Wald etal. BMJ 2002; 325:1202; Bautista etal. J Clin Epidemiol 2002; 55:882-887; Brattstrom et al. Atherosclerosis 1990; 81:51-60; Lussana et al. Thromb Res 2013; 132:681-684; Casas et al. Lancet 2005; 365:224-232; McCully KS. Am J Pathol 1969; 56:111-128; Magner et al. J Inherit Metab Dis 2011; 34:33-37; Wilcken et al. J Clin Invest 1976; 57:1079-1082; Nygard et al. N Engl J Med 1997; 337:230-236; each of which is incorporated herein by reference in its entirety). Although there is evidence of a relationship between tHcy levels and CV risk (see Boushey et al. JAMA 1995;274:1049-1057, which is incorporated herein by reference in its entirety), the relationships between tHcy and stroke / disease peripheral arterial pressure are considerably stronger (see Clarke et al. JAMA 2002; 288:2015-2022; Khan et al. Stroke 2008; 39:2943-2949; Wald et al. BMJ 2002; 325:1202; Casas et al. Lancet 2005;365:224-232; Brattstrom et al. Hemostasia 1989;19 Suppl 1:35-44; each of which is incorporated herein by reference in its entirety). Although large studies (NORVIT, HOPE-2, VITATOPS) in the general population initially concluded that reducing Hcy levels had a minor effect on major vascular events and recurrent cardiovascular disease, further more specific analysis of the data has clearly demonstrated the clinical benefits of tHcy reduction in stroke. There is considerable evidence that lowering Hcy decreases the risk of stroke in the general population with mildly elevated tHcy levels (see Saposnik et al. Stroke 2009; 40: 1365-1372; Huo et al. JAMA 2015; 313: 1325 -1335;Lonn et al. al. N Engl J Med 2006;354:15671577;Hankey et al. Lancet Neurol 2012;11:512-520;Spence JD, Lancet Neurol. 2007 Sep;6(9):830-8 , each of which is hereby incorporated by reference in its entirety). In the HOPE-2 study (see Saposnik et al. Stroke 2009; 40:1365-1372, which is incorporated herein by reference in its entirety) of 5552 patients, minor reductions in tHcy levels (3mmol / L vs placebo) led to a significant reduction in stroke incidence (27% relative risk reduction, 1.3% absolute risk reduction), suggesting that even small decreases in tHcy levels may be beneficial. This effect was most pronounced in patients with baseline Hcy in the top quartile who had a 4.3% absolute risk reduction. Although it is unclear whether lowering Hcy affects overall CV outcomes in patients with mildly elevated tHcy and without CBSDH (see Marti-Carvajal et al. Cochrane Database Syst Rev 2015;1:CD006612, which is incorporated herein by reference in its entirety ), Semin Thromb Hemost 2000; 26:335-340; Ruhoy et al. Pediatr Neurol 2014; 50:108-111, each of which is incorporated herein by reference in its entirety). Semin Thromb Hemost 2000; 26:335-340; Ruhoy ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO et al. Pediatr Neurol 2014; 50:108-111, each of which is incorporated herein by reference in its entirety). 1. Mechanism Several studies have shown that elevated levels of Hcy contribute to the development of atherosclerosis or thrombosis through mechanisms associated with oxidative stress (see Faverzani et al. Cell Mol Neurobiol 2017; Nowak et al. Arterioscler Thromb Vasc Biol 2017;37:e41- e52; Vanzin et al. Mol Genet Metab 2011;104:112-117; Vanzin etal. Gene 2014;539:270-274; Vanzin et al. Cell Mol Neurobiol 2015;35:899911; each of which is incorporated herein for reference in its entirety), including inflammatory and immune activation through NF-κΒ (see Rodriguez-Ayala et al. Atherosclerosis 2005; 180: 333-340; van Guldener et al. Curr Hypertens Rep 2003; 5: 26- 31, both of which are incorporated herein by reference in their entirety). Medial damage leading to thrombosis is thought to be caused by Hcy-mediated endothelial dysfunction (see Jiang et al. Arterioscler Thromb Vasc Biol 2005; 25:2515-2521; Hossain et al. J Biol Chem 2003; 278:30317 -30327; Cay et al. Sangre 2000; 96:2140-2148; Zhang et al. J Biol Chem 2001; 276:35867-35874; Papapetropoulos et al. Proc Nati Acad Sci USA 2009; 106:21972-21977; Szabo et al. BrJ Pharmacol 2011;164:853-865; Chiku et al. J Biol Chem 2009; 284:11601-11612; Wang et al. Antioxid Redox Signal 2010; 12:1065-1077; Saha et al. FASEBJ 2016; 30 :441-456; Ebbing et al. JAMA 2008; 300:795-804; Bonaa et al. N Engl J Med 2006; 354:1578-1588; Martí-Carvajal et al. Cochrane Database Syst Rev 2015;1: CD006612; Celermajer et al. J Am Coll Cardiol 1993; 22:854-858; Ruba et al. Metabolism 1990; 39:1191-1195; each of which is incorporated herein by reference in its entirety), improved coagulation pathways (see Spence JD. IntJStroke. 2016 Oct; 11(7)744-7; Fryeretal. ArteriosclerThromb 1993; 13:13271333; Lentzetal. J Clin Invest 1991; 88:1906-1914; each of which is incorporated herein by reference in its entirety) and increased vascular dilation. Such prothrombotic mechanisms are similar to those observed in patients with Marfan (see Kelly et al. Neurology 2003; 60:275-279; Tripathi P. International Cardiovascular Forum J 2016; 6:13; van Guldener et al. Curr Hypertens Rep 2003 De Valk et al., Stroke 1996, 27:1134-1136, each of which is incorporated herein by reference in its entirety), from Valk et al. stroke 1996; 27:1134-1136, each of which is incorporated herein by reference in its entirety), from Valk etal. stroke 1996; 27:1134-1136, each of which is incorporated herein by reference in its entirety). A causal relationship between tHcy levels and CV risk derived from a meta-analysis of data from 27 studies (more than 4000 patients) showed a graded risk of atherosclerosis of the CV, cerebrovascular and peripheral vessels, such that a 5μΜ increase in Hcy conferred an 80% increased risk for women and a 60% increased risk for men (see Boushey et al. JAMA 1995;274:1049-1057, which is incorporated herein by reference in its entirety). A meta-analysis of data from 30 prospective or retrospective studies including 5073 ischemic heart disease (IC) events and 1113 strokes found that a Hcy level 25% lower than usual (corrected for regression dilution bias) (approximately 3μmol / L) was associated with an 11% (odds ratio [OR], 0.89; 95% CI, 0.83 to 0.96) lower risk of Cl and a 19% (OR, 0.81; 95% CI, 0.69 to 0.95) lower risk of accident MA / IZ / ZUZZ / UI ÍVÓO cerebrovascular (see Clarke R, et al. JAMA 2002; 288:2015-2022, which is incorporated herein by reference in its entirety). A study in patients with and without preexisting vascular disease demonstrated an increase, after Met loading, in plasma Hcy (exceeding the highest values ​​in comparable healthy control subjects) in 1 / 21 subjects with MI (5%), 14 / 37 subjects with aortoiliac disease (38%) and 17 / 53 subjects with cerebrovascular disease (32%). This suggests that the links between Hcy levels and peripheral arterial disease (PAD) and stroke are considerably greater than the link between Hcy levels and MI (see Brattstrom et al. Haemostasis 1989;19 Suppl. 1: 35-44, which is incorporated herein by reference in its entirety). In a prospective study among a UK cohort of 457 stroke patients and 179 community-matched control subjects, an independent, graded association between Hcy levels and stroke was described (see Khan et al. Stroke 2008;39:2943-2949).pmol / L in control subjects without stroke, p<0.001 after adjusting for age, sex, vascular risk factors, vitamin levels and renal function). Within SVD cases, the highest Hcy levels were observed in individuals with lacunar infarction with confluent leukoaraiosis. Furthermore, there was a correlation between Hcy levels and the severity of leukoaraiosis (r = 0.225; p < 0.001). These findings were further supported by a Mendelian randomization study, which demonstrated a genetic association between MTHFR polymorphisms that regulate Hcy metabolism and stroke risk (see Casas et al. Lancet 2005;365:224-232, which is incorporated herein by reference in its entirety). A literature search of all relevant studies on associations between Hcy levels and MTHFR TT and CC polymorphisms on stroke risk identified 111 studies, including 15,635 individuals without cardiovascular disease (CVD). The weighted mean difference in Hcy levels between TT and CC homozygotes was 1.93pmol / L (95% CI: 1.38 to 2.47). Based on the results of a previous meta-analysis of prospective studies, where a 5 pmol / L increase in plasma Hcy levels corresponded to an OR for stroke of 1.59 (1.29 to 1.96), a 1.93 μmol / L increase in Hcy levels in healthy individuals with the TT genotype would result in an expected OR for stroke of 1.20 (1.10 to 1.31) (see Wald et al. BMJ 2002; 325:1202, which is incorporated herein by reference in its entirety). Consistent with this result, Khan et al. reported an OR of 1.26 (1.14 to 1.40) for stroke for TT versus CC homozygotes (p = 0.29), regardless of age group, ethnicity, or geographic location. Together, these results suggested a causal role for elevated Hcy levels in the pathogenesis of stroke in the general population. Yes, moderate increases in serum Hcy are typical in patients with heterozygous CBSDH because the vascular disease has been examined in much smaller studies than those conducted in the general population. According to Mudd et al, the risk of vascular events in patients with mildly elevated tHcy levels due to heterozygous CBSDH (<5% at age 50 years) is similar to that of the general population (see Mudd et al. Am J Hum Genet 1981; 33:883-893, which is incorporated herein by reference in its entirety). Consistent with this, an ultrasound study in individuals with homozygous and heterozygous CBSDH found altered endothelial function in the systemic arteries of homozygous children as young as four years of age, ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO while endothelial function was largely unaffected in heterozygous adults (see Celermajer et al. J Am Coll Cardiol 1993; 22:854-858, Although a similar study demonstrated signs of premature arterial disease in both homozygotes and heterozygotes, individuals with the homozygous disorder developed signs at a much younger age (19 years versus 45 years) and the severity of the disease was considerably greater (see Rubba et al. Metabolism 1990;39:1191-1195, which is incorporated herein by reference in its entirety). Overall, observations in patients with CBSDH were consistent with those of previous studies, with vascular risk increasing with Hcy levels (see Boushey et al.JMAA 1995; 274:1049-1057; Clarkeet a / .JAMA 2002; 288:2015-2022; Kanet a / .Stroke 2008; 39:29432949; each of which is incorporated herein by reference in its entirety). These results suggest that an elevated Hcy level is a risk factor for CV disease. Furthermore, reducing Hcy levels has been shown to significantly reduce the risk of stroke in the general population and in patients with CBSDH. Studies have shown that elevated Hcy levels caused by CBSDH can potentially contribute to the development of atherosclerosis and / or thrombosis through several mechanisms. These include molecular events such as the induction of oxidative stress and its downstream effects, such as the activation of NF-κΒ (nuclear factor kappa light chain enhancer of activated B cells), a transcriptional factor that regulates pro-inflammatory and other associated genes. to damage. Various Hcy-mediated effects that modulate the physicochemical properties of the vascular wall, such as those that cause endothelial dysfunction or arterial stiffness, could contribute to the development of hypertension, thrombosis, or other vascular abnormalities. Finally, there is evidence for direct induction of coagulation pathways by Hcy, a more direct pathway leading to thrombosis (see Faverzani et al. Cell Mol Neurobiol 2017; Hainsworth et al. Biochim Biophys Acta 2016; 1862:1008-1017; Ganguly et al. Nutr J 2015;14:6; Tripathi P. Molecular and biochemical aspects of homocysteine ​​in cardiovascular diseases. International Cardiovascular Forum J 2016;6:13; fryer et al Arterioscler Thromb 1993;13:1327-1333; each one of which is incorporated herein by reference in its entirety). After a brief overview of the molecular and biochemical mechanisms of atherosclerosis, the subsections below will review the possible mechanisms leading to vascular disease in people with elevated tHcy levels, including those with CBSDH. 2. Atherosclerosis Among the best studied conditions that lead to thrombosis and, consequently, vascular blockage, is atherosclerosis, a progressive inflammatory disease that affects the coronary, cerebral and peripheral circulations (see Libby et al. Circulation 2005; 111:3481- 3488, which is incorporated herein by reference in its entirety). In its early stages, vascular injury leads to activation of endothelial cells (ECs), recruitment of monocytes into the intima, and activation of macrophages. An inflammatory atherosclerotic lesion (the fatty streak) forms, comprising macrophages MA / t / ZUZZ / U1 loaded with lipids (foam cells) derived from monocytes and T lymphocytes. The progressive accumulation of lipids forms a lipid core surrounded by a fibrous cover. During the later stages, activated macrophages secrete enzymes that weaken the fibrous cap, leading to plaque rupture, hemorrhage or thrombosis, and ischemic attacks / acute coronary syndrome. Plaque rupture exposes tissue factor to blood within the arterial lumen, allowing it to form complexes with coagulation factors Vll / Vlla. This process initiates the coagulation cascade, which leads to thrombogenesis. Ruptured plates can lead to mural or occlusive thrombosis, resulting in partial or complete blockage, respectively. Mural thrombosis causes ischemic symptoms, such as unstable angina, while occlusive thrombosis causes acute coronary events, such as myocardial infarction and stroke. Cytokines are involved in all stages of atherosclerosis and have a profound influence on its pathogenesis (see Ramji et al. Cytokine Growth Factor Rev 2015; 26: 673-685, which is incorporated herein by reference in its entirety). In addition to being secondary to atherosclerosis, thrombosis can also be activated in the absence of plaque formation, for example, as a consequence of atrial fibrillation or by direct activation of the coagulation cascade. 3. Oxidative stress Studies in patients with elevated Hcy levels showed that treated and especially untreated patients were susceptible to oxidative stress, as demonstrated by altered biomarkers reflecting oxidative lipid, protein and DNA damage in various tissues (see Vanzin et al. Mol Genet Metab 2011;104:112-117; Vanzin et al. Gene 2014;539:270-274; Vanzin et al. Cell Mol Neurobiol 2015;35:899-911, each of which is incorporated herein for reference in its entirety). Oxidative stress, defined as an imbalance in redox homeostasis, plays a key role in vascular pathologies such as atherosclerosis and its associated thrombosis, where oxidative modification of low-density lipoproteins, endothelial activation and the initiation of inflammatory responses are involved. vascular (see Nowak et aL Arterioscler Thromb Vasc Biol 2017;37:e41-e52, which is incorporated herein by reference in its entirety). Oxidative stress can be caused by elevated levels of ROS (e.g., superoxide (O2-) and hydroxyl radicals (HO-) and hydrogen peroxide (H2O2)) and / or by reduced levels of tissue antioxidants (e.g., superoxide dismutase , catalase and glutathione peroxidase) (see Faverzani et al. Cell Mol Neurobiol 2017; Nowak et al. Arterioscler Thromb Vasc Biol 2017;37: e41-e52, both incorporated herein by reference in their entirety). In healthy individuals, ROS are produced as byproducts of normal oxidative metabolism. However, in addition, ROS generation is triggered by CV risk factors such as cigarette smoke, alcohol consumption, hypercholesterolemia, hypertension, diabetes, and elevated Hcy levels. superoxide (O2-) and hydroxyl (HO-) and hydrogen peroxide (H2O2)) and / or by decreased levels of tissue antioxidants (e.g., superoxide dismutase, catalase and glutathione peroxidase) (see Faverzani et al. Cell Mol Neurobiol 2017; Nowak et alL, Arterioscler Thromb Vasc Biol 2017;37: e41-e52, all of which are incorporated herein by reference). In healthy individuals, ROS are produced as byproducts of normal oxidative metabolism. However, in addition, the generation of ROS ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO is triggered by CV risk factors such as cigarette smoke, alcohol consumption, hypercholesterolemia, hypertension, diabetes, and elevated Hcy levels. At the molecular level, there are numerous ways in which Hcy could cause increased oxidative stress, some discussed above. For example, the accumulation of homocysteinylated immunogenic proteins in the vascular wall could promote inflammation and, consequently, the generation of ROS (O2-) by activated phagocytes). Another potential mechanism is Hcy-induced activation of NMDA receptors, which activates signaling pathways leading to ROS generation. In cardiac microvascular ECs, Hcy induced elevated levels of NADPH oxidase, cell surface enzymes that, especially in activated cells, produce high levels of O2-. A recent study (see Chen et al. Sci Rep. 2017 Jul 31 ;7(1):6932, which is incorporated herein by reference in its entirety) suggested that, in the ischemic rat brain, Hcy induced mitochondrial dysfunction, with the expected