Treatment of dyskinesia in glucose transporter type 1 deficiency syndrome without induction of ketosis

Abstract

The present invention relates to the treatment of Glut1-DS (Glucose Transporter Type 1 Deficiency Syndrome). In particular, the present invention relates to a specific medium-chain triglyceride composition enriched in C10 (capric acid) for use in the treatment of motor impairment in Glut1-DS patients.

Description

Technical Field

[0001] This invention relates to the treatment of glucose transporter deficiency syndrome type 1 (Glut1-DS). Specifically, this invention relates to a specific medium-chain triglyceride composition rich in C10 (decanoic acid) for the treatment of motor disorders in patients with Glut1-DS, particularly those who do not have epilepsy at the start of treatment. Background Technology

[0002] Type 1 glucose transporter (Glut1) deficiency syndrome (Glut1-DS) is a brain energy deficiency syndrome caused by impaired glucose transport to the brain. Active glucose diffusion is facilitated by transporters including Glut1. Patients can be treated with the ketogenic diet (KDT), which provides ketone bodies as supplemental fuel for brain energy metabolism (J. Klepper et al., (2020) Epilepsia Open; 5:354–365).

[0003] Patients typically present with epilepsy that begins in infancy, slowed head circumference growth, impaired neurodevelopment and motor function, and complex motor disorders. Symptom progression follows an age-specific pattern, with paroxysmal eye-head movement and seizures being the initial features in infancy. Developmental impairments become increasingly apparent, followed by ataxia, paroxysmal exertional dystonia, and further motor abnormalities that develop over time, often becoming the primary symptoms in adolescents and adults with Glut1-DS. Older patients, such as adolescents and adults, may present with motor disorders without accompanying epilepsy. It remains unclear whether motor disorders without accompanying epilepsy can be treated with the same treatments that have shown efficacy when epilepsy is present. The natural history of the disease is poorly defined, and even when it is, symptoms in individual patients may remit and relapse without clinical intervention (S. Olivotto et al., (2022) Orphanet J Rare Dis; 17:365). Therefore, a short-term resolution of a single symptom in a single patient does not necessarily indicate a treatment outcome.

[0004] Many rare diseases coexist with motor disorders and epilepsy, but the extent of the association between these symptoms, their partial overlap, or whether they are driven by different mechanisms of action is unclear (A. Papandreou et al., (2019) Dev MedChild Neurol; 62:178-191).

[0005] Preliminary diagnosis of Glut1-DS is usually made by biochemical methods (CSF to glucose ratio <0.50) or genetic methods (mutation of the SLC2A1 gene) (M. Schwantje et al., (2019) J InheritMetab Dis; 43:216–222). In the absence of identified mutations, a 3-O-methyl-D-glucose uptake test of erythrocytes can be performed; a value below 74% of the control group indicates a diagnosis of Glut1-DS (D. Wang et al., Glucose Transporter Type 1 Deficiency Syndrome. July 30, 2002 [Updated March 1, 2018]. Published in: Edited by Adam MP, Everman DB, Mirzaa GM et al., GeneReviews). ® [Internet. Seattle (WA): University of Washington, Seattle; 1993–2023). Therefore, although most patients carry mutations in the SLC2A1 gene, this is not always the case (O. Sánchez-Lijarcio et al., (2022) Clin Genet; 102:40–55).

[0006] The cause of most Glut1-DS patients is an autosomal dominant neonatal heterozygous mutation in SLC2A1. KDT provides the brain with supplemental metabolic fuel and effectively controls seizures in some patients. Unfortunately, its beneficial effects on developmental delay and motor abnormalities appear to be less significant (J. Klepper et al., (2020) Epilepsia Open; 5:354–365).

[0007] A review article states that "the ketogenic diet is the primary treatment for Glut1DS" (T. Pearson (2013) CurrNeurol Neurosci Rep; 13:342). However, the efficacy of different KDTs across different patient subtypes is unpredictable. As mentioned above, the therapeutic effect of KDTs in Glut1-DS is attributed to the production of ketone bodies derived from the hepatic metabolism of fatty acids, serving as an alternative energy source for the brain. This general view still holds true today (D. Wang et al., GlucoseTransporter Type 1 Deficiency Syndrome. July 30, 2002 [Updated March 1, 2018]; M. Schwantje et al., (2019) J Inherit Metab Dis; 43:216–222; and J. Klepper et al., (2020) Epilepsia Open; 5:354–365). Therefore, the treatment strategy focuses on enhancing ketone bodies by inducing ketosis, so that the patient is in a state of ketosis (β-hydroxybutyrate (BHB) > 1 mmol / L).

[0008] Standard long-chain triglyceride (LCT) diets, standard medium-chain triglyceride (MCT) diets (coconut oil-based), and the modified Atkins diet are known to produce ketones and treat some symptoms of Glut1-DS in certain patients. However, efficacy is unpredictable and may take months to achieve symptom relief, particularly in motor and cognitive symptoms (M. Schwantje et al., (2019) J Inherit Metab Dis;43:216–222). This is consistent with earlier research demonstrating better efficacy for epileptic symptoms compared to cognitive and motor impairments (W. Leen et al., (2010) Brain; 133:655–670). Therefore, a specialized treatment targeting motor symptoms in patients with Glut1-DS is needed, especially in disease stages where epilepsy has resolved or is absent (i.e., there is no accompanying epilepsy).

