A method for treating Alan Handon Dudley syndrome

Abstract

The present subject matter relates to a method of treating Alan Houghton Dudley syndrome, the method comprising administering 3,5-diiodothyropropionic acid (DITPA) to a subject in need thereof, wherein administration of DITPA reduces serum levels of triiodothyronine (“T3”) to normal, increases T3 brain levels to normal, and maintains normal serum levels of thyroxine (T4) and thyroid stimulating hormone (TSH). The subject may be a child or an adult.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 388,242, filed on July 11, 2022, the entire content of which is incorporated herein by reference.

[0002] The present technology relates to a method for treating Allan - Herndon - Dudley syndrome, the method comprising administering 3,5 - diiodothyropropionic acid (DITPA) to a subject in need thereof, which by administration at about 2.5 milligrams per kilogram of body weight of the subject per day, reduces the serum level of triiodothyronine ( "T3") to normal, increases the T3 brain level to normal, and maintains normal serum levels of thyroxine ( "T4") and thyroid - stimulating hormone ( "TSH").

Background Art

[0003] Allan - Herndon - Dudley syndrome ( "AHDS") is an X - linked recessive developmental disorder that causes intellectual and motor disabilities in males. Specifically, AHDS patients have a mutated SLC16A2 gene, as a result of which the monocarboxylate transporter 8 ( "MCT8") protein is abnormal. The symptoms of AHDS are usually caused by the lack of uptake of the thyroid hormone triiodothyronine ( "T3"), which is normally transported across the cell membrane by MCT8, into cells. Due to this MCT8 deficiency, T3 is insufficient in the tissues where it is required for proper functioning, and T3 accumulates in the serum. The other thyroid hormone, thyroxine ( "T4"), usually remains at normal serum levels in AHDS patients, although it may decrease slightly from normal levels. In AHDS patients, the thyroid - stimulating hormone ( "TSH") is slightly elevated from normal.

[0004] Currently, there is no treatment for AHDS approved by the US Food and Drug Administration. Clinical trials of triiodothyroacetic acid (“TRIAC”), a drug used for the treatment of AHDS, have been completed. However, since TRIAC is structurally similar to T3, it becomes difficult to accurately evaluate T3 serum levels. Furthermore, TRIAC has been shown to significantly reduce the serum levels of thyroxine (“T4”). See Groeneweg et al. Lancet Diabetes Endocrinol. 2019 Sep;7(9);695-706.

[0005] 3,5-Diiodothyropropionic acid (“DITPA”) is another thyroid hormone analog that has been studied for the treatment of AHDS. However, as mentioned above, DITPA is still not approved for use in the treatment of AHDS. The reason for this lack of approval may be due to the absence of an effective dosing regimen, a stable and effective composition, and extensive pharmacological evaluation. International Publication No. WO 2012 / 171065, published on December 20, 2012, attempts to establish a DITPA dosing regimen for AHDS patients, but this publication only provides theoretical examples.

[0006] Accordingly, there is a need in the art for specific DITPA dosages that are effective in treating AHDS and the symptoms of AHDS by reducing T3 levels while maintaining normal levels of T4 and TSH. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] DISCLOSURE The applicant has discovered a dosage of 3,5-diiodothyropropionic acid (“DITPA”) that is surprisingly effective in treating Alan Houghton Dudley Syndrome (“AHDS”) while maintaining normal serum levels of thyroxine (“T4”) and thyroid stimulating hormone (“TSH”).

[0008] The present technology relates to a method of treating Allan-Herndon-Dudley syndrome, the method comprising administering 3,5-diiodothyropropionic acid (DITPA) to a subject in need thereof, by administering at about 2.5 milligrams per kilogram of body weight of the subject per day, reducing the serum level of triiodothyronine (“T3”) to normal, increasing the T3 brain level to normal, increasing or maintaining the normal serum level of thyroxine (T4), and reducing or maintaining the normal serum level of thyroid stimulating hormone (TSH).

DETAILED DESCRIPTION OF THE INVENTION

[0009] The applicant has discovered a dosage of 3,5-diiodothyropropionic acid (“DITPA”) that is surprisingly effective in treating Allan-Herndon-Dudley syndrome (“AHDS”) while maintaining normal serum levels of thyroxine (“T4”) and thyroid stimulating hormone (“TSH”).