result of increased ROS production. Hcy is also thought to decrease the bioavailability of the beneficial vasodilator NO. O2-reacts with NO to produce the reactive nitrogen species peroxynitrite and, in fact, an Hcy-induced increase in tyrosine nitration, an indicator of peroxynitrite-induced protein damage, has also been reported (see Tyagi et al. Vasc Health Risk Manag 2011; 7:31-35, which is incorporated herein by reference in its entirety). More generally, thiol-thiol interactions involving Hcy would be expected to perturb the cellular redox state, for example, potentially decreasing the availability of reduced glutathione and even affecting protein assembly and folding. In a study of patients with CBSDH before and after treatment, treatment with pyridoxine, folate, betaine, and vitamin B12 supplements attenuated oxidative lipid damage in patients but did not change sulfhydryl content or total antioxidant status, both indicators of the antioxidant capacity of tissues. However, there was a significant negative correlation between the content of sulfhydryl groups and Hcy levels, and a positive correlation between the levels of the lipid peroxidation product malondialdehyde and those of Hcy. This suggested a potential mechanistic role for Hcy in the oxidative damage observed in CBSDH (see Vanzin et al. Mol Genet Metab 2011; 104:112-117, which is incorporated herein by reference in its entirety). Altered lipid profiles, particularly reduced levels of high-density lipoproteins and enrichment of pro-inflammatory lipid species, Cell Mol Neurobiol 2015; 35:899-911, which is incorporated herein by reference in its entirety). In another study, significantly more DNA damage was reported in patients with CBSDH than in healthy individuals (see Vanzin et al. Gene 2014;539:270-274, which is incorporated herein by reference in its entirety). Together, these findings implicate oxidative stress in the pathogenesis of vascular damage associated with elevated Hcy levels. No correlation was found between Met levels and any parameter associated with oxidative stress, suggesting that Met and its derivatives contribute little to oxidative damage in CBSDH (see Vanzin et al. Mol Genet Metab 2011; 104: 112-117, which is incorporated herein by reference in its entirety). Among a plethora of other molecular effects, oxidative stress is associated with the activation of NF-κΒ, a group of transcription factors that regulate the expression of pro-inflammatory genes, such as cytokines, known to be involved in the initiation and progression of atherosclerosis and thrombosis (see Rodríguez-Ayala et al., Atherosclerosis 2005; 180:333-340, which is incorporated here by reference in its ΜΛ / Ε / ΖυΖΖ / υΊ fVÓO entirety). In vitro studies showed that treatment of ECs with Hcy activated NF-kp through the production of ROS (see van Guldener et al. Curr Hypertens Rep 2003; 5:26-31, which is incorporated herein by reference in its entirety ). In addition to modulating gene expression, chemical modification of cellular macromolecules by oxidative stress can directly impact the structure and function of the vasculature and have other localized or systemic effects. 4. Changes in the vascular wall Endothelial dysfunction is generally defined as an imbalance between endothelium-associated factors that modulate vascular contractility and relaxation. Among these factors, NO or “endothelium-derived relaxation factor” is the best known, while hydrogen sulfide (H2S) is another more recently described (see Jiang et al. Arterioscler Thromb Vasc Biol 2005; 25:2515- 2521, which is hereby incorporated by reference in its entirety). Several in vitro studies examined the effects of Hcy on endothelial function, albeit using very high levels of Hcy (see Jiang et al. Arterioscler Thromb Vasc Biol 2005; 25:2515-2521; Hossain et al. J Biol Chem 2003; 278: 30317- 30327; Caí et al. Blood 2000; 96:2140-2148; Zhang et al. J Biol Chem 2001; 276:35867-35874; each of which is incorporated herein by reference in its entirety). One such study reported an unfolded protein response and programmed cell death in human umbilical vein endothelial cells (HUVECs) treated with Hcy, although Hcy concentrations were several times higher than those observed in patients with severely elevated Hcy levels ( see Zhang et al. J Biol Chem 2001;276:35867-35874, which is incorporated herein by reference in its entirety). In other reports, Cth gamma-lyase (CGL), an enzyme involved in Cth metabolism, generated excess H2S in patients with elevated Hcy levels (see Papapetropoulos et al. Proc Nati Acad Sci USA 2009; 106:21972 -21977; Szabo C et al. al. Br J Pharmacol 2011; 164:853-865; Chiku et al. J Biol Chem 2009; 284:11601-11612, each of which is incorporated herein by reference in its entirety) . This observation was important because increasing H2S levels have been reported to significantly increase collateral vessel growth, capillary density, and regional tissue blood flow (see Wang et al. Antioxid Redox Signal 2010;12:1065-1077, which is incorporated herein by reference in its entirety). However, high levels of Hcy (0.002 to 2 mM) did not significantly affect EC proliferation or phospho-eNOS levels in vitro (see Saha et al. Cystationine betasynthase regulates endothelial function via protein S-sulfhydration. FASEB J 2016 ; 30:441-456, which is incorporated herein by reference in its entirety). Overall, these results suggest a possible role for Hcy in endothelial dysfunction, although it is still unclear whether Hcy directly affects ECs in vivo due to the high levels of Hcy tested in vitro. Cystathionine beta-synthase regulates endothelial function through protein S sulfhydration. FASEBJ 2016; 30:441-456, which is incorporated herein by reference in its entirety). Overall, these results suggest a possible role for Hcy in endothelial dysfunction, although it is still unclear whether Hcy directly affects ECs in vivo due to the high levels of Hcy tested in vitro. Cystathionine beta-synthase regulates endothelial function through protein S sulfhydration. FASEBJ 2016; 30:441-456, which is incorporated herein by reference in its entirety). In general, these ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO results suggest a possible role of Hcy in endothelial dysfunction, although it is still unclear whether Hcy directly affects ECs in vivo due to the high levels of Hcy tested in vitro. In a recent pharmacological and genetic study, loss of CBS function in ECs was associated with a 50% decrease in cellular H2S and a 400% decrease in glutathione, with a concomitant increase in cellular ROS levels. (see Saña et al. FASEB J 2016; 30:441-456, which is incorporated herein by reference in its entirety). Silencing of CBS in EC compromised phenotypic and signaling responses to vascular endothelial growth factor (VEGF) and this effect was exacerbated by decreased transcription of vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin. -1 (NRP-1), primary receptors regulating endothelial functions such as angiogenesis. Transcriptional downregulation of VEGFR-2 and NRP-1 was mediated by decreased stability of the transcription factor specificity protein 1 (Sp1), a H2S sulfhydration target. Replenishment of H2S, but not glutathione, Dysregulated endothelial function or other effects on vascular contractility can lead to blood pressure (BP) abnormalities. Plasma Hcy level was directly related to BP and reduction of Hcy, using folic acid, was associated with a decrease in BP (see Tripathi P. Molecular and biochemical aspects of homocysteine ​​in cardiovascular diseases. International Cardiovascular Forum J 2016;6:13; Hackam et al. JAMA 2003;290:932-940, all of which are incorporated herein by reference). Although the mechanisms leading to these effects were unclear, Hcy levels are more strongly associated with systolic than diastolic BP. This suggests that elevated Hcy levels increase arterial stiffness. The degree of arterial stiffness is largely determined by the number and function of smooth muscle cells (SMC), the collagen:elastin ratio in the ECM, Potentially, high Hcy levels are associated with increased arterial stiffness due to increased SMC proliferation, collagen production, and elastin fiber formation (see van Guldener et al. Curr Hypertens Rep 2003;5:26-31, which is incorporated herein by reference in its entirety). However, it is also possible that Hcy reduces arterial stiffness by altering collagen cross-linking. In a study in minipigs, diet-induced elevation of Hcy led to “megaartery syndrome” with hyperpulsatile arteries, systolic (but not diastolic) hypertension, and widespread reactive hyperemia of the conduit arteries with dilation of the aorta ( see van Guldener et al. Homocysteine ​​and blood pressure (Curr Hypertens Rep 2003; 5:26-31, which is hereby incorporated by reference in its entirety). There was also fragmentation of the elastic lamina of the arterial wall, Consistent with these findings, a study conducted in mice, with and without CBSDH, found that vessel wall cross-sectional area was significantly greater in CBS+ / - mice fed a control diet (437 ±22 M2) and CBS+ / + (442 ±36 M2) and CBS+ / - (471 ±46 M2) mice fed a Met-rich diet, compared to CBS+ / + mice (324 ±18 M2) fed a control diet (p < 0.05) (see Baumbach et al. Structure of cerebral arteries in cystathionine beta-synthase-deficient mice. Circ Res 2002; 91:931-937, which is incorporated herein by reference in its entirety). During maximal vasodilation, stress-strain curves in cerebral arterioles of CBS+ / - mice on the control diet and CBS+ / + and CBS+ / - mice on the high-fat diet. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Met were shifted to the right of the curve for CBS+ / + mice on the control diet. This indicated that cerebral arteriole compliance was greater in mice with elevated plasma tHcy levels. These results suggest that elevated Hcy levels induced cerebral vascular hypertrophy and altered cerebral vascular mechanics, both effects potentially contributing to a higher incidence of thrombosis, e.g., stroke, even in the absence of atherosclerosis (see Baumbach et al. Circ. Res 2002; 91:931-937, which is incorporated herein by reference in its entirety). A study in 5 Italian patients with CBSDH and tHcy levels ranging from 193.6 to 342 further supports the effects of elevated Hcy on vasodilation. pmol / L (see Evangelisti et al. Int J Cardiol 2009; 134:251-254, which is incorporated herein by reference in its entirety). Patients showed signs of mild heart valve prolapse and / or regurgitation and connective tissue manifestation. 5. Thrombosis Elevated Hcy levels are associated with an increased risk of deep vein thrombosis, cerebral sinus thrombosis, and retinal vein thrombosis (see Spence JD. Lancet Neurol. 2007 Sep;6(9):8308, which is incorporated herein by reference in its totality) although several studies failed to find an association with the risk of myocardial infarction. Consistent with these results, additional studies, although small, suggest that CBSDH is associated with thrombosis, but not necessarily with atherosclerosis. Vascular imaging of patients with familial hypercholesterolemia (FH) and CBSDH showed that, while patients with FH presented with diffuse and focal thickening of the carotid arteries and endothelial dysfunction leading to reduced blood flow, patients with CBSDH rarely had plaques in their carotid arteries and were similar to healthy control subjects with respect to intimamedia thickness (IMT) and blood flow velocity in the middle cerebral artery (see Rubba et al. Stroke 1994; 25: 943-950, which incorporated herein by reference in its entirety). This study suggests that typical atherosclerotic lesions may not be necessary to precede thrombotic events in CBSDH and that medial damage leading to thrombosis may also be caused by arterial dilations. Support for this observation comes from a study comparing the prevalence of carotid and femoral atherosclerosis (determined by IMT and ankle-brachial index) in 13 patients with enzymatically proven heterozygous CBSDH, compared to 12 healthy subjects with normal results on the Met loading test (see de Valk et al, Stroke 1996; 27:1134-1136, which is incorporated herein by reference in its entirety). No significant differences were observed between groups in mean IMT values, IMT frequency distribution, or IMT in each of the five arterial segments. These results could be explained by the fact that the heterozygous individuals were too young (all under 50 years of age) to develop structural vascular changes. However, these data also suggest that elevated Hcy levels may primarily affect the coagulation cascade, at least in younger patients. In fact, a case report of three unrelated CBSDH patients found that one patient experienced a stroke due to intraluminal thrombosis and another patient experienced cardiac or arterial thromboembolism, also without evidence of ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO craniocervical atherosclerosis (see Kelly et al. Neurology 2003; 60: 275-279, which is incorporated herein by reference in its entirety). Consistent with these observations, the addition of Hcy to HUVEC and EC CV1 irreversibly inactivated anticoagulants, protein C, and thrombomodulin (see Lentz et al. J Clin Invest 1991; 88:1906-1914, which is incorporated herein by reference in its entirety). Furthermore, addition of Hcy to cultured human ECs increased procoagulant tissue factor activity in time- and concentration-dependent manners (see Fryer et al. Arterioscler Thromb 1993; 13:1327-1333, which is incorporated herein by reference in its entirety ). In both studies, Hcy improved coagulation pathways through a mechanism involving its free thiol group. Together, these data support the hypothesis that perturbations in vascular coagulation mechanisms contribute to increased vascular risk in patients with CBSDH and that this may play a role earlier in patients with CBSDH, before the effects of Hcy on atherosclerosis. Reducing plasma Hcy levels reduces the risk of vascular complications, particularly stroke, in patients with CBSDH and in the general population. Recent analyzes have found a strong link in the general population between elevated tHcy and stroke risk (see Saposnik et al. Stroke 2009; 40:1365-1372; Spence JD. Homocysteine ​​lowering for stroke Prevention: Unraveling the complexity of the Evidence. Int J Stroke. 2016 Oct;11(7):744-7;Hankey et al. Lancet Neurol 2012;11:512-520, each of which is incorporated herein by reference in its entirety). In the past, the benefits of interventions to reduce Hcy in patients with elevated Hcy levels appeared mixed, with some studies showing a reduction in vascular risk (see Yap et al. J Inherit Metab Dis 1998; 21:738-747; Yap et al. Arterioscler Thromb Vasc Biol 2001;21:20802085;Wilcken et al. J Inherit Metab Dis 1997;20:295-300;Yap et al. Semin Thromb Hemost 2000;26:335340;Saposnik et al. Stroke 2009; 40:1365-1372; Huo et al. JAMA 2015; 313:1325-1335; Hankey et al. Lancet Neurol 2012; 11:512-520, each of which is incorporated herein by reference in its entirety) and others show no benefit (see Marti-Carvajal et al. Cochrane Database Syst Rev 2015;1:CD006612; Ebbing et al. JAMA 2008; 300:795-804; Bonaa et al. N Engl J Med 2006; 354:1578- 1588; Liem et al. Heart 2005; 91:1213-1214; Toole et al. JAMA 2004; 291:565-575; B vitamins in patients with recent transient ischemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomized, double-bind, parallel, placebo-controlled trial (see Lancet Neurol 2010; 9:855-865; Albert et al. JAMA 2008; 299:2027-2036, each of which is incorporated herein by reference in its entirety). Many of these trials tested vitamin interventions, primarily vitamin B (B6 and B12) and folate supplements, to reduce Hcy. Consequently, the study results were subject to confounding factors, such as whether subjects lived in regions where folate fortification is practiced, had kidney dysfunction that made them more vulnerable to cobalamin toxicity, had related vitamin B12 deficiencies with malabsorption, which is relatively common in the elderly, or were taking antiplatelet medication. These recent analyzes considered these confounding factors and concluded that, when taken into account ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO such key variables, elevated tHcy increases the risk of stroke in the general population (see Mudd et al. Arterioscler Thromb Vasc Biol 2000; 20:1704-1706; Spence JD. Int J Stroke. 