[0009] A recent review article summarized the lack of significant therapeutic effect of ketogenic diet (KDT) in treating Glut1-DS (M. Tang and U. Monani (2021) Neurosci Insights; 16:1-7), in which the authors concluded that "although the ketogenic diet reduces seizures in patients with Glut1-DS, its effect on cognitive and motor dysfunction in the disease varies from person to person and is at best only moderate." Furthermore, standard KDT may be associated with osteopenia, osteoporosis, potential cardiovascular risk, and unclear effects on pregnancy (J. Klepper et al., (2020) Epilepsia Open; 5:354–365). Therefore, there is a need for a treatment for Glut1-DS that alleviates motor dysfunction in a wide range of patients, especially those without seizures, without side effects.

[0010] Specialized fat-based interventions have also been considered to treat certain symptoms of Glut1-DS.

[0011] K.Vita ® (MCT containing C10:C8 in an 8:2 ratio) is a thickened liquid supplement containing a specific blend of MCT for dietary management of drug-resistant epilepsy in adults and children aged 3 years and older. Active triglycerides are known to treat seizures in animal models of epilepsy (WO 2018 / 189113; N. Jancovski et al. (2021) Epilepsia; 00:1–12), and K. Vita ® The product treats drug-resistant epilepsy (N. Schoeler et al., (2021) Brain Comms; 3:1–13). Compared to the standard MCT diet (coconut oil-based), K. Vita... ® It is rich in C10 (decanoic acid) rather than C8 (caprylic acid). This is because decanoic acid is considered the active ingredient for treating epilepsy (WO 2013 / 186570; P. Chang et al., (2013) Neuropharmacology; 69:105–114), and decanoic acid treats epilepsy through direct action on AMPA receptors (P. Chang et al., (2016) Brain; 139:431–443). Caprylic acid is believed to have secondary effects by preventing the oxidation of decanoic acid (A. Khabbush et al., (2017) Epilepsia; 58:1423–1429; WO / 2018189113). In contrast, C8 has a stronger ketogenic effect than C10 or C12 (V. St-Pierre et al., (2019) Front. Nutr.; 6:46).

[0012] Compositions rich in decanoic acid are known to enhance mitochondrial function in neurons and fibroblasts (WO2013 / 186570). However, it is presumed that in the treatment of epilepsy, this effect is driven by influencing the brain within the central nervous system. It is unclear whether decanoic acid can induce clinically significant effects in the peripheral nervous system of Glut1-DS patients without epilepsy, or whether its therapeutic effect is specific to the symptoms of epilepsy. This is because K. Vita ® While significantly effective in treating drug-resistant epilepsy (N. Schoeler et al., (2021) Brain Comms; 3:1-13), its exact efficacy against Glut1-DS has not been clinically confirmed, particularly in cases other than epilepsy, especially in the absence of concomitant epilepsy. In a general trial of drug-resistant epilepsy, only 4 out of 61 participants were characterized as having Glut1-DS, and no diagnostic information (i.e., clinical, metabolic, genetic, or biochemical) was provided. The metabolic marker of Glut1-DS is a reduction in glucose in the central nervous system, as detected in CSF. This leads to a lack of glucose in the brain. However, unlike other fat-based interventions, K. Vita... ® Reliable ketosis could not be induced; only 4 out of 61 participants were in a state of "ketosis" (BHB > 1 mmol / L). Therefore, K. Vita ® It's not a true "ketogenic" diet or KDT. Given the classic view of KDT's mechanism of action—that it works by providing ketone bodies as an alternative energy source for the brain—it is predicted that K. Vita... ® It may not be as effective as fat-based interventions in treating Glut1-DS. Its effect may only be to treat epileptic symptoms. Perhaps for this reason, the MCT diet is not usually used to treat Glut1-DS (M. Schwantje et al., (2019) J Inherit Metab Dis;43:216–222).

[0013] This is further complicated by the fact that caprylic and capric acids share structural similarities with the branched medium-chain fatty acid valproic acid (WO 2012 / 069790), a known antiepileptic drug believed to inhibit glucose transport and contraindicated in Glut1-DS (H. Wong et al., (2005) J Cell Biochem; 96:775–785, or A. Brukner et al., (2018) Front Pharmacol; 9:1054). Therefore, one or both fatty acids may exacerbate Glut1-DS symptoms. It is even possible that these effects may be cell type specific. Therefore, it is impossible to predict K. Vita's... ®The therapeutic effect on Glut1-DS, especially symptoms other than epilepsy, particularly in the absence of accompanying epilepsy.

[0014] There is also no information about K.Vita. ® Information regarding the potential treatment of epilepsy in patients with Glut1-DS (N. Schoeler et al., (2021) Brain Comms; 3:1–13). The authors note that "a child with Glut1-DS and gait difficulties, but currently without seizures, experienced complete resolution of paroxysmal symptoms." However, they also note that "a child with Glut1-DS, after recent discontinuation of KD, gained 10.8 kg (a 14% increase according to the UK-WHO growth chart) due to a significant increase in the variety and quantity of food consumed." Therefore, it remains unclear whether this improvement is attributable to K. Vita. ® The treatment effect is defined as the short-term effect resulting from improved diet or spontaneous symptom relief. It is unclear what symptoms require treatment. It is also unclear whether the treatment was effective for any of the other three patients with Glut1-DS. Therefore, it is unclear whether K. Vita's treatment is effective. ® Can it treat human Glut1-DS?