[0010] T4 is the main thyroid hormone that passes through the blood-brain barrier, and TSH regulates the production of both T3 and T4 by the thyroid gland. Therefore, it is important to maintain normal serum levels of T4 and TSH.

[0011] In one embodiment, the subject matter relates to a method of treating Allan-Herndon-Dudley syndrome, the method comprising a) administering 3,5-diiodothyropropionic acid (“DITPA”) to a subject in need thereof daily for 2 weeks at a first daily dosage; b) administering DITPA to the subject daily for 2 weeks at a second daily dosage that is higher than the first daily dosage; c) measuring the serum level of triiodothyronine (“T3”) in the subject; d) adjusting the dosage of DITPA administered to the subject based on the T3 serum level of the subject, wherein if the T3 serum level is too high, a third daily dosage higher than the second daily dosage is administered, and if the T3 serum level is too low, a fourth daily dosage lower than the second daily dosage is administered.

[0012] In another embodiment, the subject matter relates to a method of treating Allan-Herndon-Dudley syndrome, the method comprising: a) administering 3,5-diiodothyropropionic acid ("DITPA") to a subject in need thereof at a first daily dosage for two weeks; and b) administering DITPA to the subject at a second daily dosage greater than the first daily dosage for two weeks, wherein administration begins on the third day after the subject's birth.

[0013] In one embodiment, the technology relates to a method of treating AHDS, the method comprising administering DITPA to a subject in need thereof, wherein administering at about 2.5 milligrams per kilogram of the subject's body weight per day reduces T3 serum levels to normal, increases T3 brain levels to normal, increases or maintains normal serum levels of thyroxine (T4), and reduces or maintains normal serum levels of thyroid stimulating hormone (TSH).

[0014] As used herein, the term "normal T3 serum level" refers to a T3 serum level that is considered normal for the age of the subject.

[0015] As used herein, the term "normal T3 brain level" refers to a T3 brain level that is considered normal for the age of the subject.

[0016] As used herein, the term "normal T4 serum level" refers to a T4 serum level that is considered normal for the age of the subject.

[0017] As used herein, the term "normal TSH serum level" refers to a TSH serum level that is considered normal for the age of the subject.

[0018] As used herein, the "normal" serum levels of T3, T4 and TSH by age of the subject are disclosed in Lem et al., Serum thyroid hormone levels in healthy children from birth to adulthood and in short children born small for gestational age, J Clin Endocrinol Metab, 2012 Sep, 97(9), 3170-8, doi:10.1210 / jc.2012-1759, Epub 2012 Jun 26.

[0019] As used herein, the term "too high" with respect to T3 serum levels refers to a T3 serum level that exceeds by about 15% the T3 serum level considered normal for the age of the subject.

[0020] As used herein, the term "too low" with respect to T3 serum levels refers to a T3 serum level that is lower by about 15% or more than the T3 serum level considered normal for the age of the subject.

[0021] In a preferred embodiment, the daily dose of DITPA is administered once daily to a subject in need thereof, more preferably, the daily dose of DITPA is divided into two portions, each portion being administered every 12 hours or twice a day, and most preferably, the daily dose of DITPA is divided into three portions, each portion being administered every 8 hours or three times a day. The subject may be a child or an adult.

[0022] In another preferred embodiment, the method of treating AHDS is a) administering DITPA daily to a subject in need thereof at a first daily dose for two weeks; and b) administering DITPA daily to the subject at a second daily dose that is higher than the first daily dose for two weeks, Preferably, the daily administration is started after at least 3 days have elapsed since the birth of the subject.

[0023] In a preferred embodiment, a method of treating Alan Houghton Dudley syndrome comprises a) administering DITPA to a subject in need thereof daily for 2 weeks at a first daily dosage; b) administering DITPA to the subject daily for 2 weeks at a second daily dosage greater than the first daily dosage; c) measuring the serum level of triiodothyronine ("T3") in the subject, and if the T3 serum level is normal, administering the second daily dosage daily; d) optionally, adjusting the daily dosage of DITPA administered to the subject based on the T3 serum level of the subject measured in step c), wherein if the T3 serum level is too high, a third daily dosage greater than the second daily dosage is administered daily, and if the T3 serum level is too low, a fourth daily dosage less than the second daily dosage is administered daily; e) optionally, measuring the T3 serum level of the subject on or about the 28th day after the first administration of the third or fourth dosage, and if the T3 serum level is normal, administering the third or fourth dosage daily; f) optionally, adjusting the daily dosage of DITPA administered to the subject based on the T3 serum level of the subject measured in step e), wherein if the T3 serum level is too low after daily administration of the third dosage, the second daily dosage is administered to the subject, if the T3 serum level is too low after daily administration of the fourth dosage, the first dosage is administered to the subject, and if the T3 serum level is too high after daily administration of the fourth dosage, the second dosage is administered to the subject.