2016 Oct;11(7):744-7; Spence JD, Clin Chem Lab Med. 2013 Mar 1 ;51 (3):633-7, each of which is incorporated herein by reference in its entirety ). Hcy-lowering therapy reduces the risk of stroke, even in people without CBSDH. In the HOPE-2 (Heart Outcomes Prevention Evaluation 2) trial, 5,522 adults aged 55 years or older, with a history of vascular disease or diabetes mellitus and at least one additional cardiovascular risk factor, were randomized to receive vitamin supplements (folic acid, vitamin B6 and vitamin B12) or placebo for 5 years (see Saposniket al. Stroke 2009; 40:1365-1372, which is incorporated herein by reference in its entirety). Mean baseline Hcy concentrations were 11.5pmol / L in both groups, and patients taking a daily vitamin supplement containing >0.2 mg folic acid at baseline were excluded from the study. Overall, Hcy reduction (mean 3.0pmol / L vs. placebo) was associated with a significant 27% relative risk reduction (1.3% absolute reduction) of stroke (HR, 0.75; 95% CI, 0.59). to 0.97) and nonsignificant reductions in ischemic stroke (HR, 0.81; 95% CI, 0.60 to 1.09) and hemorrhagic stroke (HR, 0.80; 95% CI, 0.32 to 2.02). In subgroup analyses, the relative risk of stroke was reduced most among patients with baseline Hcy levels in the highest quartile (4.3% absolute risk reduction). The benefit of treatment was greatest in patients younger than 69 years, those from regions without folic acid food fortification, and those not receiving antiplatelet or lipid-lowering medications at the time of enrollment. Thus, the HOPE-2 trial reported a reduced incidence rate of stroke in people receiving B vitamins versus placebo (hazard ratio (HR), 0.75; 95% CI, 0.59 to 0.97), while the risk of MI was similar in both treatment groups (RR 0.98; 95% CI, 0.85 to 1.14) (see Saposnik et al. Stroke 2009; 40:13651372; Lonn E, Yusuf S, Arnold MJ et al. Homocysteine ​​lowering with folie acid and B vitamins in vascular disease. N Engl J Med 2006; 354:1567-1577, both incorporated herein by reference in their entirety). According to the results of the HOPE-2 trial, a subanalysis of the VITATOPS trial, where 8,164 patients with recent stroke or transient ischemic attack were randomly assigned to double-blind treatment with B vitamins or placebo for a median of 3.4 years, found that B vitamins significantly reduced the primary composite outcome (stroke, myocardial infarction, or death from vascular causes) among patients not taking antiplatelet therapy at baseline (17 vs. 21% placebo; HR 0.76, 0.60 to 0.96). No significant effect of B vitamins was observed in people receiving antiplatelet therapy (see Hankey et al. Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischemic attack: a post-hoc subanalysis of VITATOPS, a randomized, placebo-controlled trial Lancet Neurol 2012;11:512-520, which is incorporated herein by reference in its entirety). In this study, tHcy levels were significantly reduced from 12.4 to 13.7pmol / L at baseline to 9.9 to 10.5 pmol / L after vitamin therapy, regardless of whether patients received ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO antiplatelet therapy (p < 0.0001 for both treatment groups) (see Hankey et al. Lancet Neurol 2012; 11:512-520, which is incorporated herein by reference in its entirety). Inflammatory cascades are thought to contribute to the pathogenesis of ischemic stroke. A report from the Framingham Offspring Study in 3,224 participants (see Shoamanesh et al. Neurology. 2016 Sep;87(12):1206-11, which is incorporated herein by reference in its entirety) found that elevated levels of tHcy and three other The markers were strongly associated with the risk of ischemic stroke and improved the predictive ability of the Framingham Stroke Risk Profile score. A meta-analysis of data from the VISP and VITATOPS studies found that patients with normal renal function who had not previously been exposed to high-dose cyanocobalamin significantly benefited from vitamin therapy, including high-dose cyanocobalamin (0.78, 0.67 to 0.90; interaction p = 0.03), while vitamin therapy including high doses of cyanocobalamin (a form of vitamin B) had no effect on the risk of stroke in people with kidney failure (RR 1.04, 95% CI: 0.84 to 1.27) (see Spence JD. Lancet Neurol. 2007 Sep;6(9): 830-8, which is incorporated herein by reference in its entirety). These results suggested potentially confounding effects of cyanocobalamin, known to be nephrotoxic, associated with cyanide accumulation, in patients with significantly impaired renal function (see Spence JD, Clin Chem Lab Med. 2013 Mar 1 ;51(3):633 -7, which is incorporated herein by reference in its entirety). Consistent with this, in the DIVINe (Diabetic Intervention with Vitamins in Nephropathy) trial, high doses of B vitamins, including cyanocobalamin at 1000 pg, were harmful and exacerbated the decline in eGFR (see Spence JD. Int J Stroke. 2016 Oct;11(7):744-7; House et al. JAMA 2010;303:1603-1609, all of which are incorporated herein by reference). Together, these findings support the use of non-cyanide-containing B vitamins, such as methylcobalamin, instead of cyanocobalamin, to reduce Hcy levels in people at high risk of stroke, especially those with kidney failure. Cyanocobalamin and cyanide toxicity were further implicated in previous trials as confounding factors in the presence of renal failure based on the results of the CSPPT (China Stroke Primary Prevention Trial (see Huo et al. JAMA. 2015 Apr 7;313(13 ):1325-35), which is incorporated herein by reference in its entirety). The treatment benefit demonstrated with renal failure in the CSPPT was contrary to the lack of benefit observed in the DIVINe, VISP and VITOPS trials, probably due to cyanocobalamin treatment in the latter trials. Because folate fortification has not yet been implemented in China, the effect of folic acid supplementation on reducing tHcy levels could be studied there in a large population. The CSPPT was a randomized double-blind trial in 20,702 adults with hypertension but no history of stroke or myocardial infarction, which demonstrated that folic acid significantly decreased the risk of a first stroke (2.7 vs. 3.4% without folic acid). , HR 0.79, 95% CI 0.68 to 0.93), first ischemic stroke (2.2 vs 2.8% without folic acid, HR 0.76, 95% CI 0.64 to 0.91), and composite CV events (CV death, MI, and stroke cerebrovascular; 3.1% vs 3.9% without folic acid, HR 0.80, 95% CI 0.69 to 0.92). On the contrary, not ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO there were significant differences between the two groups in the risks of hemorrhagic stroke, all-cause deaths, or frequencies of adverse events. In a substudy of the CSPPT CSPPT (see Xu et al. JAMA Intern Med. 2016 Oct 1 ;176(10):1443-1450, which is incorporated herein by reference in its entirety), both subjects with or without renal impairment (eGFR less than 60 ml / min / 1.73 m2) benefited from folic acid, and the substudy further confirmed that the group treated with folic acid had a much greater drop in serum Hcy than the group that did not receive folic acid (1.9 vs 0.2 pmol / L, respectively, p <0.001). A 2017 Cochrane review (see Martí-Carvajal et al. Cochrane Database Syst Rev. 2017 Aug 17;8:CD006612, which is incorporated herein by reference in its entirety), which analyzed 15 randomized controlled trials with 74,422 participants, reported a small difference in effect of Hcy reduction with B vitamins on stroke but no effect on myocardial infarction, death from any cause, or adverse events. Compared with placebo / standard care, Hcy-lowering interventions were associated with a lower incidence of fatal or non-fatal strokes (4.33% vs 5.1% for control; RR 0.90, 95% CI 0.82 to 0.99) , but had no effect on the incidence of nonfatal stroke or fatal myocardial infarction (7.1% vs 6.0% for placebo; relative risk [RR] 1.02, 95% CI 0.95 to 1.10) or death from any cause ( 11.7% vs 12.3% for placebo (RR 1.01, 95% CI 0.96 to 1.06) in the general population. This review was an update of three previous versions (2009, 2013 and 2015), which had previously concluded that there was no evidence to support the effects of Hcy-lowering interventions on cardiovascular events, although the 2015 review had indicated a trend. not significant in reducing the incidence of stroke (see Marti-Carvajal Cochrane Database Syst Rev. 2015;1:CD006612, which is incorporated herein by reference in its entirety). The strength of the evidence for interventions to reduce Hcy in stroke strengthened as additional trials became available. The studies included in the review used various vitamin supplement regimens as HCI-lowering therapy (see Martí-Carvajal et al. Cochrane Database Syst Rev. 2017 Aug 17;8:CD006612, which is incorporated herein by reference in its entirety). The 2017 review added three new trials to those in the 2015 review. Of the total, ten trials used pyridoxine plus vitamins B9 (folate) and B12, five used vitamin B9 alone, and one of the ten used 5-methyltetrahydrofolate instead of acid. folic. Some trials included concomitant drugs (both in the control and vitamin groups), 7 trials with lipid-lowering agents and one with antihypertensive agents. Overall, Hcy-depleting treatments resulted in a relatively small decrease in mean tHcy levels. Furthermore, three studies were conducted in a folic acid-fortified population and two in a mixed population (some subjects received a fortified diet and others did not), which may have masked the Hcy-lowering effects. Given the confounding factors that could influence such studies, it is not surprising that previous reviews did not identify significant CV effects of vitamin treatment regimens and that the most recent review reported only modest effects on stroke. It is also notable that the many potential causes of elevated Hcy levels were not examined in the studies included in the Cochrane review (see Marti-Carvajal et al. Cochrane ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Database Syst Rev 2015;1:CD006612, which is incorporated herein by reference in its entirety). There may be additional factors affecting the pathophysiology of vascular risk in patients with CBSDH and at younger ages than in the general population. Of note, even modest decreases in Hcy levels are significantly associated with reductions in stroke risk. An interesting question that arises from several of these analyzes is why some studies indicated an effect of Hcy levels on stroke but not MI. In relation to this question, Spence (see Spence JD. Lancet Neurol. 2007 Sep;6(9):830-8, which is incorporated herein by reference in its entirety) pointed out the key differences between MI and stroke, being Cerebral infarction is closely associated with thrombosis / embolic events, but in situ thrombosis is secondary to plaque rupture in a coronary artery in almost all MI events. Therefore, Spence concluded that a substantial proportion of strokes are related to thrombotic processes, which may be associated with elevated tHcy. Elevated tHcy levels may be important not only in cardioembolic stroke but also in atheroembolic and lacunar infarction. A study in elderly patients with atrial fibrillation treated with anticoagulant therapy found that high tHcy levels (>90th percentile) were associated with a 4.7-fold increase in ischemic complications (see Poli et al. J Am Coll Cardiol 2009 ; 54: 999-1002, which is incorporated herein by reference in its entirety). Another study in patients with cryptogenic ischemic stroke found that those with patent foramen ovale (a risk factor for cerebral infarction) had significantly higher plasma tHcy levels than those without (8.9 ± 3 vs 7.9 ± 2.6gmol / L respectively; p = 0.021) (see Ozdemir et al. J Neurol Sci 2008; 275:121-127, which is hereby incorporated in its entirety by reference). In reviewing such findings, Spence (see Spence JD. Homocysteine ​​reduction for stroke prevention: unraveling the complexity of the evidence. Int J Stroke. 2016 Oct;11(7):744-7, which is incorporated herein as reference in its entirety) suggested that Hcy primarily affects the formation of red thrombi (a fibrin polymer mesh with trapped red blood cells, which forms in the context of stasis), but that lacunar infarction and carotid plaques are also significantly affected. related to tHcy, since tHcy levels were also significantly higher in patients with microemboli on transcranial Doppler (16.2 vs. 10.1 mmol / L) and the majority of these microemboli are believed to be platelet aggregates, reduced by the dual antiplatelet therapy (see Spence JD. Homocysteine ​​lowering for stroke Prevention: Unraveling the complexity of the Evidence. Int J Stroke. 2016 Oct;11(7):744-7, which is incorporated herein by reference in its entirety). A study conducted in 32 patients with CBSDH (aged 9 to 66 years) treated with pyridoxine, folic acid, and hydroxocobalamin for a total of 539 patient-years, reported two vascular events (a fatal pulmonary embolism and a myocardial infarction) during treatment (see Wilcken et al., J Inherit Metab Dis 1997, 20:295-300, which is incorporated herein by reference in its entirety). According to the epidemiological study by Mudd et al., 21 events would have been expected in the same period of time without treatment (RR 0.09 (95% CI 0.02 to 0.38); p=0.0001). A second study, conducted in 84 patients from three countries, aged 2.5 to 70 years, reported five cases of venous embolism (VE) during 1314 patient-years of treatment, one ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO pulmonary embolism, two myocardial infarctions, and two abdominal aneurysms (see Yap et al., Semin Thromb Hemost 2000, 26:335-340, which is incorporated herein by reference in its entirety). According to Mudd et al., (see Mudd et al. Am J Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety) 53 cases of VE would have been expected in untreated patients (RR 0.091 (CI 95% 0.043 to 0.190), p <0.001). Evidence supporting these results is derived from a large international multicenter observational study of 158 patients with CBSDH (see Yap et al. Arterioscler Thromb Vasc Biol 2001; 21:2080-2085, which is incorporated herein by reference in its entirety), the majority ranging from 10 to 30 years of age. In this study, 17 vascular events were observed among 12 treated individuals, three cases of pulmonary embolism, two myocardial infarctions, five cases of deep vein thrombosis, three cerebrovascular accidents, one transient ischemic attack, one sagittal sinus thrombosis and two abdominal aortic aneurysms. . Without treatment, 112 vascular events would have been expected in a similar population (RR 0.09 (95% CI 0.036 to 0.228); p < 0.0001). This study also highlights how even young adult patients with CBSDH treated and followed up extensively suffer poor clinical outcomes compared to the general population. An elevated plasma tHcy level is a risk factor for vascular disease and a strong predictor of mortality in patients with CAD, with and without CBSD (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Karaca et al. Gene 2014;534:197-203; Kelly et al. Neurology 2003; 60:275-279; Faeh et al. Swiss Med Wkly 2006; 136:745-756; Boushey et al. JAMA 1995; 274:1049 -1057; Clarke et al. JAMA 2002; 288:2015-2022; Hankey etal. Lancet 1999; 354:407-413; Khan et al. Stroke 2008; 39:2943-2949; Graham et al. JAMA 1997; 277: 1775-1781;Clarke et al. N Engl J Med 1991;324:1149-1155;Clarke et al. Ir J Med Sci 1992;161:61-65;Woodward etal. Blood Coagul Fibrinolysis 2006;17:1-5; Refsum etal. Annu Rev Med 1998; 49:31-62; Yoo et al. Stroke 1998; 29:2478-2483; Selsun etal. N Engl J Med 1995; 332:286-291; Wald etal. BMJ 2002; 325: 1202; Bautista etal. J Clin Epidemiol 2002; 55:882-887; Brattstrom etal. Atherosclerosis 1990; 81:51-60; Lussana etal. Thromb Res 2013; 132:681-684; Casas etal. Lancet 2005; 365:224-232; McCully KS. Am J Pathol 1969; 56:111-128; Magner et al. J Inherit Metab Dis 2011; 34:33-37; Wilcken et al. J Clin Invest 1976; 57:1079-1082; Nygard et al. N Engl J Med 1997; 337:230-236, each of which is incorporated by reference herein in its entirety). Of the evidence for a causal relationship between tHcy levels and CV risk (see Boushey et al. JAMA 1995;274:1049-1057, which is incorporated herein by reference in its entirety), the strongest relationships were demonstrated between tHcy and stroke or PAD., (see Clarke et al. JAMA 2002; 288:2015-2022; Khan et al. Stroke 2008; 39:2943-2949; Wald et al. BMJ 2002; 325:1202; Casas et al. Lancet 2005;365:224-232; Brattstrom etal. Haemostasis 1989;19 Suppl. 1:35-44, each of which is incorporated herein by reference in its entirety) even in patients with both homozygous and heterozygous CBS mutations (see Rubba et al. Metabolism 1990;39:1191-1195, which is incorporated herein by reference in its entirety). The mechanisms that potentially link elevated Hcy with vascular damage are varied and complex. Several studies implicated oxidative stress (see Faverzani et al. Cell Mol Neurobiol 2017; Nowak et al. Arterioscler Thromb Vasc Biol 2017;37: e41-e52; Vanzin et al. Mol Genet Metab 2011; ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO 104:112-117; Vanzin et al. Gene 2014;539:270-274;Vanzin et al. Lipid, Cell Mol Neurobiol 2015;35:899-911, each of which is incorporated herein by reference in its entirety), including inflammatory / immune activation through NF-κΒ (see Rodriguez-Ayala et al. Atherosclerosis 2005;180:333-340; van Guldener et al. Curr Hypertens Rep 2003;5:26-31, both incorporated herein by reference in their entirety). Although such inflammatory processes are characteristic of atherosclerosis, typical atherosclerotic lesions need not precede thrombotic events in patients with CBSDH (see Rubba et al. Stroke 1994; 25: 943-950; de Valk et al. Stroke 1996; 27 : 1134-1136, both incorporated herein by reference in their entirety). Instead, medial damage leading to thrombosis is thought to be caused by Hcy-mediated endothelial dysfunction (see Marti-Carvajal et al. Cochrane Database Syst Rev 2015;1:CD006612; Celermajer et al. J Am Coll Cardiol 1993 ; 22:854- 858; Rubba et al. Metabolism 1990; 39:1191-1195; Jiang et al. Arterioscler Thromb Vasc Biol 2005; 25:2515-2521; Hossain et al. J Biol Chem 2003; 278:30317-30327 Caí et al. Blood 2000;96:2140-2148;Zhang et al.J Biol Chem 2001;276:35867-35874;Papapetropoulos et al.Proc Nati Acad Sel USA 2009;106:21972-21977;Szabo et al. Br J Pharmacol 2011;164:853-865, Chiku et al. J Biol Chem 2009;284:11601-11612;Wang et al. Antioxid Redox Signal 2010;12:1065-1077;Saha S, et al. FASEBJ 2016; 30:441-456; Ebbing et al. JAMA 2008;300:795-804; Bonaa et al. N Engl J Med 2006;354:1578-1588, each of which is hereby incorporated by reference in its entirety ) improved coagulation pathways (see Spence JD. Int J Stroke. 