[0015] Despite the emergence of some anecdotal evidence, such as the aforementioned individual patient reports, the condition of K. Vita remains unclear. ® Whether it can provide clinically meaningful treatment for patients with Glut1-DS. There is currently no information indicating that K. Vita... ® Can it treat motor disorders in patients with Glut1-DS, especially in the absence of concomitant epilepsy? Based on K. Vita ® The fact that K. Vita plays a major role in the brain, with decanoic acid having a direct effect on the brain, makes it impossible to predict its effects. ® It is expected to have a therapeutic effect on motor disorders in patients with Glut1-DS without epilepsy. Any effect of the ketogenic diet on motor disorders in patients with Glut1-DS without epilepsy is likely driven entirely by peripheral ketosis, rather than by the direct pharmacological effects of decanoic acid in the central nervous system as in the treatment of epilepsy. This ketogenic effect will not occur in patients receiving K. Vita. ® Within the patient being treated. Therefore, K.Vita ® It is not currently applicable to Glut1-DS patients without concurrent epilepsy.

[0016] Animal data suggest that varying proportions of the MCT diet can treat symptoms associated with seizures (e.g., myoclonic jerks) and movement disorders (delayed dystonia). However, the model requires acute induction of seizures (with insulin or pentylenetetrazol) to observe movement disorders, and the treatment fails to treat dystonia—only slowing its onset. Therefore, it remains unclear whether the mouse model faithfully reproduces the human condition or whether it is suitable for treating movement disorders not causally linked to epilepsy, such as in patients without concomitant epilepsy. Furthermore, it remains unclear whether this effect on dystonia (inducible by seizures) is related to other human movement disorders, such as common paroxysmal dyskinesia (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events presenting with severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), motor abnormalities (e.g., involuntary movements), pyramidal tract symptoms, spasticity, ataxia, hypotonia, gait abnormalities, chorea, tremor, non-epileptic myoclonus (optionally including startle myoclonus, action myoclonus, and postural myoclonus or weakness / paralysis), axiolytic disorders (e.g., oculomotor axiolytic and orofacial axiolytic), or paroxysmal nonmotor seizures (e.g., migraine, behavioral abnormalities, periodic vomiting, and sleep attacks, as well as confusion, somnolence, somnolence-induced irritability, mild hemiparesis, cataplexy, and generalized paralysis). Additionally, it remains unclear whether acute mouse models are associated with persistent movement disorders observed in humans.

[0017] Triheptanoic acid glyceride (UX007; Ultragenyx Pharmaceuticals, Novato, USA) is a state-of-the-art treatment for Glut1-DS, with its human trials in Phase III (NCT02960217). Its active ingredient is a medium-odd-chain triglyceride containing three 7-carbon fatty acids. A small, open-label pilot study of six patients carrying missense mutations reported a significant increase in ketone bodies, suggesting a possible improvement in this type of patient (F. Mochel et al., (2016) J Neurool Neurosurg Psychiatry; 87:550–553). Missense mutations typically account for approximately 40% of all cases, and these patients usually have the mildest phenotype (T. Pearson et al., (2013) Curr Neurol Neurosci Rep; 13:342).

[0018] However, Ultragenyx Pharmaceuticals issued a press release on October 26, 2018, confirming the early termination of the Phase III trial (NCT02960217) because it failed to meet the primary endpoint (a statistically significant reduction in the frequency of paroxysmal motor events) or secondary endpoint "in patients with type 1 glucose transporter deficiency syndrome (Glut1DS) and disabling paroxysmal dyskinesia". In adults with drug-resistant epilepsy, triheptanyl triglyceride was also less effective than standard MCT oil (K. Borges et al., (2019) Epilepsia Open; 4:153–163). There is also a suggestion that triheptanyl triglyceride has a short-term effect on drug-resistant epilepsy in children previously treated with a standard ketogenic diet. However, this was also a small, open-label study. This further confirms the fact that a composition for treating epilepsy in one patient population cannot be considered a treatment for Glut1-DS, or vice versa. Furthermore, the preliminary effects observed in a small, open-label study do not confirm a therapeutic effect on Glut1-DS.

[0019] Possibly due to the failure of fat-based interventions in treating Glut1-DS, recent clinical trials are considering alternative treatments such as sodium lactate (NCT04112862). This is also expected to have an effect in the brain (L van Gemert et al., (2023) Neuropediatrics; 54:365–370).

[0020] The failure to identify an effective treatment for Glut1-DS and its motor symptoms may be related to the fact that most clinical trials were not designed or statistically effective specifically for Glut1-DS. Typically, Glut1-DS patients comprise about 10% of patients in trials for drug-resistant epilepsy (N. Schoeler et al., (2021) Brain Comms; 3:1-13), or the Glut1-DS status is not publicly disclosed (M. Cervenka et al., (2017) Neurology; 88: 938–943). An exception is the trihexyglycerol trimethylolpropionate phase III trial, which aimed to recruit 44 Glut1-DS patients but was prematurely terminated due to lack of efficacy (NCT02960217). Therefore, there is a need for active ingredients that demonstrate efficacy against specific Glut1-DS patient populations in late-stage clinical trials, particularly those that upregulate relevant pathways in Glut1-DS cells and treat motor disorders in Glut1-DS patients without accompanying epilepsy.