[0024] In a preferred embodiment, the first dosage is about 1 milligram per kilogram of body weight per day ("mg / kg / day").

[0025] In another preferred embodiment, the second dosage is about 2 mg / kg / day.

[0026] In another preferred embodiment, the third dosage is about 2.5 mg / kg / day.

[0027] In another preferred embodiment, the fourth dosage is about 1.5 mg / kg / day.

[0028] In a preferred embodiment, DITPA is administered to subjects under 18 years of age.

[0029] In a preferred embodiment, the administration of DITPA is carried out via the oral route.

[0030] In one embodiment, DITPA can be formulated in a composition comprising DITPA or a salt thereof and one or more pharmaceutically acceptable excipients.

[0031] In a preferred embodiment, DITPA or a salt thereof can be present in the pharmaceutical composition of the present subject matter at a concentration of about 0.001% to about 10% w / w or w / v. The formulation may be administered orally, for example. Oral tablets may be, for example, dispersible tablets for oral suspensions. The oral dosage may be in the range of, for example, 0.5 to 2.5 mg / kg / day based on the patient's T3 level.

[0032] In a preferred embodiment, one or more pharmaceutically acceptable excipients can be present in the pharmaceutical composition of the present subject matter at a concentration of about 90% to about 99.999% w / w or w / v.

[0033] Pharmaceutically acceptable excipients suitable for use in the present technology include, but are not limited to, disintegrants, binders, fillers, plasticizers, lubricants, penetration enhancers, surfactants, sweeteners, sweetening enhancers, flavoring agents, and pH adjusters.

[0034] As used herein, the term "disintegrant" refers to a pharmaceutically acceptable excipient that promotes the disintegration of a tablet when the tablet comes into contact with water or other liquids. Disintegrants suitable for use in the present technology include, but are not limited to, natural starches such as corn starch and potato starch, directly compressible starches such as starch 1500, modified starches such as carboxymethyl starch, sodium hydroxymethyl starch, and sodium starch glycolate, as well as starch derivatives such as amylose, cross-linked polyvinylpyrrolidones such as crospovidone, cross-linked sodium carboxymethyl cellulose, sodium hydroxymethyl cellulose, calcium hydroxymethyl cellulose, modified celluloses such as croscarmellose sodium and low-substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, methacrylic acid divinylbenzene copolymer salts, and combinations thereof.

[0035] Binders suitable for use in the present subject matter include, but are not limited to, polyethylene glycol, soluble hydroxyalkyl cellulose, polyvinylpyrrolidone, gelatin, natural rubber, and combinations thereof.

[0036] Fillers suitable for use in the present application include, but are not limited to, dibasic calcium phosphate, tribasic calcium phosphate, calcium hydrogen phosphate anhydrous, calcium sulfate and dicalcium sulfate, lactose, sucrose, amylose, dextrose, mannitol, inositol, and combinations thereof.

[0037] Plasticizers suitable for use in the present subject matter include, but are not limited to, microcrystalline cellulose, triethyl citrate, polyhexanediol, acetylated monoglyceride, glyceryl triacetate, castor oil, and combinations thereof.

[0038] Lubricants suitable for use in the present technology include, but are not limited to, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, micronized polyoxyethylene glycol, talc, anhydrous silica colloid, and combinations thereof.

[0039] Penetration enhancers suitable for use in the present technology include, but are not limited to, precipitated silica, maltodextrin, β-cyclodextrin, menthol, limonene, carvone, methyl chitosan, polysorbate, sodium lauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride, cetylpyridinium chloride, disodium edetate dihydrate, sodium deoxycholate, sodium deoxyglycocholate, sodium glycocholate, sodium caprate, sodium taurocholate, sodium hydroxybenzoyl aminocaprylate, dodecyldimethylaminopropionate, L-lysine, glyceryl oleate, glyceryl monostearate, citric acid, peppermint oil, and combinations thereof.