2016 Oct; 11 (7): 744-7; Fryer et al. Arterioscler Thromb 1993; 13:1327-1333; Lentz et al. J Clin Invest 1991; 88:1906-1914, each of which is incorporated herein by reference in its entirety) and increased vascular dilation, similar to the thrombotic processes involved in patients with Marfan (see Kelly et al. al., Neurology 2003; 60 :275-279; Tripathi P. Molecular and biochemical aspects of homocysteine ​​in cardiovascular diseases. International Cardiovascular Forum J 2016; 6:13; van Guldener et al. Curr Hypertens Rep 2003; 5:26-31; Hackam et al. JAMA 2003;290:932-940;Baumbach et al. Circ Res 2002;91:931-937;Evangelisti et al. Int J Cardiol 2009;134:251-254;de Valk et al. stroke 1996;27:1134 -1136, each of which is incorporated herein by reference in its entirety). Consistent with observations of endothelial dysfunction in patients with CBSDH, pharmacological and genetic research implicated CBS-mediated protein S sulfhydration in the maintenance of vascular health and function (see Celermajer et al. J Am Coll Cardiol 1993; 22:854-858; Rubba et al., Metabolism 1990; 39:1191-1195, both hereby incorporated by reference in their entirety). Therefore, the mechanisms of vascular damage in patients with CBSDH are likely to be more varied than in the general population with CV disease. There is considerable evidence that Hcy reduction is beneficial against stroke risk in people with and without CBSDH (see Saposnlk et al. Stroke 2009; 40: 1365-1372; Huo et al. JAMA 2015; 313: 1325-1335 Lonn et al. each of which is incorporated by reference in its entirety). Although mean baseline Hcy levels were relatively low in studies in the general population, reductions in stroke incidence were significantly correlated with Hcy-lowering interventions, pointing to the benefits of even small decreases in Hcy. tHcy levels. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Updated reviews of relevant trials support the beneficial effects of Hcy-lowering treatments in stroke (see Martí-Carvajal et al. Cochrane Database Syst Rev. 2017 Aug 17;8:CD006612, which is incorporated herein by reference in its entirety). Confounding factors, such as whether there was folate fortification, vitamin B12 deficiency or kidney dysfunction that left patients vulnerable to high doses of cyanocobalamin, or whether subjects were taking antiplatelet medications, have clouded the trial results. Recent analyzes showed that, when these factors were taken into account, the link between tHcy and stroke risk was strong in the general population (see Spence JD, Clin Chem Lab Med. 2013 Mar 1 ;51 (3):633 -7, which is hereby incorporated by reference in its entirety). However, it is important to note that in patients with CBSDH with much higher tHcy levels than the general population, Wilcken etal. J Inherit Metab Dis 1997; 20:295-300; Yap et al. Semin Thromb Hemost 2000; 26:335-340; Ruhoy et al. Pediatr Neurol 2014; 50:108111, each of which is incorporated herein by reference in its entirety). These findings suggest that elevated Hcy level is a risk factor for CV disease, especially stroke, in patients with and without CBSDH and that CV or cerebrovascular risk can be reduced by long-term Hcy-lowering therapy. Thromboembolism is the main cause of morbidity and premature death in patients with CBSDH (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Karaca et al. Gene 2014; 534:197-203; Yap S. J Inherit Metab Dis 2003;26:259-265, each of which is incorporated herein by reference in its entirety). The overall rate of thromboembolic events in patients with untreated CBSDH is approximately 10% per year (see Cattaneo M. Semin Thromb Hemost 2006; 32:716-723, which is incorporated herein by reference in its entirety), and the risk increases after surgery, and during or immediately after pregnancy (see Mudd et al. Am J Hum Genet 1985; 37:1-31; Novy et al. Thromb Haemost 2010; 103:871873, both incorporated herein by reference in their totality). Thromboembolism can affect any blood vessel, but venous thrombosis (particularly cerebral sinovenous thrombosis (CSVT)) is more common than arterial thrombosis in patients with CBSDH (see Mudd et al. Am J Hum Genet 1985;37: 1-31; Karaca et al. Gene 2014;534:197-203; Eslamiyeh et al. Iran J Child Neurol 2015; 9:53-57; Sabou et al. J Child Neurol 2015; 30:107-112, each of which is incorporated herein by reference in its entirety). A study in 629 untreated CBSDH patients showed that, of the 253 vascular events observed (occurring in 158 patients), 81 (32%) were cerebrovascular accidents, 130 (51%) involved peripheral veins (32 resulted in pulmonary embolism). , 10 (4%) led to myocardial infarctions (MI), 28 (11%) affected peripheral arteries, and four (2%) did not fall into any of these categories (see Mudd et al. Am J Hum Genet 1985; 37: 1-31, which is incorporated herein by reference in its entirety). Strokes, especially CSVT, have been described in infants (see Mahale et al. J Pediatr Neurosci. 2017 Apr-Jun; 12(2):206-207, which is incorporated herein by reference in its entirety), although more appear typically in young adults (see Yap et al. Arterioscler Thromb Vasc Biol 2001; 21:2080-2085, which is hereby incorporated in its entirety by reference). Cerebrovascular events were reported to be only marginally related to patients' pyridoxine response category. ΜΛ / Ε / ΖυΖΖ / υΊ fVÓO The risk of vascular events was approximately 30% in patients younger than 20 years, increasing to 50% at the age of 30 years. However, symptoms can occur at any age and fatal thrombosis has been described in infants as young as 6 months (see Cardo et al. Dev Med Child Neurol 1999; 41:132-135, which is incorporated herein by reference in its entirety). ). After 10 years of age, a vascular event is expected every 25 years. In general, the first signs of CBSDH in children are mental retardation, presenting as developmental delay during the first or second year of life and / or lens dislocation / high myopia. In contrast, adults are more likely to experience vascular events. D. Effects of diet on phenotypic outcomes In some embodiments, I278T mice, a mouse model of HCU, were used to evaluate the long-term impact of enzyme therapy for HCU with 20NHS PEG-CBS on clinical endpoints relevant to human patients. The efficacy of 20NHS PEG-CBS in a context of normal methionine intake (REG) and a Met-restricted diet (MRD), as well as with MRD alone. Treatment with 20NHS PEG-CBS can result in a 90% decrease in plasma homocysteine ​​concentrations and correction of learning / cognition, endothelial dysfunction, hemostasis, bone mineralization, and body composition phenotypes associated with HCU. In certain embodiments, treatment with 20NHS PEG-CBS with a background of plasma Hcy normalized by MRD. MRD alone has been observed to reduce plasma Hcy by 67% and correct the HCU phenotype in I278T mice. However, MRD increased anxiety and reduced bone mineral content in both I278T mice and wild-type controls. Therefore, 20NHS PEG-CBS is very effective for the treatment of HCU in subjects with a history of a REG or Met-restricted diet. In fact, ET with 20NHS PEG-CBS in the context of a normal Met intake works as well or produces better results compared to a Met-restricted diet. E. Neurological complications Studies have shown that early decreases in Hcy levels, induced by a low-Met diet, folic acid / vitamin B supplements, and / or pyridoxine and betaine therapy, can prevent and sometimes reverse the progression of several disorders. neurological disorders and allow normal development of IQ in patients with CBSDH (see El Bashir et al. JIMD Rep 2015; 21:89-95; Yap et al J Inherit Metab Dis 2001; 24:437- 447; Mech AW, Farah A Correlation of clinical response with homocysteine ​​reduction during therapy with reduced B vitamins in patients with MDD who are positive for the MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2016;77 :668-671; Grabe H. Eur J Pediatr 1980; 135:199-203; each of which is incorporated herein by reference in its entirety). Additional evidence is provided in case studies in patients with CBSDH, where significant decreases, even normalization, of Hcy levels resulted in complete or partial correction of CNS outcomes (see Yap et al. J Inherit Metab Dis 2001;24:437-447; Brenton et al. J Child Neurol 2014;29:88-92; Rezazadeh et al. Child Neurol Open 2014;1:2329048X14545870; Kaeser et al. J Neurol Neurosurg Psychiatry 1969;32:88- 93; ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Colafrancesco et al. Eur J Pediatr 2015; 174:1263-1266; Yokoi et al. to the. Pediatr Int 2008; 50:694-695; Lí etal. Pathology 1999; 31:221-224, each of which is incorporated herein by reference in its entirety). Associations between elevated Hcy levels and CNS symptoms, including mental retardation, neurodegenerative diseases, seizures, dystonia, psychosis, cognitive impairment, dementia, and depression, are well documented in patients with CBSDH and in the general population (see Morris et al .. J Inherit Metab Dis 2017; 40:49-74; Abbott et al. Am J Med Genet 1987; 26:959-969; Mudd et al. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Diseases. 7th ed. New York: McGraw Hill; 2001; 1279-1327; Hidalgo et al. Eur Child Adolesc Psychiatry 2014; 23:235-238; Smith et al. PLoS One 2010 ;5: e12244; Seshadri et al. N Engl J Med 2002; 346:476-483; Bottiglieri et al. J Neurol Neurosurg Psychiatry 2000; 69:228-232; Bjelland et al. Arch Gen Psychiatry 2003; 60:618 -626, Tolmunen et al Am J Clin Nutr2004, 80:1574-1578, Kaeser et al J Neurol Neurosurg Psychiatry 1969, 32:88-93, Golimbet et al Psychiatry Res 2009, 170:168-171; Clarke et al. Arco Neurol 1998; 55:14491455; Permoda-Osip et al. Neuropsychobiology 2014; 69:107-111; Oliveira et al. BMJ Case Report 2016;2016; Traen et al. Proc Nati Acad Sci U S A 2008; 105:12474-12479; Sudduth et al. J Cereb Blood Flow Metab 2013; 33:708-715; Hainsworth et al. Biochim Biophys Acta 2016; 1862:1008-1017; Hermann et al. Clin Chem Lab Med 2011; 49:435-441; Kim et al. J Nutr 2007; 137:2093-2097; Selhub et al. Am J Clin Nutr 2000; 71:614S-620S; McCaddon et al. Dement Geriatr Cogn Disord 2001; 12:309-313; Smallwood et al. Neuropathol Appl Neurobiol 2012; 38:337-343; Beydoun et al. BMC Public Health 2014; 14:643; Gortz et al. J Neurol Sci 2004; 218:109-114; Health Quality O. Vitamin B12 and cognitive function: an evidence-based analysis. Ont.Health Technol.Assess.Ser.13 (23), 1e45. 2013. Reference type: Online source; Salagre et al. Eur Psychiatry 2017; 43:81-91, each of which is incorporated herein by reference in its entirety). The mechanisms leading to CNS disorders in individuals with elevated Hcy levels are thought to involve tHcy-mediated neuronal damage (see Mudd et al. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Diseases.7 ed.New York: McGraw Hill;2001;1279-1327;Hainsworth etal.Biochim Biophys Acta 2016;1862:1008-1017;Stefanello et al.Metab Brain Dis 2007;22:172 -182; Toborek et al. Atherosclerosis 1995;115:217-224, each of which is incorporated herein by reference in its entirety), damage to the vascular endothelium caused by Hcy-mediated oxidative stress (see Vivitsky et al. Am J Physiol Regul IntegrComp Physiol 2004;287: R39-R46, which is incorporated herein by reference in its entirety), neuron loss (see Yeganeh et al. J Mol Neurosci 2013; 50:551-557; Helder et al. J Neural Transm Suppl 2004;1-13, both hereby incorporated by reference in their entirety) and attenuated neural network activity (se and Gortz et al. J Neurol Sci 2004; 218:109-114, which is incorporated herein by reference in its entirety). Depression and seizures are thought to be caused, at least in part, by Hcy-mediated decreases in brain adenosine levels, with subsequent decreases in norepinephrine and dopamine levels (see Mech et al. J Clin Psychiatry 2016;77 :668-671; Domagala et al. Thromb Res 1997; 87:411-416; Vivitsky et al. Am J Physiol Regul IntegrComp Physiol 2004;287: R39-R46; Folstein et al. Am J Psychiatry 2007; 164:861- 867, each of which is incorporated herein by reference in its entirety). ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO These findings demonstrated a strong correlation between Hcy levels and an increased risk of CNS disorders in patients with CBSDH. Early Hcy-lowering therapy is essential for the normal development of children with early-onset CBSDH and for the correction or improvement of CNS disorders in patients diagnosed with CBSDH later in life. A study in 63 CBSDH patients found that 51% had psychiatric disorders, such as anxiety and episodic depression (10%), chronic behavioral disorders (e.g., aggression and drug or alcohol abuse) (17%), obsessive-compulsive disorder chronic (5%) and personality disorders (19%) (see Abbott et al. Am J Med Genet 1987; 26:959-969, which is incorporated herein by reference in its entirety). Psychosis may be a presenting sign in adolescence (see Hidalgo et al. Eur Child Adolesc Psychiatry 2014; 23:235-238, which is incorporated herein by reference in its entirety). If left untreated, approximately 90% of patients who do not respond to pyridoxine have learning difficulties (see Mudd et al. Am J Hum Genet 1985; 37:1-31, which is incorporated herein by reference in its entirety). , with IQs typically ranging from 10 to 138, with a mean of 57 in pyridoxine-unresponsive individuals, compared with 79 in untreated pyridoxine-sensitive patients and 105 in treated pyridoxine-sensitive patients with good compliance (see Yap et al. J Inherit Metab Dis 2001; 24:437-447, which is incorporated herein by reference in its entirety). Seizures affect 20% of unresponsive patients by the age of 12 years, and several cases of movement disorders unrelated to basal ganglia infarction, including polymyoclonus, dystonia, and Parkinson's disease, have been reported (see Morris et al. J Inherit Metab Dis 2017;40:49-74, Rezazadeh et al. Niño Neurol Open 2014;1:2329048X14545870, both hereby incorporated by reference in their entirety). An association between CBSDH and neuropsychiatric symptoms was first described by Schimke et al. in 1965 (see Schimke et al. JAMA 1965; 193:711-719, which is incorporated herein by reference in its entirety). The association was later supported by a study that reported psychopathology in more than 50% of patients with CBS deficiency (see Abbott et al. Am J Med Genet 1987; 26:959-969, which is incorporated here by reference in its whole). Since then, numerous epidemiological studies have shown positive, dose-dependent relationships between even mild increases in plasma tHcy and the risk of CNS disorders, including mental retardation and neurodegenerative diseases (see Morris et al. J Inherit Metab Dis 2017 ; 40:49-74; Seshadri et al. N Engl J Med 2002; 346:476-483; Clarke et al. Arch Neurol 1998;55:1449-1455; Hainsworth etal. Biochim Biophys Acta 2016; 1862:1008-1017 ; Hermann et al. Clin Chem Lab Med 2011; 49:435-441; Kim J et al. J Nutr 2007; 137:2093-2097; Selhub et al. Am J Clin Nutr 2000; 71:614S-620S; McCaddon et al. Dement Gerlatr Cogn Disord 2001;12:309-313; Smallwood et al. Neuropathol Appl Neurobiol 2012;38:337-343; Beydoun et al. BMC Public Health 2014;14:643; each of which is incorporated herein by reference in its entirety). In general, patients with severely elevated Hcy levels (50 to 200 μΜ / L) tend to present with acute neuronal dysfunction, including seizures and psychosis, while more moderate Hcy levels (15 to 50 μΜ / L) are associated with cognitive impairment and dementia (see Mudd et al. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle MA / IZ / ZUZZ / UI ÍVÓO D, eds. The Metabolic and Molecular Basis of Inherited Diseases. 7th ed. New York: McGraw Hill; 2001; 12791327; Gortz et al. J Neurol Sci 2004; 218:109-114, both incorporated herein by reference in their entirety). Elevated Hcy level is widely accepted as a robust and independent risk factor for cognitive decline (see Smith et al. PLoS One 2010;5:e12244; Seshadri et al. N Engl J Med 2002; 346:476-483, both incorporated herein by reference in their entirety) onset of dementia (see Quality of health O. Vitamin B12 and cognitive function: an evidence-based analysis. Ont.Health Technol.Assess.Ser.13 (23), 1e45. 