[0021] Typically, a therapeutic intervention for Glut1-DS is needed that provides improved treatment for patients' motor disorders compared to standard KDT and is effective for a wide range of Glut1-DS patients, especially those without seizures. Summary of the Invention

[0022] The inventors predict that specific medium-chain triglyceride (MCT) compositions with enhanced levels of decanoic acid (C10) can provide targeted therapeutic effects for motor disorders in patients with Glut1-DS, even in the absence of concomitant epilepsy.

[0023] Based on the fact that valproic acid (a known antiepileptic drug with a structure similar to decanoic acid and caprylic acid (WO 2012 / 069790)) is believed to inhibit glucose transport (H. Wong et al., (2005) J. Cell Biochem.; 96:775–785, or A. Brukner et al., (2018) Front. Pharmacol.; 9:1054), the inventors evaluated the effects of decanoic acid and caprylic acid on GLUT1 (SLC2A1) expression in U251 human glioblastoma astrocytoma cells. Decanoic acid and caprylic acid are known to have different effects on astrocyte-derived cells and are considered suitable for evaluating the effects of different fatty acids in the brain (F. Damiano et al., (2020) Front. Neurosci.; 14:783). Surprisingly, decanoic acid led to a significant decrease in GLUT1 expression in this central nervous system cell type. Figure 1 A). Even more surprisingly, caprylic acid did not have the same effect, but instead induced a modest increase in GLUT1 expression (SLC2A1; Figure 1 A). The effect of caprylic acid can partially offset the reducing effect of decanoic acid on GLUT1 expression; therefore, when the combined decanoic acid:caprylic acid (8:2) is added, the reduction is no longer significant. Figure 1 A).

[0024] The inventors expanded the scope of this research to include other genes involved in glucose metabolism, fatty acid metabolism, the citric acid cycle (including citric acid synthase), and oxidative phosphorylation (including mitochondrial genes encoding the NADH dehydrogenase (ubiquinone) subunit). Overall, the data indicate that decanoic acid downregulates glucose metabolism in astrocytes. Figure 1 A), thus transforming into fatty acid metabolism ( Figure 2 A). The combined decanoic acid:octanoic acid (8:2) treatment ensured enhanced fatty acid metabolism without significantly reducing GLUT1 expression.

[0025] The inventors expanded this research to pluripotent stem cells (iPSCs) derived from fibroblasts of Glut1-DS patients (GM27896 iPSC from Coriell Institute, USA: K. Meyer et al., (2018) Cell;175:239-253). This model is more specific to Glut1-DS patients and is suitable for assessing effects driven by cell types present outside the central nervous system. Surprisingly, the expression effects in iPSCs differed from those in astrocyte lines. In Glut1-DS iPSCs, combined decanoic acid:caprylic acid (8:2) treatment resulted in the expression of glucose metabolism (… Figure 1 B) and fatty acid metabolism ( Figure 2 B) The upregulation of genes in both suggests that these compositions are particularly suitable for treating glucose and fatty acid metabolism defects present in Glut1-DS cells that are not adapted to the central nervous system (i.e., in the peripheral).

[0026] This suggests that these fatty acids have specific and unique direct effects on cells carrying the Glut1-DS mutation, effects not observed in non-Glut1-DS mutant cell lines present in the central nervous system. For example, CPT1B (an isoform of carnitine palmitoyltransferase I (CPT1) present in muscle) is upregulated in Glut1-DS iPSCs but not in non-Glut1-DS astrocytes. CPT1B is a rate-controlling enzyme in the long-chain fatty acid β-oxidation pathway in muscle mitochondria and therefore plays a crucial role in muscle energy supply (J. McGarry et al., (1977) J. Clin. Invest.;60:265). The data suggest that combined decanoic acid:caprylic acid (8:2) treatment (i.e., a decanoic acid-rich composition compared to standard MCT) may have a direct effect on cells carrying the Glut1-DS mutation, especially when these cells are not derived from cell types present in the central nervous system. Treatment with decanoic acid upregulated genes associated with glucose and fatty acid metabolism in Glut1-DS cells, suggesting they could overcome GLUT1 function inhibition that may be induced by decanoic acid. Combined decanoic acid:caprylic acid (8:2) treatment may be particularly effective in peripheral Glut1-DS cells, such as myocytes. This provides evidence that the ameliorative effects on movement disorders may be decoupled from symptoms related to major brain functions, such as epilepsy.