[0040] Surfactants suitable for use in the present application include, but are not limited to, sorbitan esters, sodium docusate, sodium lauryl sulfate, cetrimide, and combinations thereof.

[0041] Sweeteners suitable for use in the present application include, but are not limited to, aspartame, saccharin, acesulfame potassium, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, sucrose, dextrose, mannitol, glycerin, xylitol, and combinations thereof.

[0042] Sweetness enhancers suitable for use in the present technology include, but are not limited to, the ammonium salt forms of crude and purified glycyrrhizic acid.

[0043] Flavoring agents suitable for use in the present technology include, but are not limited to, peppermint oil, menthol, spearmint oil, citrus oils, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, tutti frutti flavor, and combinations thereof.

[0044] pH adjusters suitable for use in the present subject matter include, but are not limited to, hydrochloric acid, citric acid, fumaric acid, lactic acid, sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate, ammonium carbonate, sodium acetate, and combinations thereof.

[0045] In another preferred embodiment, the pharmaceutical composition of the present application does not contain a preservative.

[0046] The pharmaceutical composition of the present technology can be formulated in any dosage form including, but not limited to, aerosol containing measured, powder and spray, chewable bar, beads, coated, film-coated, gel-coated capsules, liquid-filled and coated pellets, cell sheets, chewable gels, concentrates, elixirs, emulsions, films including soluble, film for solution and film for suspension, gels including measured gels, microspheres, granules including granules for solution, granules for suspension, chewing gum, inhalants, injections including foams, liposomes, emulsions, lipid complexes, powders, lyophilized powders and liposome suspensions, liquids, lozenges, ointments, patches, electrically controlled patches, pellets, implantable pellets, pills, powders, powders, measured powders, solutions, measured solutions, solution concentrates, gel-forming solutions / solution drops, sprays, measured sprays, suspensions, suspensions, syrups, tablets, chewable tablets, coated tablets, coated particles in tablets, film-coated tablets, tablets for solution, tablets for suspension, orally disintegrating tablets, soluble tablets, sugar-coated tablets, dispersible tablets, tablets with sensors, tapes, lozenges and wafers, and their sustained-release and delayed-release forms.

[0047] In a preferred embodiment, the pharmaceutical composition of the present technology is in the form of tablets. In a more preferred embodiment, the pharmaceutical composition of the present subject matter is in the form of dispersible tablets. In an even more preferred embodiment, the pharmaceutical composition of the present subject matter is in the form of water-dispersible tablets. In the most preferred embodiment, the pharmaceutical composition of the present technology is in the form of water-dispersible tablets, and the tablets are scored so that they can be divided into four equal parts.

[0048] In a preferred embodiment, when the pharmaceutical composition of the present application is in the form of water-dispersible tablets, the dispersion time of the tablets is within about 70 seconds, more preferably within about 60 seconds, even more preferably within about 40 seconds, even more preferably within about 30 seconds, even more preferably within about 20 seconds, even more preferably within about 10 seconds, and even more preferably within about 5 seconds.

[0049] As used herein, the term "pharmaceutically acceptable" refers to components that are not biologically or otherwise undesirable in oral applications.

[0050] As used herein, all numerical values regarding amounts, weights, etc. are defined as the respective specific values "about", i.e., plus or minus 10%. For example, the phrase "10% w / w" should be understood as "9% - 11% w / w". Accordingly, amounts within 10% of the claimed value are included within the scope of the claims.

[0051] As used herein, "% w / w" refers to the weight percentage of the entire formulation.

[0052] As used herein, "% w / v" refers to the weight percentage based on the volume of the entire formulation.

[0053] As used herein, the term "effective amount" refers to the amount necessary to treat a subject in need of treatment.

[0054] As used herein, the terms "treatment" or "treating" refer to alleviating or ameliorating AHDS or the symptoms of AHDS.

[0055] As used herein, the term "stable" includes, but is not limited to, physical and chemical stability.

[0056] Pharmaceutically acceptable salts that can be used in accordance with this application include, but are not limited to, hydrochloride, hydrochloric acid dihydrate, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, mesylate, maleate, gentisinate, fumarate, tannate, sulfate, tosylate, esylate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p - toluenesulfonate, and pamoate (i.e., 1,1’ - methylene - bis-(2 - hydroxy - 3 - naphthoate)) salts.