2013 Reference Type: Online Source, which is hereby incorporated by reference in its entirety) and Alzheimer's disease (see Seshadri et al. N Engl J Med 2002; 346:476-483, which is incorporated herein by reference In its whole). lIn addition, increased Hcy levels (>15 μmol / L) were present in up to 90% of patients with depression (see Bottiglieri et al. J Neurol Neurosurg Psychiatry 2000; 69:228-232; Bjelland et al. Arch Gen Psychiatry 2003; 60:618-626, all of which are incorporated herein by reference), with men in the highest tertile for tHcy levels more than twice as likely to suffer from depression as those in the lowest tertile (see Tolmunen et al. Am J Clin Nutr 2004; 80:1574-1578, which is incorporated herein by reference in its entirety). An elevated level of Hcy is commonly reported in cases of schizophrenia, multiple sclerosis, Parkinson's disease, fibromyalgia / chronic fatigue syndrome (see Kaeser et al. J Neurol Neurosurg Psychiatry 1969; 32:88-93; Golimbet et al. Psychiatry Res 2009;170:168-171, Clarke et al. Arch Neurol 1998, 55:1449-1455; each of which is incorporated herein by reference in its entirety) and recurrent dystonia without cerebrovascular disease (see Sinclair et al. Mov Disord 2006; 21:1780-1782, which is incorporated herein by reference in its entirety). A possible association between the T833C polymorphism of the CBS gene and bipolar disorder has been described (see Permoda-Osip et al. Neuropsychobiology 2014; 69:107-111, which is incorporated herein by reference in its entirety) and a recent meta-analysis indicated a relationship between elevated Hcy levels and mania / euthymia in individuals with bipolar illness (see Salagre et al. Eur Psychiatry 2017; 43:81-91, which is incorporated herein by reference in its entirety). The first known case of peripheral neuropathy associated with CBSDH was recently described in an 18-year-old man with CBSDH (see Oliveira et al. BMJ Case Rep 2016;2016, which is incorporated by reference in its entirety), and a fatal case of psychosis was described in a 17-year-old person with CBSDH without a previous diagnosis (see Hidalgo et al. Eur Child Adolesc Psychiatry 2014; 23:235-238, which is incorporated by reference in its entirety). Direct evidence for a relationship between Hcy levels and dementia derives from animal studies in which Hcy administration was associated with the development of brain lesions (see Troen etal. ProcNatlAcadSciUSA2008; 105:12474-12479; Sudduth etal. J Cereb Blood FlowMetab2013;33:708715, each of which is incorporated herein by reference in its entirety). In the first study of its kind, male C57BL6 / J mice with elevated Hcy levels (induced by a vitamin B-deficient diet) had significantly impaired spatial learning and memory, with significant rarefaction of hippocampal microvasculature without gliosis or concomitant neurodegeneration (see Troen et al. Proc Nati Acad Sci USA 2008;105:12474-12479, which is incorporated herein by reference in its entirety). -0.757, p <0.001) and with plasma tHcy (r = -0.631, p<0.007). Mice fed a Met-rich diet showed similar, but less pronounced, effects. These findings suggested that the levels Elevated Hcy ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO are associated with cerebral microvascular rarefaction leading to cognitive dysfunction in the absence or before neurodegeneration. This may explain the link between elevated Hcy levels and cognitive decline in humans. In the second study, healthy mice were fed a diet deficient in folate, vitamins B6 and B12 and supplemented with Met to induce moderately elevated Hcy levels (plasma tHcy 82.93 ±3.56 μηηοΙ / L). These mice had spatial memory deficits, as assessed with the two-day radial arm water maze (see Sudduth et al. J Cereb Blood Flow Metab 2013; 33:708-715, which is incorporated herein by reference in its entirety ). MRI and histology revealed significant rates of microbleeds. Neuroinflammation and increased expression and activity of MMP2 and MMP9, both enzymes involved in the pathogenesis of cerebral hemorrhage, were also observed. This suggested a link between elevated Hcy levels and vascular dementia, such as in Alzheimer's disease. In humans, white matter changes (a sign of vascular damage) are frequently associated with elevated Hcy levels, both in individuals with (see El Bashir et al. JIMD Rep 2015; 21:8995; Vatanavicharn et al. J Inherit Metab Dis 2008;31 Suppl. 3:477-481; Brenton et al. J Child Neurol 2014; 29:8892; Ruhoy et al. Pediatr Neurol 2014; 50:108-111; each of which is incorporated herein as reference in its entirety) and without (see Hogervorst et al. Arch Neurol 2002; 59:787-793; Kloppenborg et al. Neurology 2014; 82:777-783; each of which is hereby incorporated by reference in its entirety) CBSDH. However, these changes are not always associated with evidence of stroke. Additionally, brain imaging studies in patients with CBSDH often show signs of venous atrophy or occlusion (see Vatanavicharn et al. J Inherit Metab Dis 2008;31 Suppl. 3:477-481, which is incorporated herein by reference in its entirety ). The examination reveals a diffuse symmetrical abnormal increase in the signal of the subcortical white matter and, to a lesser extent, the deeper white matter, in the cerebral hemispheres, mainly in the parieto-occipital regions. 1. Mechanism The precise mechanisms by which elevated Hcy levels affect neurological health are unknown. Several animal studies showed associations between elevated tHcy levels and neurotoxicity and accompanying nervous and mental impairment. An initial study showed that very high intraperitoneal doses of Hcy induced generalized convulsive status epilepticus in rats with cobalt-induced lesions in the motor cortex (see Mudd et al. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle D (eds. The Metabolic and Molecular Basis of Inherited Diseases. 7 ed. New York: McGraw Hill; 2001; 1279-1327, which is incorporated herein by reference in its entirety.) Seizures increased with the addition of Met and vitamin B and There was some evidence for synergistic effects of pyridoxal 5'-phosphate and Hcy in blocking the postsynaptic gaminobutyric acid receptor. Furthermore, Hcy treatment of rodent neocortical tissues led to the trapping of adenosine in the form of AdoHcy (see Heinecke et al. J Biol Chem 1987;262:10098-10103, ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO which is incorporated herein by reference in its entirety). The authors stated that adenosine is predominantly a depressant of brain actions and that seizure conditions and mental changes associated with high levels of Hcy may be mediated by reduced levels of brain adenosine. Hcy is associated with both neurotoxicity and morphological changes in the brain (see Hainsworth et al. Biochim Biophys Acta 2016; 1862:1008-1017, which is incorporated herein by reference in its entirety). For example, studies in rats and rabbits showed that neuronal damage was caused by Hcy-mediated increases in thiobutyric acid reactive substances (TBARS), indicators of oxidative stress (see Stefanello et al. Metab Brain Dis 2007; 22: 172-182; Toborek et al. Atherosclerosis 1995;115:217-224, both incorporated herein by reference in their entirety). Similar increases in plasma TBARS were also observed in humans after an orally administered Met load (see Domagala et al. Thromb Res 1997;87:411-416, which is incorporated herein by reference in its entirety). Furthermore, a study in a murine model for elevated Hcy levels suggested that cellular damage caused by oxidative stress may be increased in patients with CBSDH because reduced levels of Cys result in low levels of neuronal glutathione, an important antioxidant synthesized from of glutamate, Cys and glycine (see Vivitsky et al., Am J Physiol Regul IntegrComp Physiol 2004; 287:R39-R46, which is incorporated by reference in its entirety). In vivo injection of Hcy into the left ventricle of rat brains produced a dose-dependent neuronal loss (see Yeganeh et al. J Mol Neurosci 2013; 50:551-557, which is incorporated herein by reference in its entirety) and Incubation of rat mesencephalic tegmental neurons with Hcy led to fewer and shorter dopaminergic neurites (see Heider et al. J Neural Transm Supl. 2004; 1-13, which is incorporated herein by reference in its entirety). In both studies, the effects of Hcy were attenuated by coadministration of Hcy with NMDA antagonists and metabotropic glutamate receptors, suggesting a glutamate receptor-mediated pathway for Hcy-induced neuronal damage. Additional evidence for this pathway comes from a study where Hcy administration led to dose-dependent lipid peroxidation in rat brain synaptosomes (see Jara-Prado et al Neurotox Res 2003; 5:237-243, which is incorporated herein by reference in its entirety). Once again, the effects were inhibited by administration of an NMDA receptor antagonist. A study in spontaneously active embryonic rat cortical neurons showed that Hcy levels above the range for severely elevated Hcy caused a dose-dependent suppression of neuronal network activity (see Gortz et al. J Neurol Sci 2004; 218 : 109-114, attached below), incorporated by reference in its entirety). The effects observed in this study were not clinically relevant because these exaggerated Hcy levels are never achieved in patients with CBSDH. However, modest elevations in homocysteine ​​sulfinic acid and homocysteic acid (oxidized forms of Hcy often found in patients with elevated Hcy levels) had a similar effect. In each case, damage to the neuronal network was inhibited by 2-amino-5-phosphonovaleric acid, again implicating the NMDA receptor as a mediator of this Hcy-induced neuronal dysfunction. These results suggested ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO that the neuronal dysfunction associated with elevated levels of Hcy is probably caused by oxidized forms of Hcy, rather than by Hcy itself. The absence of mental retardation, seizures, and other CNS disorders in patients with Marfan syndrome and other connective tissue disorders suggests that the neurological disorders in patients with CBSDH are not caused by defects in fibrillin or collagen (see Mudd et al. , Transsulfuration disorders. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Diseases. 7 ed. New York: McGraw Hill; 2001; 1279-1327, which is incorporated into the present for reference in its entirety). In patients with untreated CBSDH, elevated levels of SAM and reduced levels of SAH inhibit transmethylation reactions required for myelin synthesis, leading to further nerve damage (see Mudd et al. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Diseases. 7th ed. New York: McGraw Hill, 2001; 1279-1327, which is incorporated herein by reference In its whole). Decreased myelin synthesis may also be caused by low serine levels in patients with CBSDH, due to increased remethylation rates (see Orendac et al. J Inherit Metab Dis 2003; 26:761-773, which is incorporated here for reference in its entirety). Finally, Hcy metabolism plays a key role in monoamine synthesis by providing methyl groups for the production of norepinephrine and dopamine (see Mech et al. J Clin Psychiatry 2016; 77:668-671; Folstein et al. Am J Psychiatry 2007;164:861-867, both hereby incorporated by reference in their entirety). In fact, the “homocysteine ​​depression hypothesis” (see Folstein et al. Am J Psychiatry 2007; 164:861-867, which is incorporated herein by reference in its entirety) states that low levels of norepinephrine and dopamine, resulting from elevated levels of Hcy, are one of the main causes of depression. Electron microscopy of rat brain biopsies showed cerebrovascular structural alterations in animals fed a high Hcy diet for 8 weeks. These alterations were associated with elevated plasma tHcy levels (see Lee et al. J Nutr 2005; 135:544-548, which is incorporated herein by reference in its entirety). Consumption of dietary folic acid for another 8 weeks reduced plasma tHcy to normal levels and significantly decreased the incidence of damaged vessels. This suggested that Hcy reduction, using folic acid supplementation, could reduce the detrimental effects on vascular endothelium of experimentally induced elevated Hcy levels. A study designed to evaluate the efficacy and safety of reduced B vitamins as monotherapy in adults with major depressive disorder (MDD) and CBSDH, due to at least one MTHFR polymorphism (N = 330), found that treatment with a combination of vitamins Reduced B significantly decreased tHcy levels in 131 treated patients (82.4%) (the mean reduction in this subgroup was 25%; p < 0.001), while placebo-treated patients demonstrated a small elevation in tHcy levels ( see Mech et al. J Clin Psychiatry 2016;77:668-671, which is incorporated herein by reference in its entirety). Treated patients, on average, had a 12-point reduction on the Montgomery Asberg Depression Rating Scale (MADRS) at week 8, and 42% achieved complete remission (p < 0.001). Further clinical improvement was correlated with a significant decrease in tHcy levels in the majority of responders. Although this study was not carried out in patients ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO with CBSDH, demonstrated a clear benefit for Hcy reduction in individuals with depression, supporting the 'Hcy hypothesis of depression' (see Folstein et al. Am J Psychiatry 2007; 164: 861-867, which is incorporated herein by reference in its entirety). The benefits of Hcy-lowering therapy in individuals with psychiatric symptoms associated with CBSDH were first demonstrated in a study of 12 patients with late diagnosis (see Grobe H. Eur J Pediatr 1980;135:199-203, which is incorporated here for reference in its entirety). Three of these patients were never treated effectively and presented severe psychological disorders, with premature death. The remaining 8 patients were between 1 and 26 years of age (average 13 years) and all had psychiatric symptoms, such as irritability, ADHD, apathy, and psychosis. Treatment with pyridoxine or a low-Met diet with supplemental L-cystine for 2 to 9 years was associated with marked improvement in behavior and intellectual development, correlated with biochemical normalization. The authors emphasized the need to treat all patients, regardless of age at diagnosis and previous treatment, due to the reversibility and improvement of the sequelae associated with CBSDH observed in their study. More recent data from the Irish screening program were used to compare the mental abilities of 23 pyridoxine-unresponsive individuals with CBSDH (339 patient-years of treatment) with those of 10 unaffected sibling controls (see Yap et al. J Inherit Metab Dis 2001; 24:437447, which is incorporated herein by reference in its entirety). Of the 23 patients identified, 19 were diagnosed with CBSDH through NBS and treated early in life (within 6 weeks of birth), two were detected late (age 2.2 and 2.9 years), and two were not had been treated at the time of evaluation. All patients were treated with a Met-free, cysteine-supplementary synthetic amino acid mixture with vitamin B12 and folate supplementation as needed. Betaine was used in the last 5 years as an adjuvant to treatment in early treated patients who were poor adherers of the diet and in all patients with late detected CBSDH. Overall, 13 of 19 patients in the early treatment group (mean age 14.4 years; range 4.4 to 24.9) were adherent to treatment (defined by median lifetime plasma fHcy <11pmol / L) and had no complications. , while the remaining 6 (mean age 19.9 years; range 13.8 to 25.5), who had poor compliance, developed complications. The mean full-scale IQ (FIQ) was 105.8 (range 84 to 120) in the compliance group compared with 80.8 (range 40 to 103) in the poor compliance group. The control group (n = 10) with a mean age of 19.4 (range 9.7 to 32.9) years had a mean FIQ of 102 (range 76 to 116). The two late-detected patients, aged 18.9 and 18.8 years, had an FIQ of 80 and 102, respectively, while the two untreated patients, aged 22.4 and 11.7 years, had an FIQ of 52 and 53, respectively. There were no significant differences between people who complied with early treatment and their unaffected siblings (controls), except in FIQ, which was significantly higher in affected siblings (p = 0.0397). Despite the relatively small numbers, these results suggest that early treatment with good biochemical control prevents mental retardation. ΜΛ / Ε / ΖυΖΖ / υΊ fVÓO Similar results were obtained in a case-control study that reported on neurodevelopmental, educational and cognitive outcomes in 32 CBSDH cases and 25 sibling controls in Qatar (see El Bashir et al. JIMD Rep 2015;21:89- 95, which is incorporated herein by reference in its entirety). The mean age of subjects in this study was 11.2 years (range 0.6 to 29) and 56% were men. Compared to unaffected siblings, affected individuals had lower overall IQ (particularly in terms of short-term memory, quantitative reasoning, and visuospatial domains) and a significant number of adolescent and adult cases had medical comorbidities, as well as emotional and behavioral problems. Of these, 9 cases (28%) of CBSDH were diagnosed by NBS and treated in the first month of life. The rest were diagnosed between 14 and 240 months of age. tHcy and Met levels during treatment were significantly better in those diagnosed through NBS than in those diagnosed clinically, possibly due to better compliance with diets and medications at an early age. A significant difference in IQ was observed between patients with early and clinical diagnosis. Although differences in language