[0027] The distinctly opposite effects of decanoic acid and caprylic acid on GLUT1 expression in U251 cells led the inventors to predict that certain MCT compositions (such as K. Vita) rich in decanoic acid but containing small amounts of caprylic acid, compared to decanoic acid alone, would be more effective. ®It is possible that decanoic acid maintains stronger GLUT1 function in the brain. The unexpected finding that decanoic acid upregulates many genes involved in glucose and fatty acid metabolism in Glut1-DS iPSCs ensures its effectiveness in the periphery of Glut1-DS patients, even in the absence of ketosis. Such compositions may be suitable for treating motor disorders in Glut1-DS patients, even in the absence of accompanying seizures. Although KDT has been established to treat Glut1-DS by inducing “ketosis,” the compositions described herein can treat Glut1-DS without inducing ketosis, which would minimize the side effects of ketosis, including hypotension, kidney stones, constipation, nutritional deficiencies, and an increased risk of heart disease. Furthermore, there is evidence that fatty acids with a similar number of carbon atoms, namely valproic acid, can inhibit GLUT1 function (H. Wong et al., (2005) J. Cell Biochem.; 96:775–785, or A. Brukner et al., (2018) Front. Pharmacol.; 9:1054), and it is unclear whether decanoic acid and caprylic acid may have similar effects. A specific medium-chain fatty acid (MCFA) and MCT combination with enhanced levels of decanoic acid but retaining some caprylic acid appears to have a lower inhibitory effect on GLUT1 than decanoic acid or valproic acid alone.

[0028] Decanoic acid may typically enhance glucose metabolism in Glut1-DS cells, suggesting that MCFA and MCT combinations rich in decanoic acid may be particularly suitable for treating Glut1-DS, especially its motor symptoms.

[0029] Therefore, in a first general embodiment, the present invention provides a composition for treating movement disorders in patients with Glut1-DS who require treatment, the composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0030] In a second general embodiment, the present invention provides the use of a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8) in the preparation of a medicament for treating movement disorders in patients with Glut1-DS of need, wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0031] In a third general embodiment, the present invention provides a method for treating Glut1-DS movement disorder, the method comprising administering to a Glut1-DS patient in need a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0032] In a highly preferred embodiment associated with the first, second, and third general embodiments, the Glut1-DS patient is a person carrying a mutation in the SLC2A1 gene who has a motor disorder but no accompanying epilepsy prior to the start of treatment (e.g., a period of at least 4 weeks prior to the start of treatment). Most preferably, the Glut1-DS patient has been diagnosed with a mutation in the SLC2A1 gene, and the treatment method includes a step of identifying the mutation in the SLC2A1 gene. Attached Figure Description

[0033] The invention will now be described in detail with reference to the accompanying drawings, in which:

[0034] Figure 1 The text shows expression data (based on changes in transcriptional levels) of genes related to glucose metabolism in astrocytes (A) and iPSCs (B) derived from Glut1-DS patients. For easier understanding of the grayscale heatmap, downregulated genes are enclosed in dashed boxes (---), and each box is topped with a [missing information - likely a typo]. Symbol. The change represents a change in gene expression (log2 (fold change)).

[0035] Figure 2 The text presents expression data (based on transcriptional level changes) of genes related to fatty acid metabolism in astrocytes (A) and iPSCs (B) derived from Glut1-DS patients. For easier understanding of the grayscale heatmap, downregulated genes are enclosed in dashed boxes (---), and each box is topped with a [missing information - likely a typo]. Symbol. The change represents a change in gene expression (log2 (fold change)). Detailed Implementation

[0036] A. Definition

[0037] Unless otherwise limited in a specific instance, the following definitions apply to the terminology used throughout this specification.

[0038] The term “treatment” refers to the complete or partial treatment of one or more symptoms of Glut1-DS, as described below. Similarly, “treatment” may refer to the prevention of known symptoms of Glut1-DS that a patient does not yet have but is expected to have based on their age or the severity of the disease.

[0039] The term “management,” particularly in the context of “dietary management,” means the prevention or reduction of the severity or frequency of one or more symptoms of a disease or condition, including improving one or more existing symptoms of a disease or condition, preventing one or more existing symptoms of a disease or condition, preventing one or more underlying causes of a disease or condition, improving one or more underlying causes of a disease or condition, reducing the prevalence of one or more symptoms of a disease or condition, and / or reducing the occurrence of one or more symptoms of a disease or condition. It should be understood to include stabilizing a disease or condition and preventing its progression. Technicians will be familiar with the diagnosis and management of such diseases or conditions, and more specifically with dietary management (see, for example, Commission Directive 1999 / 21 / EC, including its amendments; Commission notification on the classification of foods for special medical purposes (2017 / C 401 / 01); Commission Authorisation Regulation (EU) 2016 / 128 supplemented by Regulation (EU) 609 / 2013 of the European Parliament and of 25 September 2015).

[0040] The term "dietary intervention" is defined as adding the composition described herein to the diet of an individual suffering from Glut1-DS in order to manage (particularly dietary management), prevent, and / or treat one or more symptoms of Glut1-DS. The composition is preferably in the form of a medical food, tube feeding preparation, nutritional composition, or nutritional supplement.

[0041] The term "glucose transporter type 1 deficiency syndrome" or "Glut1-DS" is a condition diagnosed by clinical, metabolic, genetic, or biochemical methods (J. Klepper et al., (2020) Epilepsia Open; 5:354–365). A diagnosis is made if two of the following criteria are met: clinical, metabolic, or genetic. Genetic diagnosis is preferred. In cases where genetic diagnosis is not possible, a biochemical diagnosis may be used for confirmation.