[0057] Throughout this application, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural references.

[0058] The disclosed embodiments are merely exemplary embodiments of the inventive concepts disclosed herein and should not be regarded as limiting, unless expressly stated otherwise in the claims.

[0059] The following examples are intended to illustrate the technology and teach those skilled in the art the method of using the formulations of the subject matter. They are not intended to be limiting in any way.

Examples

[0060] Example 1 - Administration of 2.5 mg / kg / day of DITPA to Pediatric Subjects (Predictive) Method 3,5-Diiodothyropropionic acid (「DITPA」) was administered to pediatric patients with Allan-Herndon-Dudley syndrome at a daily dose of 2.5 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. Twenty-eight days after the first administration, T3 serum level, T3 brain level, T4 serum level, and TSH serum level were evaluated.

[0061] Results The T3 serum level of pediatric patients decreased to normal levels, the T3 brain level increased to normal levels, the T4 serum level was maintained at normal levels or increased to normal levels, and the TSH serum level was maintained at normal levels or decreased.

[0062] Example 2 - Dosage Schedule for Pediatric Subjects (Predictive) Method 3,5-Diiodothyropropionic acid (「DITPA」) was administered to pediatric patients with Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, the daily dose was increased to 2 mg / kg / day for another 2 weeks. After another 2 weeks, the T3 serum level was evaluated. The T3 serum level of the patient was found to be more than 15% lower than normal. Thereafter, the patient was administered DITPA at a daily dose of 1.5 mg / kg / day for 28 days, and the T3 serum level was re-evaluated at that time. As a result of the re-evaluation, the T3 serum level was normal.

[0063] Results This dosage schedule can successfully identify the appropriate dosage for pediatric patients to maintain normal T3 serum levels.

[0064] Example 3 - Dosage Schedule for Pediatric Subjects (Predictive) Method DITPA was administered to pediatric patients with Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, the daily dose was increased to 2 mg / kg / day for another 2 weeks. After another 2 weeks, the T3 serum level was evaluated. The patients' T3 serum levels were found to be more than 15% higher than normal. Subsequently, the patients were administered DITPA at a daily dose of 2.5 mg / kg / day for 28 days, and the T3 serum levels were re-evaluated at that time. As a result of the re-evaluation, the T3 serum levels were normal.

[0065] Results This dosing regimen enables the appropriate dose for pediatric patients to maintain normal T3 serum levels to be successfully identified.

[0066] Example 4 - Dosing Regimen for Pediatric Subjects (Predictive) Method DITPA was administered to pediatric patients with Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, the daily dose was increased to 2 mg / kg / day for another 2 weeks. After another 2 weeks, the T3 serum level was evaluated. The patients' T3 serum levels were found to be more than 15% lower than normal. Subsequently, the patients were administered DITPA at a daily dose of 1.5 mg / kg / day for 28 days, and the T3 serum levels were re-evaluated at that time. As a result of the re-evaluation, the T3 serum levels were again found to be more than 15% lower than normal. Subsequently, the patients were administered DITPA at a daily dose of 1.0 mg / kg / day for 28 days, and the T3 serum levels were re-evaluated at that time. As a result of the re-evaluation, the T3 serum levels were found to be normal.

[0067] Results This dosing regimen enables the appropriate dose for pediatric patients to maintain normal T3 serum levels to be successfully identified.

[0068] Example 5 - Detailed Case Report Family #8 (Subjects A1 and A2) The affected twin boys (hereinafter referred to as Subject A1 and A2) were born in Israel to Ashkenazi parents who were non-related and living in Australia. The mother was a carrier of Gaucher disease and had gestational diabetes, which was managed by diet. Amniocentesis revealed a normal male karyotype. The weights of Twin 1 and Twin 2, born at 36 - 37 weeks of gestation, were 2490 and 2733 grams respectively (10 - 25th percentile). The Apgar scores were 9, 9 for both twins. The twins were referred to a doctor because of a delay in the ability to make eye contact until 3 months and to smile until 4 months. At 5 months of age, both were hospitalized for bronchiolitis. The twins were referred to a child development center and were found to have gross motor delay and fine motor delay. By 10 months of age, they were able to roll over but could not sit without support. More specifically, they had poor head control and marked axial hypotonia with delay. They also had a dystonic posture of clenching both hands and holding an extreme supine position, and hyperextension of the legs. Deep tendon reflexes were hyperactive with extensor plantar responses, but there was no clonus. The twins had a wide forehead, a broad nasal bridge, a high arched palate, dolichocephaly (head circumference at the 10th percentile), and several bilateral parietal foramina.