proficiencies, attendance at special schools and access to additional support in class were not statistically significant between the groups, the 'clinically detected' group clearly had more reported difficulties. Although the number of patients studied here is small, a notable difference is seen between children diagnosed at birth and those diagnosed when they were young. A mean tHcy level of 115pmol / L in the clinically diagnosed group was associated with poor clinical outcomes and very low IQs. Additional evidence for the benefits of Hcy-lowering treatment on psychopathology in patients with CBSDH comes from a retrospective review of data on all patients with HCU presenting to Boston Children's Hospital since 1963 (unpublished data courtesy of M Almuqbil, et al.). Overall, 19 patients with HCU were identified, three of whom were excluded from the analysis due to potential confounding by the presence of methylmalonic acidemia (also associated with psychological defects) in addition to CBSDH. Of the remaining 16 patients, 7 (6 with CBSDH and one with cobalamin (Cbl) deficiency) complied well with early treatment (four with diet alone, two with diet plus betaine, and one with Cbl). Six of these patients had no obvious psychiatric symptoms other than mild cognitive deficits. In contrast, 9 patients (7 with pyridoxine-unresponsive CBSDH and two with CblG deficiency) had poor or variable compliance with treatment (two with betaine and diet, one with diet alone, three with B vitamins, and two with folic acid and betaine). The 7 patients with CBSDH and poor compliance had psychiatric problems, such as depression (n = 4), paranoid experiences (n = 2), paranoia and delusional psychosis (n = 1), anxiety and mood dysregulation (n = 1) and ADHD that improved with good metabolic control (n = 1). Both CblG cases were markedly anxious or agitated. Age, sex, and cognitive levels did not appear to significantly differentiate between psychiatrically affected and unaffected individuals. These results suggest that good metabolic control (reduction of Hcy and / or Met) has the potential to delay, and possibly prevent, the onset of psychiatric and behavioral conditions in patients with CBSDH. However, the study does not ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO determined whether poorly controlled CBSDH leads to psychopathology, or whether comorbidity with psychopathology itself prevents good compliance with the treatment outcome. Associations between elevated Hcy levels and CNS symptoms, including mental retardation, neurodegenerative diseases, seizures, dystonia, psychosis, cognitive impairment, dementia, and depression, are well documented in people with and without CBSDH (see Morris et aL J Inherit Metab Dis 2017; 40:49-74; Abbott et al. Am J Med Genet 1987; 26:959-969; Mudd et al. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Diseases. 7th ed. New York: McGraw Hill; 2001;1279-1327; Hidalgo et al. Eur Child Adolesc Psychiatry 2014; 23:235-238; Schimke et al. JAMA 1965; 193:711- 719; Smith et al. PLoS One 2010;5:e12244; Seshadri et al. N Engl J Med 2002; 346:476-483; Bottiglieri et al. J Neurol Neurosurg Psychiatry 2000; 69:228-232; Bjelland et al. Arch Gen Psychiatry 2003;60:618-626;Tolmunen et al. Am J Clin Nutr 2004;80:1574-1578;Kaeser et al. J Neurol Neurosurg Psychiatry 1969;32:88-93;Golimbet et al. Psychiatry Res 2009 ; 170:168-171; Clarke et al. Arco Neurol 1998; 55:1449-1455; Sinclair et al. Mov Disorder 2006; 21:1780-1782; Pemnoda-Osip et aL Neuropsychobiology 2014; 69:107-111; Oliveira et al. BMJ Case Report 2016;2016; Troen et al. Proc Nati Acad Sci USA 2008; 105:12474-12479; Sudduth et al. J Cereb Blood Flow Metab 2013; 33:708-715; Hainsworth et al. Biochim Biophys Acta 2016; 1862:1008-1017; Hermann et al. Clin Chem Lab Med 2011; 49:435-441; Kim et al. J Nutr 2007; 137:2093-2097; Selhub et al. Am J Clin Nutr 2000; 71:614S-620S; McCaddon et aL Dement Geriatr Cogn Disord2001; 12:309-313; Smallwood et al. Neuropathol Appl Neurobiol 2012; 38:337-343; Beydoun et al. BMC Public Health 2014; 14:643; Gortz et al. J Neurol Sci 2004; 218:109114; Health Quality O. Vitamin B12 and cognitive function: an evidence-based analysis. Ont.Health Technol.Assess.Ser.13 (23), 1e45. 2013. Reference type: Online source; Salagre et al. Eur Psychiatry 2017; 43:81-91, each of which is incorporated herein by reference in its entirety). The mechanisms leading to CNS disorders in individuals with elevated Hcy levels are thought to involve tHcy-mediated neuronal damage (see Mudd et al. Disorders of transsulfuration. In: Scriver CL, Beaudet AL, Sly WS, Valle D, eds The Metabolic and Molecular Basis of Inherited Diseases. 7 ed. New York: McGraw Hill; 2001;1279-1327; Hainsworth et al. Biochim Biophys Acta 2016; 1862:1008-1017; Stefanello et al. Metab Brain Dis 2007; 22 :172-182; Toborek et al. Atherosclerosis 1995; 115:217-224, each of which is incorporated herein by reference in its entirety), damage to the vascular endothelium caused by Hcy-mediated oxidative stress (see Vivitsky et al. Am J Physiol Regul IntegrComp Physiol 2004;287: R39-R46, which is incorporated herein by reference in its entirety), neuron loss (see Yeganeh et al. J Mol Neurosci 2013; 50: 551-557; Heider et al. J Neural Transm Supl. 2004;1-13, both incorporated herein by reference in their entirety) and attenuated neural network activity (see Gortz et al. J Neurol Sci 2004; 218:109-114, which is incorporated herein by reference in its entirety). Depression and seizures are thought to be caused, at least in part, by Hcy-mediated decreases in brain adenosine levels, with subsequent decreases in norepinephrine and dopamine levels (see Mech et al. J Clin Psychiatry 2016; 77:668-671; Domagala et al Thromb Res 1997; 87:411-416; Vivitsky et al. Am J Physiol Regul IntegrComp Physiol 2004;287: R39- R46; Folstein et al. Am J Psychiatry 2007; 164:861- 867; each of which is incorporated herein by reference in its entirety). ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO Numerous studies, both in animal models for CBSDH (see Lee et al. J Nutr 2005; 135:544-548, which is incorporated herein by reference in its entirety) and in patients with CBSDH (see El Bashir et al. JIMD Rep 2015 ; 21:89-95; Yap et al. J Inherit Metab Dis 2001; 24:437-447; Mech et al. J Clin Psychiatry 2016; 77:668 -671; Grobe H. Eur J Pediatr 1980; 135:199- 203, each of which is incorporated herein by reference in its entirety), have shown that early decreases in Hcy levels, induced by a low-Met diet, folic acid / vitamin B supplements, and / or pyridoxine therapy / betaine can prevent, and sometimes reverse, the progression of several neurological disorders. Additional evidence is provided by a series of 6 case studies in patients with CBSDH, where significant decreases, even normalization, of Hcy levels resulted in complete or partial correction of CNS outcomes (see Yap et al. J Inherit Metab Dis 2001;24:437-447; Brenton et al. J Child Neurol 2014;29:88-92; Rezazadeh et al. Child Neurol Open 2014;1:2329048X14545870; Kaeser et al. J Neurol Neurosurg Psychiatry 1969;32: 88-93; Colafrancesco et al. Eur J Pediatr 2015; 174:1263-1266; Yokoi et al. Pediatr Int 2008; 50:694-695; Lí et al. Pathology 1999; 31:221-224, each one of which is incorporated herein by reference in its entirety). These findings demonstrate a strong correlation between Hcy levels and an increased risk of CNS disorders in patients with CBSDH and in the general population. Early Hcy-lowering therapy is essential for the normal development of children with early-onset CBSDH and for the correction or improvement of CNS disorders in patients diagnosed with CBSDH later in life. IX. DEFINITIONS As used in this description, the singular forms “a”, “an”, “the” and “the” include plural references unless the context clearly indicates otherwise. Where a range of values ​​is provided, it is intended that each intermediate value between the upper and lower limit of that range and any other stated or intermediate value in that stated range be included within the disclosure and specifically disclosed. For example, if a range is set from 1 pm to 8 pm, it is intended that 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, and 7 pm, as well as the range of larger values ​​less than or equal to to 1 pm and the range of values ​​less than or equal to 8 pm. As used herein, “coadministered” or “coadministration” means the administration of two or more therapeutic components, including the pharmaceutical composition. As used herein, a “drug product” refers to a dosage form of a pharmaceutical composition that includes the drug substance of a PEGylated human truncated CBS protein with an amino acid sequence of SEQ ID NO: 1 (e.g. , 20NHS PEGCBS). As used herein, a “drug substance” refers to a PEGylated CBS protein with an amino acid sequence of SEQ ID NO: 1 (e.g., 20NHS PEGCBS). As used herein, a “negative clinical outcome” refers to an undesirable phenotypic outcome resulting from a disease, disorder, or condition. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO As used herein, “recombinant,” when used with reference to, for example, a cell, nucleic acid, polypeptide, expression cassette or vector, refers to a material, or a material corresponding to the natural form. or native to the material, which has been modified by the introduction of a new moiety or alteration of an existing moiety, or is identical to it but produced or derived from synthetic materials. For example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell (i.e., “exogenous nucleic acids”) or express native genes that are otherwise expressed at a different level, typically they are underexpressed, or not expressed at all. Recombinant techniques may include, for example, the use of a recombinant nucleic acid, such as a cDNA encoding a protein or an antisense sequence, for insertion into an expression system, such as an expression vector; The resulting construct is introduced into a cell and the cell expresses the nucleic acid and protein, if appropriate. Recombinant techniques also encompass the ligation of nucleic acids to coding or promoter sequences from different sources in an expression cassette or vector for the expression of a fusion protein, constitutive expression of a protein or inducible expression of a protein. As used herein, the terms "subject", "individual" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans. As used herein, “associated” refers to coincidence with the development or manifestation of a disease, condition or phenotype. The association may be due to, but is not limited to, genes responsible for housekeeping functions whose alteration may provide the basis for a variety of diseases and conditions, those that are part of a pathway that is involved in a disease, condition or phenotype specific and those that indirectly contribute to the manifestation of a disease, condition or phenotype. As used herein, “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to an excipient that may optionally be included in the compositions of the disclosure and that does not cause significant adverse toxicological effects to the patient. In particular, in the present case, it refers to an excipient that can be taken into the body of the mammalian subject in association with an active compound (here PEGylated htCBS or "20NHS PEG-CBS") without significant adverse toxicological effects for the subject. As used herein, the terms "adjuvant", "diluent" or "carrier" mean any substance, which is not itself a therapeutic agent, used as a carrier for the administration of a therapeutic agent and suitable for administration to a subject, for example, a mammal or added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a dosage unit of the composition in a discrete article such as a capsule or tablet suitable for oral administration. The terms "adjuvant", "diluent" or "carrier" encompass "excipients", including "pharmaceutically acceptable excipients", "carriers", "solvents" and the like, as those terms are used herein. The ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO excipients and carriers include any material known in the art, for example, any liquid, gel, solvent, liquid diluent, solubilizer or the like, that is non-toxic, and that does not interact with other components of the composition in a harmful way. Administration may mean oral administration, inhalation, enteral administration, feeding, or inoculation by intravenous injection. Excipients may include standard pharmaceutical excipients and may also include any components that can be used to prepare foods and beverages for human and / or animal consumption, feed or bait formulations or other food products. As used herein, “drug” or “pharmacologically active agent” or any other similar term means any chemical or biological material or compound, including peptides, suitable for administration by methods previously known in the art and / or by the methods taught in the present disclosure, which induces a desired biological or pharmacological effect, which may include, but is not limited to (1) having a prophylactic effect on the organism and preventing an unwanted biological effect such as preventing an infection, (2) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of the disease, and / or (3) either alleviating, reducing, or completely eliminating the disease from the body. The effect may be local, such as providing a local anesthetic effect, or it may be systemic. This disclosure does not refer to new permeants or new classes of active agents. Rather, it is limited to the mode of delivery of agents or permeants that exist in the state of the art or that may later be established as active agents and that are suitable for delivery according to the present disclosure. As used herein, the term “approximately,” particularly in reference to a given quantity, is intended to encompass deviations of plus or minus five percent. As used herein, the terms “pharmacologically effective amount” or “therapeutically effective amount” in relation to the present composition refer to a non-toxic but sufficient amount of the active agent (or composition containing the active agent) to provide the desired level, in the bloodstream or at the site of action (e.g., intracellularly) in the subject to be treated, and / or to provide a desired physiological, biophysical, biochemical, pharmacological or therapeutic response, such as the improvement of manifestations of homocystinuria. The exact amount required will vary from subject to subject and will depend on numerous factors, such as the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, the patient's intended use (i.e. These factors and considerations can be readily determined by one skilled in the art, based on the information provided herein. An appropriate “effective” amount in any individual case can be determined by one skilled in the art using routine experimentation, based on the information provided herein. These factors and considerations can be readily determined by one skilled in the art, based on the information provided herein. An appropriate “effective” amount in any individual case can be determined by one skilled in the art. normal in the art using routine experimentation, based on the information provided in this document. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO As used herein, the term “nucleic acid” may be in the form of RNA or in the form of DNA, and includes messenger RNA, synthetic RNA and DNA, cDNA, and genomic DNA. DNA can be double-stranded or single-stranded, and if it is single-stranded it can be the coding strand or the non-coding strand (antisense, complementary). As used herein, a “mutant” is a mutated protein designed or manipulated to alter properties or functions related to glycosylation, protein stabilization and / or ligand binding. As used herein, the terms “native” or “wild type” in relation to a given cell, polypeptide, nucleic acid, trait or phenotype, refers to the form in which it is typically found in nature. As used herein, the terms "protein", "polypeptide", "oligopeptide" and "peptide" have their conventional meaning and are used interchangeably to indicate a polymer of at least two amino acids covalently linked by an amide bond, regardless of the length or post-translational modification (e.g., glycosylation, phosphorylation, lipidation, myristylation, ubiquitination, etc.). Furthermore, the polypeptides described herein are not limited to a specific length. Included within this definition are D- and L-amino acids, and mixtures of D- and Lamino acids. This term also does not refer to or exclude modifications subsequent to the expression of the polypeptide, for example, glycosylations, acerations, phosphorylations and the like, as well as other modifications known in the art, both natural and non-natural. A polypeptide can be a complete protein or a subsequence thereof. Polypeptides can also refer to amino acid subsequences that comprise epitopes, that is, antigenic determinants substantially responsible for the immunogenic properties of a polypeptide and that are capable of eliciting an immune response. As used herein, “position corresponding to” and the like refers to a position of interest (i.e., base number or residue number) on a nucleic acid or protein molecule relative to the position on another molecule. of reference nucleic acid or protein. Corresponding positions can be determined by comparing and aligning sequences to maximize the number of matching nucleotides or residues, for example, so that the identity between sequences is greater than 90%, greater than 95%, greater than 96%, greater than 97 %, greater than 98% or greater than 99%. The position of interest is then assigned the assigned number on the reference nucleic acid molecule. For example, if a particular polymorphism in Gene-X occurs at nucleotide 2073 of SEQ ID NO: Since various alleles may have different lengths, the position designated by 2073 may not be nucleotide 2073, but rather is at a position that “corresponds” to the position in the reference sequence. As used herein, the term “long-term administration” refers to the administration of the CBS enzyme, htCBS or mutant htCBS (e.g., with a C15S mutation) conjugated to a PEG moiety for a period of time. 6 weeks or more. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO As used herein, the term “continuous administration” refers to repeated administration of the CBS enzyme, htCBS, or mutant htCBS (e.g., with a C15S mutation) conjugated to a PEG moiety over the course of a study. by subcutaneous injection or implanted osmotic pump. . Described herein are methods for treating homocystinuria through enzyme therapy (ET) with the drug product described herein that includes a PEGylated truncated human CBS protein with a mutation at amino acid position 15 from a cysteine ​​to a serine. Details of one or more types of disclosure are set forth in the description attached below. Although any materials and methods similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, preferred materials and methods are now described. Other features, objects and advantages of the disclosure will be apparent from the description. In description, singular forms also include the plural unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this disclosure pertains. In the event of a conflict, this description will prevail. The present description is further illustrated by the following non-limiting examples. EXAMPLES Example 1. Experimental Protocols A. Fermentation An expression vector, harboring the sequence encoding truncated human CBS, was transformed into E. coli BI-21 (DE3) bacteria, and bacteria from kanamycin-resistant clones were grown in 5 ml of Luria-Bertani medium ( LB), with 30 pg / ml kanamycin, overnight at 37°C on a rotary shaker at 275 rpm. One ml of the overnight culture was added to 100 ml of Terrific Broth (TB) medium with 30 pg / ml kanamycin and cultured overnight. Ten ml of the preculture was then added to 1 liter of TB medium containing 0.001% thiamine-HCI pH 8.0, 0.0025% pyridoxine-HCI pH 8.0, 0.3 mM δ-ALA pH 8.0, 150 pM ferric chloride, 30 pg / mL of kanamycin. The culture was then grown at 30°C on a rotary shaker at 275 rpm until the OD600 reached the value of approximately 0.6-0.7 and protein expression was induced by the addition of 1 mM IPTG. Fermentation was continued for a further 16 hours. Cells were harvested by 10 min of centrifugation with relative centrifugal force (rcf) of 6000 at 4°C, washed with ice-cold 0.9% NaCl, centrifuged again as before, and frozen at −80°C. Next, lysis buffer (20 mM NaH2PO4, pH 7.2, 40 mM NaCl, 0.1 mM PLP) was added to the cell pellet and the latter was homogenized in a Dounce homogenizer and treated with lysozyme (2 mg / ml final), incubated for 1 hour at 4°C on a rocking platform, sonicated to reduce viscosity, and centrifuged at 53,000 rcf. The supernatant, comprising the soluble fraction, was then stored at −80°C. MA / t / ZUZZ / U1 Optimization and scale-up plans were designed to establish a fermentation process for high-level expression of CBS, quantities and addition profiles of media supplements such as 5-aminolevulinic acid (ALA), thiamine (vitamin B1), pyridoxine HCl and / or ferric chloride, C source and its starting and feeding conditions, temperature, pH and induction conditions (concentration of the inducer and duration of the induction period). The highest cell density and best expression levels were achieved with minimal salt medium (source C: glycerol), supplemented with a total of 0.05 g / L B6 and 0.5 g / L ALA during an induction period of 24 hours to 30 °C. At the end of fermentation (EOF), a cell density at 600nm (OD600) of approximately 110±10 was achieved, which corresponded to a wet weight of approximately 90±10g / L. The CBS titer of the fermentation process was approximately 2.5-3.0 g CBS / L as determined by colorimetric and radioactive activity assays. B. Purification The overall enzyme activity recovery target for enzyme purified from cell lysate was 30%, assuming at least three chromatography steps were required. The developed process was evaluated on the scale of a 60 mL capture column. 1. Capture Step Anion exchange chromatography (AEX) was used as the first capture step in the production of recombinant CBS. The eluate was then polished for further purification by capture on DEAE-Sepharose resin at near-neutral pH, followed by a linear gradient of KH2PO4. DEAE-Sepharose is a weak exchanger, meaning that the loading of the system depended on the pH of the environment. Therefore, pH has a close relationship with the dynamic binding capacity (DBC) of the resin. Reducing the binding pH to 6.4 did not decrease the performance of the capture step. The loading time was approximately 30 minutes if the cell paste dilution used 5 volumes of disruption buffer for solubilization. Washing was performed for a column volume of 10 with a loading capacity close to the determined maximum of 7 g / L CBS (equivalent to a DBC of approximately 35 g total protein per L resin). Elution was carried out under conditions of elution conductivity of 16 mS / cm in the presence of 120 mM NaCl. The recovery was observed to be approximately 90% as long as the cell extract was loaded in a narrow time frame. Depending on the CBS titer within the cell extract, a purification factor of approximately 3.5 was achieved in this capture step. ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO 2. Immobilized metal affinity chromatography (IMAC) IMAC, also known as immobilized metal affinity chromatography Co2+, with zinc (Zn) ions, uses binding selectivity for orthogonal separation between CBS and host cell protein (HCP). A purification factor of approximately 2.5 was observed. The elution step included 11 mM imidazole in combination with desalting the CBS fraction. The sodium chloride concentration was reduced from 400 mM (load / wash) to 50 mM within the elution buffer. It could be demonstrated in small-scale projections that conductivity has a great influence on the elution behavior itself. For example, it was possible to elute CBS only with pure water, without imidazole. The stability of CBS was increased by increasing the amount of sodium chloride within the elution buffer. At 150 mM sodium chloride, the elution behavior only changed slightly. Using HEPES as a buffer system, a DBC of 12-15 g / L could be measured. Furthermore, the stability of the sample increased not only for precipitation, but also degradation decreased. By adding EDTA, degradation was stopped by using HEPES buffer, in contrast to the phosphate buffer system currently used. In scaling, EDTA and ammonium sulfate were added immediately after completing the elution, which should inhibit degradation. Furthermore, the following polishing was performed as quickly as possible to keep the incubation time in this state short. The IMAC elution pool was loaded onto a hydrophobic interaction chromatography (HIC) column within 3 h for polishing. 3. Polishing step The separation in the final chromatography step of the CBS purification train was based on the hydrophobic interaction. The main column separated the protein of interest, CBS, from the majority of the HCPs by differences in elution conditions. Most HCP binds more strongly to HIC than to CBS, indicating that CBS is less hydrophobic than most of the remaining HCPs. Compared with IMAC, HIC has low bond separation (less than 10%). More than 90% of the remaining HCP impurities were separated from the HIC by the elution step. CBS recovery from HIC was approximately 95%. The DBC was between approximately 16 g / L and approximately 18 g / L. The performance of this polishing step was quite robust. The pH for the elution step was between 6 and 8. The buffer system (phosphate or 20 mM HEPES) had no measurable influence. The purification factor for this polishing step was approximately 1.1 due to the low remaining HCP content within the batch, which was typical of a final chromatography step. The purity of the final CBS among all subsequent production processes performed was similarly high, indicating that this polishing step compensated for different degrees of impurities within the filler. Adaptations can be made in order to adapt the process steps to the existing equipment and allow later scaling up to a fermentation volume of 100 I for production. To ensure reliable product quality, EDTA (e.g. 10 mM) can be added at various process steps, to avoid product degradation caused by metalloproteases. ivia / t / zuzz / u i rao o C. PEGylation The PEGylation reaction behaved as a second-order reaction with product-induced inhibition. Since hydrolysis in NHS-PEG cannot be the reason for reaction inhibition and the final PEGylation pattern was reached after 4 h of PEGylation, the remaining NHSPEG (approximately 50%) was observed to be still active. Interestingly, addition of more NHS-PEG to the reaction mixture increased the PEGylation pattern. The concentration of CBS was 8 g / L within the reaction mixture to obtain the desired PEGylation pattern without increasing the ratio of NHS-PEG to CBS in the absence of DMSO. D. Data and statistical analysis Table 4 provides details on the software, analytical tools, and algorithms used for data analysis in the Examples herein. ivia / t / zuzz / u ι rao o Table 4. Programs v Statistical Analysis Acquisition of chromatograms and integration of chromatographic peaks Software AB Sciex ANALYSTTM 1.6 Standard regression, concentration calculations, data management Thermo Scientific Watson LIMS™ Interface between Watson LIMS and the data system Text file Calculations for control SS and WS Microsoft Excel Linear Regression Model Weight factor 1 / x2 Concentration presentation 3 significant figures concentration unit pmol / L or matrix equivalent μΜ Reported summary statistics Mean, SD, %DEV, %CV Number of decimal places for % DEV and %CV 2 The analyst reviewed all chromatograms to ensure that chromatographic peak shape and peak integrations were satisfactory. The manually transferred data were cross-checked with the source data that is part of the raw data of the study. Run acceptance criteria were established prior to analysis based on the results of calibration standards, quality control, and blank quality controls. Data are presented as mean ± standard error of the mean (SEM). Statistical analysis was performed using ANOVA followed by Tukey's multiple comparison test to determine significance. E. CBS Activity Assay Based on Conversion of Being Radiolabeled CBS catalyzes a β-replacement reaction where serine (Ser) condenses with Hcy in a pyridoxal 5'-phosphate (PLP)-dependent manner to form Cth. CBS enzyme activity was determined by a radioisotope assay using 14C-labeled Ser as a substrate: 14C-L-Ser + L-Hcy14C-L-Cth + H2O A 7 μΙ aliquot (total 420 ng) of pure 20NHS PEG-CBS in dilution buffer (0.1 M Tris-HCI at pH 8.6 containing 1 mM DTT, 10 μΜ PLP, and 0.5 mg / ml bovine serum albumin (BSA)) or 7 μΙ Plasma (no need for dilution for samples D25 and D27) was added to 88 μΙ reaction mixture (0.1 M Tris-HCI at pH 8.6 containing 10 mM L-Ser, 0. mM PLP , 0.5 mg / ml BSA and 0.3 pCi L- [14C (U)]-Ser). Samples were equilibrated at 37°C by incubating in a water bath for 5 min. The reaction was started with 5 μΙ of 0.2 M Hcy (final concentration 10 mM) and incubated for an additional 30 min at 37°C. The start of the assay and the sampling of the resulting mixture were alternated so that each reaction time was exactly 30 min. Falling paper chromatography was used to separate the radioactive product (Cth) from the labeled substrate (Ser). To stop the reaction, the assay mixture was cooled in an ice bath and a 20 μΙ aliquot was pipetted onto CHR grade 3 chromatography paper (Whatman, GE Healthcare, Pittsburgh, PA, USA) for separation. The 14C-Cth formed in the reaction was separated from 14C-Ser by eluting overnight with 2-propanol:formic acid:H2O (75:5.7:18.9 v / v). A standard containing a mixture of Cth and Ser was run along with samples on each side of the chromatography paper. The chromatography paper was dried and the standard lanes were stained with an acid ninhidñna solution. Areas from each sample lane containing labeled Cth were excised, immersed in 5 ml of Opti-flour scintillation cocktail (PerkinElmer, North Billerica, MA, USA), and counted in a Beckman LS3801 scintillation counter. An enzyme-free sample was used as a blank to monitor background radioactivity and this was subtracted from the counts in each sample. For the pure enzyme control, CBS-specific activity values ​​were expressed as units of enzyme (the amount of enzyme that produces 1 μmol of Cth / h) per mg of CBS (i.e., U / mg of protein). For plasma samples, activity values ​​were expressed as milliunits (the amount of enzyme that produces 1 nmol of Cth / h) per μΙ of plasma (i.e., mU / μΙ of plasma). These stock solutions with a nominal value of 25 mg / ml (24.8-26.7 mg / ml in phosphate-buffered saline, pH 7.4 (PBS)) were stored in aliquots at −80°C. On each treatment day, fresh single-use enzyme solutions were prepared by diluting the stock solutions in PBS to final concentrations of 1 mg / ml and administered to the mice at a dose of 7.5 mg / kg. The volumes injected to deliver the target dose were calculated based on the weights on the indicated days. Any remaining solution was discarded at the end of that day's injections. F. Immunoblot The drug product was injected into four I278T − / − mice, and blood was collected 24 hours after the first injection and 72 hours after the last injection to serve as a control. Plasma samples D25 and D27 from all groups of Example 5 were analyzed by immunoblot to detect possible dePEGylation in vivo. Plasma samples (4 μΙ per lane) were loaded onto MiniProtean TGX gradient gels (4%-20%) (Bio-Rad, Hercules, CA, USA) and proteins were separated by electrophoresis under denaturing and reducing conditions. Molecular weight markers (Precision Plus Protein Dual Color Standard, Bio-Rad) and aliquots of each preparation (150-500 ng per lane) were processed similarly and electrophoresed along with the plasma samples. After ΜΛ / Ε / ΖυΖΖ / υΊ ÍVÓO electrophoretic separation, protein bands were transferred to PVDF membranes (BioRad). Individual membranes were blocked overnight at 4°C in blocking solution (5% skim milk in PBS with 0.02% Tween 20). The membranes were then washed and incubated with rabbit polyclonal anti-hCBS antibody (Orphan Technologies UCD Kraus lab lot # R2B2, antiserum diluted 5000-fold in blocking solution) for 1 h. The membranes were then washed and incubated with horseradish peroxidase (HRP)-conjugated anti-rabbit IgG (Jackson Laboratories, Bar Harbor, ME, USA, diluted 5000-fold in blocking solution) for 30 minutes. After washing the membranes, the bands were visualized by incubating with a chemiluminescent substrate (SuperSignal West Pico, ThermoFisher Scientific, Waltham, MA, USA) for 5 min, followed by signal capture on light blue X-ray film (CL -Xposure Film, ThermoFisher Scientific). The developed films were scanned using a flatbed scanner (Perfection V550 Photo Color Scanner, Epson, Long Beach, CA, USA). G. Chemicals Unless otherwise noted, all materials were purchased from Sigma or Fisher Scientific. L-[U-14C]-serine was obtained from Perkin Elmer Life Sciences. H. Plasma collection and analysis A single-use submandibular bleeding lancet was used for blood collection into BD Microtainer PST tubes with lithium heparin (Becton, Dickinson and Company, NJ, USA). The tubes were then centrifuged at 10,000 x g for 5 min, followed by plasma transfer to 1.5 ml tubes and storage at −80°C. Plasma sulfur amino acid metabolites were determined by stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS / MS) as described elsewhere. I. Animal studies Studies were carried out using a strain of CBS knockout mice expressing the human I278T mutant CBS transgene (I278T CBS − / − (I278T − / −) mice). A breeding pair of heterozygous transgenic I278T mice on the C57BL6 background were provided by Dr. Warren Kruger (Fox Chase Cancer Center, Philadelphia, PA, USA). The mice have the mouse CBS gene inactivated and also express the human CBS I278T, under the control of the metallothionein promoter (see Wang, et al. (2005) Hum Mol Genet 14, 2201-2208, which is incorporated herein by reference in its entirety). The mutant enzyme has approximately 2% to 3% of the activity of WT CBS, so expression of the transgene rescue...