[0042] The term "medical food" refers to food formulated for the dietary management of a medical condition or ailment, whereby the medical food can reduce one or more symptoms of a specific disease or ailment. For example, a medical condition or ailment may have unique nutritional needs that cannot be met by a normal diet alone. Medical foods can be administered under medical supervision. Medical foods can be administered enterally, including orally or via tube feeding.

[0043] The term "movement disorder" refers to a group of conditions that cause abnormal movement. In the context of this application, movement disorder refers to those conditions known to be associated with Glut1-DS, as outlined below. These conditions are known to experienced clinicians (J. Klepper et al., (2020) Epilepsia Open; 5:354–365). However, this definition excludes epilepsy that may affect movement, as well as seizure-induced epilepsy, such as myoclonic jerks.

[0044] Therefore, the term "motor dysregulation without accompanying epilepsy" refers to motor dysregulation when epilepsy and / or seizures have subsided or ceased. Generally, epilepsy should have subsided or ceased for at least 4 weeks, more preferably at least 3 months, and most preferably at least 1 year before treatment with the composition claimed to protect is initiated.

[0045] The term “epilepsy” refers to a group of conditions caused by excessive excitation of synapses in the brain, resulting in epileptiform activity and seizures. These conditions are known to experienced clinicians (J. Klepper et al., (2020) EpilepsiaOpen; 5:354–365). In Glut1-DS, epilepsy is associated with low levels of glucose in the brain.

[0046] The term “mutation of the SLC2A1 gene” refers to known or suspected pathogenic mutations of the SLC2A1 gene identified in patients with other symptoms of Glut1-DS.

[0047] The term “developmental and / or cognitive impairment” associated with Glut1-DS is known to experienced clinicians (J. Klepper et al., (2020) Epilepsia Open; 5:354–365) and is associated with mild to severe intellectual disability.

[0048] The term "atypical presentation" in Glut1-DS refers to rare symptoms that do not fall into the standard categories of epilepsy, motor disorders, or developmental and / or cognitive impairments as described in Glut1-DS (J. Klepper et al., (2020) Epilepsia Open; 5:354–365) as known to experienced clinicians. These symptoms are specifically listed below.

[0049] The term “adult-onset Glut1DS” refers to symptoms that a patient with Glut1DS will experience later in life and that are known to experienced clinicians (J. Klepper et al., (2020) Epilepsia Open; 5:354–365). These symptoms are specifically listed below.

[0050] The term “common paroxysmal dyskinesia” is defined as paroxysmal dyskinesia (i.e., not persistent dyskinesia) that is assessed by an experienced clinician as being prevalent in patients with Glut1-DS (J. Klepper et al., (2020) Epilepsia Open; 5:354–365). Specifically, “common” or “prevalent” symptoms are those that affect 20% or more, preferably 40% or more, more preferably 60% or more of a particular patient population (see, for example, R. Pons et al., (2010) Movement Disorders; 25:275–281).

[0051] The term "child" refers to a human being under the age of 18.

[0052] The term “infant” refers to a human child who is 2 years of age or younger, preferably 1 year of age or younger.

[0053] The term "adolescent" refers to human children who are in or after puberty. This term typically refers to children aged 11 to 17.

[0054] The term "adult" refers to a human being who is 18 years of age or older.

[0055] The term "C10:C8 ratio" refers to the weight ratio (wt:wt) of decanoic acid (C10) to octanoic acid (C8), or the C10:C8 ratio. In the case of triglycerides, this relates to the weight ratio of the fatty acids after they have been cleaved from the glycerol backbone. To avoid ambiguity, experimental examples include decanoic acid:octanoic acid with a mol:mol ratio of 80:20, which relates to a C8:C10 ratio (wt:wt) of 83:17 or 8:2.

[0056] The term "homogeneous triglyceride" refers to a glycerol molecule esterified by three identical fatty acid molecules (e.g., three decanoic acid molecules or three caprylic acid molecules). Homoglycerides can be mixed to provide the desired C10:C8 ratio.

[0057] The term "heteroglycerides" refers to glycerol esterified with different fatty acids (e.g., decanoic acid molecules and caprylic acid molecules). Heteroglycerides containing the desired C10:C8 ratio are produced by esterifying glycerol with the desired C10:C8 ratio.

[0058] The term "substantially free of" means less than 2% by weight of the composition (i.e., less than 2g / 100g), preferably less than 1% by weight of the composition (i.e., less than 1g / 100g).

[0059] Those skilled in the art, when implementing the claimed invention, can understand and implement other variations of the disclosed embodiments by studying this disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude multiple / a plurality of elements / steps. The mere fact that certain measures are stated in mutually different dependent claims does not imply that a combination of these measures cannot be used advantageously.