[0069] With the exception of high levels of lactate, ammonia, and creatine kinase, the chemical tests were normal. Amino acids, uric acid, pyruvate acylcarnitine, acylglycine in blood and urine, and guanidinoacetic acid in urine were normal. TSH was 4.7 and 4.1 mU / L (normal range 0.35 - 5.5). Examination of the cerebrospinal fluid of Twin 2 for neurotransmitter disorders gave negative results. Electroencephalogram (EEG) was normal both during wakefulness and sleep. At 9 months of age, both twins showed delayed myelination on magnetic resonance imaging (MRI) and a large choline peak on magnetic resonance spectroscopy (MRS) (1).

[0070] At 18 months of age, the inventors found that in each of Twins 1 and 2, their serum T3 was 54% and 60% higher than the upper limit of normal (ULN), respectively, T4 was 26% and 20% lower than the lower limit of normal (LLN), rT3 was 44% and 37% lower than the LLN, and normal TSH was 4.0 and 3.7 mU / L. Also, a mutation in the MCT8 gene was identified, which is a single nucleotide substitution (c.962 C>T) that generates a missense mutation (P321L) located in the fifth transmembrane domain of the molecule. The mother is heterozygous for the mutation and has a normal sibling.

[0071] Their postnatal growth was similar to that of other subjects with MCT8 deficiency. Body length increased between the 10th and 25th percentiles, but weight decreased to below the 1st percentile by 6 months of age. Treatment with DITPA was initiated in both twins at 25 months of age.

[0072] Family #10 (Subject B) The affected male infant (hereinafter referred to as Subject B) was born at term to unrelated white European (Swiss) parents. His birth weight and length were 2840 g and 47.5 cm, and his Apgar scores were 9 / 9 / 10. Neonatal screening TSH was <15 mU / L (the program's cut-off value). Hypotonia was noted at 1 month of age, and at 4 months of age, thyroid testing showed that FT4 was 15% lower than the age-appropriate LLN and total T3 was 63% higher than the ULN. The MCT8 gene sequenced in Dr. Theo Visser's laboratory showed a single nucleotide substitution (c.733 C>T) that generates a stop codon (R245X). The mother is heterozygous for the same mutation, and the maternal uncle, who is now 22 years old, cannot walk or talk and has seizures. MRI obtained at 3, 8, and 13 months of age showed delayed myelination of white matter to varying degrees, particularly bilaterally. MRS showed an elevated peak of myo-inositol. Currently, at 45 months of age, he cannot talk or walk, but has no dyskinesia or seizures. Treatment with DITPA was initiated at 8.5 months of age.

[0073] Family #11 (Subject C) The affected boy (hereinafter referred to as Subject C) was born in Canada to Iranian parents who were not blood-related. His birth weight and length at 40 weeks of gestation were 3875 g and 50 cm, respectively. Neonatal screening TSH was <17 mU / L (the program's cut-off value). At 3 months of age, prolonged crying and sleep deprivation were thought to be due to colic, and the infant was treated with ranitidine. By 4 months of age, his grandmother noticed poor head control, and by 5 months, hypotonia was evident. As a result, many analyses were initiated, including amino acids in blood and urine, and quantitative acylcarnitines in blood, but no major abnormalities were shown. The karyotype was normal. Brain MRI at 5 months showed delayed myelination, which, although less severe at 17 months of age, was still present. Muscle biopsy showed a decrease in cytochrome oxidase and an increase in citrate synthase. When he was 18 months old, he had a thyroid test that showed FT4 was 40% lower than the LLN and FT3 was 60% higher than the ULL. At this point, genetic diagnosis was requested. The inventors identified a single nucleotide substitution (c.1238 C>T) in the MCT8 gene that generates a stop codon (Q380X). Since this was not found in the mother, it was a de novo mutation. The child's height was growing normally between the 50th and 75th percentiles, and weight was between the 10th and 25th percentiles. Movement disorder episodes were only observed during febrile illnesses. The basal metabolic rate was +79% at 21 months of age. Treatment with DITPA was initiated at 25 months of age.