Claims

1. A pharmacological substance comprising: (a) an isolated cystathionine β-synthase (CBS) protein comprising SEQ ID NO: 1; and (b) a PEG molecule covalently linked to the CBS protein.

2. The pharmacological substance according to claim 1, wherein the PEG molecule is ME-200GS.

3. A pharmaceutical composition comprising: the pharmacological substance according to any of claims 1 and 2 and a pharmaceutically acceptable excipient, adjuvant, diluent or carrier.

4. A formulation of the pharmaceutical composition according to claim 3, wherein the formulation is lyophilized.

5. The lyophilized formulation according to claim 4, wherein, after reconstitution, the reconstituted liquid formulation comprises: (a) the drug substance at a concentration of approximately 20-30 mg / ml; (b) approximately 15 mM potassium phosphate; and (c) approximately 8% (w / v) trehalose.

6. A reconstituted formulation according to claim 5, wherein a unit dose of the formulation comprises: (a) approximately 25 mg of the drug substance; and (b) 1 ml of water.

7. A method for treating homocystinuria in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition in accordance with any of claims 4-6.

8. The method according to claim 7, wherein the therapeutically effective amount is a dosage selected from the range of approximately 0.25 mg / kg to approximately 10 mg / kg.

9. The method according to claim 8, wherein the dosage is approximately 0.33 mg / kg.

10. The method according to claim 8, wherein the dosage is approximately 0.66 mg / kg.

11. The method according to claim 8, wherein the dosage is approximately 1.0 mg / kg.

12. The method according to claim 8, wherein the dosage is approximately 1.5 mg / kg.

13. The method according to any of claims 7-12, further comprising administering to the subject at least one selected from the group consisting of: pyridoxine, vitamin B6 and betaine.

14. The method according to any of claims 7-13, wherein the subject follows a methionine (Met) restricted diet.

15. The method according to any of claims 7-14, further comprising administering an antiplatelet agent.

16. The method according to claim 15, wherein the antiplatelet agent is a warfarin blood thinner or an anticoagulant agent.

17. The method according to any of claims 7-16, wherein the administration step occurs approximately once every 3 days.

18. The method according to any of claims 7-16, wherein the administration step occurs approximately once a day.

19. The method in accordance with any of claims 7-16, wherein the administration step occurs approximately once a week.

20. The method according to any of claims 7-19, wherein the administration step is repeated for approximately 6 weeks.

21. The method according to any of claims 7-19, wherein the administration step is repeated for approximately 3 months.

22. The method according to any of claims 7-19, wherein the administration step is repeated for approximately 6 months.

23. The method according to any of claims 7-19, wherein the administration step is repeated for more than 6 months.

24. The method in accordance with any of claims 7-19, wherein the administration step is repeated for the remainder of the subject's life.

25. A method for lowering the homocysteine ​​(Hcy) level in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition in accordance with any of claims 4-6.

26. The method according to claim 25, wherein the Hcy level is less than approximately 80 μM after the administration step.

27. The method according to claim 25, wherein the Hcy level is reduced by up to 10% after the administration step.

28. The method according to claim 25, wherein the Hcy level is reduced by up to 20% after the administration step.

29. The method according to claim 25, wherein the Hcy level is reduced by up to 30% after the administration step.

30. The method according to claim 25, wherein the Hcy level is reduced by up to 40% after the administration step.

31. The method according to claim 25, wherein the Hcy level is reduced by up to 50% after the administration step.

32. The method according to claim 25, wherein the Hcy level is reduced by up to 60% after the administration step.

33. The method according to claim 25, wherein the Hcy level is reduced by up to 70% after the administration step.

34. The method according to claim 25, wherein the Hcy level is reduced by up to 80% after the administration step.

35. The method according to claim 25, wherein the Hcy level is reduced by up to 90% after the administration step.

36. The method according to any of claims 25-35, wherein the 0 level of Hcy is within the range of approximately 10 pM to approximately 20 pM after the administration step.

37. The method according to any of claims 25-35, wherein the Hcy level is less than 10 pM after the administration step.

38. The method according to any of claims 25-35, wherein the Hcy level is approximately 55 pM after the administration step.

39. The method according to any one of claims 25 to 38, wherein the therapeutically effective amount is a dosage selected from the range of approximately 0.25 mg / kg to approximately 10 mg / kg.

40. The method according to claim 39, wherein the dosage is approximately 0.33 mg / kg.

41. The method according to claim 39, wherein the dosage is approximately 0.66 mg / kg.

42. The method according to claim 39, wherein the dosage is approximately 1.0 mg / kg.

43. The method according to claim 39, wherein the dosage is approximately 1.5 mg / kg.

44. The method according to claim 39, wherein the dosage is approximately 7.0 mg / kg.

45. The method according to claim 39, wherein the dosage is approximately 10 mg / kg.

46. The method according to claim 39, wherein the dosage is less than 10 mg / kg.

47. The method according to any of claims 25-46, further comprising administering to the subject at least one selected from the group consisting of: pyridoxine, vitamin B6, and betaine. 48.The method according to any of claims 25-47, wherein the subject follows a methionine (Met) restricted diet.

49. The method according to any of claims 25-48, further comprising administering an antiplatelet agent.

50. The method according to claim 49, wherein the antiplatelet agent is a warfarin blood thinner or an anticoagulant.

51. The method according to any of claims 25-50, wherein the administration step occurs approximately once every 3 days.

52. The method according to any of claims 25-50, wherein the administration step occurs approximately once a day.

53. The method according to any of claims 25-50, wherein the administration step occurs approximately once a week. 54.The method according to any of claims 25-50, wherein the administration step is repeated for approximately 6 weeks.

55. The method according to any of claims 25-50, wherein the administration step is repeated for approximately 3 months.

56. The method according to any of claims 25-50, wherein the administration step is repeated for approximately 6 months.

57. The method according to any of claims 25-50, wherein the administration step is repeated for more than 6 months.

58. The method according to any of claims 25-50, wherein the administration step is repeated for the remainder of the subject's life. 59.A method for increasing the level of cysteine ​​(Cys) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition according to any one of claims 4-6.

60. A method for increasing the level of cystathionine (Cth) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition according to any one of claims 4-6.

61. A method for treating, alleviating, or preventing adverse clinical outcomes associated with the ocular system, skeletal system, vascular system, and / or central nervous system of a subject, the method comprising: administering to the subject a therapeutically effective amount of the formulation of the pharmaceutical composition according to any one of claims 4-6.