[0060] B. Treatment of Glut1-DS with a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein C10:C8 The ratio is 70:30 to 90:10

[0061] In a first general embodiment, the present invention provides a composition for treating movement disorders in patients with Glut1-DS of need, the composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0062] In a second general embodiment, the present invention provides the use of a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8) in the preparation of a medicament for treating movement disorders in patients with Glut1-DS of need, wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0063] In a third general embodiment, the present invention provides a method for treating Glut1-DS movement disorder, the method comprising administering to a Glut1-DS patient in need a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0064] In a highly preferred embodiment associated with the first, second, and third general embodiments, the Glut1-DS patient is a person carrying a mutation in the SLC2A1 gene who has a motor disorder but no accompanying epilepsy prior to the start of treatment (e.g., a period of at least 4 weeks prior to the start of treatment). Most preferably, the Glut1-DS patient has been diagnosed with a mutation in the SLC2A1 gene, and the treatment method includes a step of identifying the mutation in the SLC2A1 gene.

[0065] These general implementation schemes can be easily combined with specific compositions, patient groups, and symptoms described below.

[0066] Composition

[0067] The composition according to the invention comprises a mixture of decanoic acid (C10) and octanoic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0068] In a preferred embodiment, the composition according to the invention comprises a mixture of C10 (decanoic acid) and C8 (caprylic acid), wherein the C10:C8 ratio is 75:25 to 85:15, more preferably about 8:2 wt:wt, and most preferably about 80:20 wt:wt. Surprisingly, data in Section E below confirm that compositions rich in decanoic acid but retaining a portion of caprylic acid can upregulate specific genes, such as CPT1B (an isotype of carnitine palmitoyltransferase I (CPT1) present in muscle), while potentially offsetting the reduction in GLUT1 expression in astrocytes caused by decanoic acid alone. CPT1B is a rate-controlling enzyme in the long-chain fatty acid β-oxidation pathway in muscle mitochondria and therefore plays a crucial role in muscle energy supply (J. McGarry et al., (1977) J. Clin. Invest.; 60:265).

[0069] Although decanoic acid and caprylic acid are typically used in the form of triglycerides when treating patients, the cellular effects demonstrated in this application confirm the role of free fatty acids or their salts (e.g., sodium or potassium salts) or prodrugs (e.g., methyl esters or succinyl esters).

[0070] In one embodiment, decanoic acid and caprylic acid are in the form of heteroglycerides, which are obtained by re-esterification of glycerol from free fatty acids (at the above wt:wt ratio) such that the C10 and C8 are randomly distributed at SN1 (peripheral) and SN2 (central) positions, as described in WO 2017 / 093449. These triglycerides can form part of the compositions described herein. The preparation of such heteroglycerides is relatively simple.

[0071] In a preferred embodiment, decanoic acid and caprylic acid are in the form of homoglycerides, which are obtained by re-esterification of glycerol from free fatty acids and then combined (at the wt:wt ratio described above) such that decanoic acid or caprylic acid is uniformly distributed in all positions, as described in WO 2017 / 093449. These triglycerides can form part of the compositions described herein. Compared to corresponding heteroglycerides, such homoglycerides increase the proportion of ketones and C10 fatty acids in body fluids (such as plasma or CSF).

[0072] In another embodiment, decanoic acid and caprylic acid account for at least 80% by weight of the total fatty acid content of the composition, preferably 85% by weight, more preferably 90% by weight, even more preferably 95% by weight, or most preferably 99% by weight.

[0073] In another embodiment, the composition is substantially free of monounsaturated or polyunsaturated fatty acids.

[0074] In another embodiment, the composition is substantially carbohydrate-free.

[0075] In another embodiment, the composition is substantially protein-free.

[0076] In another embodiment, the composition is in the form of an oil-in-water emulsion.

[0077] In another embodiment, the composition is encapsulated.

[0078] In another embodiment, the composition is self-stabilized at room temperature for at least 3 months.

[0079] In another embodiment, the composition is in the form of a medical food, tube feeding preparation, nutritional composition, or nutritional supplement.

[0080] In a preferred embodiment, the composition contains 25 g to 40 g / 100 mL, preferably 30 g to 35 g / 100 mL, and most preferably about 33.5 g / 100 mL of the above-described forms of decanoic acid and caprylic acid triglycerides. This ensures that each package (e.g., each 120 mL package) delivers the required dose. These doses are expected to achieve a therapeutic effect in Glut1-DS patients without causing significant "ketosis".

[0081] dose

[0082] The composition described herein can be administered in an effective amount to treat Glut1-DS. Preferably, the dosage is administered to human patients. The dosage can be titrated by an experienced clinician. In a preferred embodiment, the composition is administered in doses of 60 mL to 480 mL per day. In a preferred embodiment, the composition is administered in doses of 240 mL per day (e.g., 2 x 120 mL packets containing 33.5 g / 100 mL of decanoic acid and caprylic acid triglycerides as described above). This dose is particularly suitable for adult patients. In a more preferred embodiment, the composition is administered in doses of 240 mL per day (e.g., 4 x 60 mL packets containing 33.5 g / 100 mL of decanoic acid and caprylic acid triglycerides as described above). Although the predicted maximum plasma concentration of decanoic acid is low, this dosage regimen ensures good patient tolerance while maintaining good efficacy.

[0083] In another preferred embodiment, the composition is administered in a dose of 120 mL per day (e.g., a 1×120 mL package containing 33.5 g / 100 mL of decanoic acid and caprylic acid triglycerides as described above). This dose is particularly suitable for pediatric patients.