[0074] The method of treating AHDS by administering DITPA is not limited to the above specific embodiments, but includes any embodiment within the scope of the general terms of the following claims enabled by the embodiments described herein, or any embodiment shown in the drawings or described in terms sufficient for one skilled in the art to make and use the claimed subject matter. It should be understood that it is inclusive.

Claims

**Claim 1** A method for treating Alan Houghton Dudley syndrome, comprising administering 3,5-diiodothyropropionic acid (DITPA) to a subject in need thereof, wherein the administration is at a total daily dose of about 2.5 milligrams per kilogram of body weight of the subject, and said administration reduces serum levels of triiodothyronine (T3) to normal, increases T3 brain levels to normal, increases or maintains normal serum levels of thyroxine (T4), and reduces or maintains normal thyroid-stimulating hormone (TSH) serum levels. A method. **Claim 2** The method according to claim 1, wherein said total daily dose of DITPA is administered once daily to a subject in need thereof. **Claim 3** The method according to claim 1, wherein said total daily dose of DITPA is divided into two parts, and each part is administered every 12 hours or twice a day. **Claim 4** The method according to claim 1, wherein said total daily dose of DITPA is divided into three parts, and each part is administered every 8 hours or three times a day. **Claim 5** The method according to any one of claims 1 to 4, wherein said subject in need thereof is under 18 years of age. **Claim 6** a) administering 3,5-diiodothyropropionic acid (DITPA) daily to a subject in need thereof at a first daily dose for 2 weeks; b) administering DITPA daily to said subject at a second daily dose greater than said first daily dose for 2 weeks; c) measuring the serum level of triiodothyronine (T3) in said subject, and if the T3 serum level is normal, said second daily dose is continued to be administered. The method according to any one of claims 1 to 5, further comprising the step of: **Claim 7** d) adjusting the daily dose of DITPA administered to said subject based on the T3 serum level of said subject measured in step c), wherein if the T3 serum level is too high, a third daily dose greater than said second daily dose is administered, wherein if the T3 serum level is too low, a fourth daily dose less than said second daily dose is administered daily; e) measuring the T3 serum level of said subject on about the 28th day after the first administration of said third daily dose or said fourth daily dose. When the T3 serum level is normal, the method according to claim 6, further comprising the step of continuing to administer the third daily dose or the fourth daily dose daily.

8. f) Adjusting the daily dose of DITPA administered to the subject based on the T3 serum level of the subject measured in step e), wherein if the T3 serum level is too low after daily administration of the third daily dose, the second daily dose is administered to the subject; if the T3 serum level is too low after daily administration of the fourth daily dose, the first daily dose is administered to the subject, and if the T3 serum level is too high after daily administration of the fourth daily dose, the method according to claim 7, further comprising the step of continuing to administer the second daily dose to the subject.

9. The method according to any one of claims 6 to 8, wherein the first daily dose is about 1 milligram per kilogram of body weight of the subject.

10. The method according to any one of claims 6 to 8, wherein the second daily dose is about 2 milligrams per kilogram of body weight of the subject.

11. The method according to claim 7 or 8, wherein the third daily dose is about 2.5 milligrams per kilogram of body weight of the subject.

12. The method according to claim 7 or 8, wherein the fourth daily dose is about 1.5 milligrams per kilogram of body weight of the subject.

13. The method according to any one of claims 6 to 8, wherein each daily dose of DITPA is administered once daily to the subject in need thereof, all at once.

14. The method according to any one of claims 6 to 8, wherein each daily dose of DITPA is divided into two parts, and each part is administered about every 12 hours, or twice daily.

15. The method according to any one of claims 6 to 8, wherein each daily dose of DITPA is divided into three parts, and each part is administered about every 8 hours, or three times daily.

16. A method for treating Alan Houghton Dudley syndrome, comprising: a) Administering 3,5-diiodothyropropionic acid (DITPA) daily to a subject in need thereof at a first daily dose for 2 weeks; b) Administering DITPA to the subject daily at a second daily dose greater than the first daily dose for 2 weeks, wherein the daily administration starts on the third day after the birth of the subject.

17. The method according to claim 16, wherein the first daily dosage is about 1 milligram per kilogram of the weight of the subject. **Claim 18** The method according to claim 16 or 17, wherein the second daily dosage is about 2 milligrams per kilogram of the weight of the subject.

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