[0084] Alternatively, the dosage (in grams) can be administered based on the patient's weight (in kilograms). The inventors have determined that a dosage of about 1 g / kg / day is suitable for a wide range of weights. Therefore, in a preferred embodiment, the composition is administered at an amount of 0.5 g / kg / day to 2.5 g / kg / day, more preferably 0.8 g / kg / day to 1.5 g / kg / day, and most preferably about 1.0 g / kg / day. This amount is particularly suitable for the general patient population. Preferably, the daily dose is divided into 2 to 4 doses, more preferably 4 individual daily doses (e.g., 4 × 60 mL containing 33.5 g / 100 mL of decanoic acid and caprylic acid triglycerides as described above).

[0085] The above dosage can be easily combined with the above composition for administration.

[0086] patient group

[0087] The composition is used to treat patients with Glut1-DS, most preferably, patients with Glut1-DS are individuals carrying a mutation in the SLC2A1 gene who have a motor disorder but no accompanying epilepsy before the start of treatment.

[0088] age

[0089] In one embodiment, the patient can be defined according to their age. For example, the patient can be an infant, child, adolescent, or adult. Preferably, the patient is a child (e.g., over 3 years old), adolescent, or adult. Since the composition is expected to show good efficacy in treating motor disorders in patients with Glut1-DS (even in the absence of concomitant epilepsy), and since epilepsy and / or seizures generally subside with age, while certain motor disorders appear with age, the composition detailed above is more preferably used to treat adolescents or adults, and even more preferably adults.

[0090] As mentioned above, patients with Glut1-DS are preferably those who have motor disorders but no accompanying epilepsy before starting treatment (e.g., 4 weeks before starting treatment).

[0091] Patients with Glut1-DS typically develop motor disorders at age 3 or older, and K. Vita is currently recommended. ® For adults and children aged 3 and up.

[0092] Previous treatments and dietary interventions

[0093] Patients can be defined based on their previous treatment.

[0094] In one implementation, the patient may have previously received one or more KDT treatments selected from the following groups: standard LCT diet, standard MCT diet (coconut oil-based, C10:C8 wt:wt ratio of approximately 40:60), and a modified Atkins diet. In another implementation, the patient simultaneously receives one or more KDT treatments selected from the following groups: standard LCT diet and modified Atkins diet. In a preferred implementation, the patient discontinued one or more KDTs (selected from the group consisting of standard LCT diet, standard MCT diet (coconut oil-based), and modified Atkins diet) before starting treatment (e.g., due to lack of efficacy or unacceptable side effects). In a more preferred implementation, the patient does not respond to one or more KDTs (selected from the group consisting of standard LCT diet, standard MCT diet (coconut oil-based), and modified Atkins diet).

[0095] In another implementation, the patient has not previously received one or more KDT treatments selected from the following groups: standard LCT diet, standard MCT diet (coconut oil-based), and modified Atkins diet.

[0096] In another implementation, the patient is not currently following a low-carbohydrate diet (defined in R. Feinman et al. (2015) Nutrition; 31:1-13 as providing <26% of daily calories from carbohydrates).

[0097] Disease severity

[0098] In another implementation, patients can be categorized into four groups based on their disease severity according to the Columbia Neurological Score (CNS): mild (CNS 70–76), mild (CNS 60–69), moderate (CNS 50–59), or severe (CNS 40–49) (T. Pearson et al., (2013) Curr Neurol Neurosci Rep; 13:342). Patients with the classic early-onset epilepsy phenotype fall into the moderate to severe range in this classification system. Disease severity is generally associated with specific types of SLC2A1 mutations (described in detail below): missense mutations are primarily detected in individuals with mild to moderate clinical syndromes. Splice sites and nonsense mutations, as well as insertions, deletions, and exon deletions, are associated with moderate to severe clinical syndromes. Complete gene deletions fall into the severe clinical category.

[0099] diagnosis

[0100] According to recent clinical recommendations, the diagnostic criteria for Glut1-DS (J. Klepper et al., (2020) Epilepsia Open; 5:354–365) are:

[0101] a) Clinically, symptoms are selected from the following groups: eye-head movement disorders, seizures, neurodevelopmental impairment, slowed head circumference growth, and motor disorders;

[0102] b) Metabolically, it has a cerebrospinal fluid (CSF) to blood glucose ratio of <0.50;

[0103] c) Genetically, possessing a mutation in the SLC2A1 gene; and / or

[0104] d) Biochemically, the uptake of 3-O-methyl-D-glucose in erythrocytes was 74% lower than that in the control group.

[0105] Therefore, in one embodiment, a patient diagnosed with Glut1-DS has (possibly) a confirmed diagnostic criterion selected from at least one of the following groups: symptoms (clinical diagnosis), low CSF glucose (metabolic diagnosis), mutation in the SLC2A1 gene (genetic diagnosis), and impaired 3-O-methyl-D-glucose uptake in erythrocytes (biochemical diagnosis).

[0106] Generally, meeting two of the criteria in a) through c) is sufficient for a diagnosis, in which case KDT treatment should be considered. In the absence of a pathogenic SLC2A1 variant, d) can be used instead of c) for diagnosis.

[0107] In a preferred embodiment, a patient diagnosed with Glut1-DS has a (possible) symptomatic diagnosis (clinical diagnosis) and at least one of the following diagnostic criteria: low CSF glucose (metabolic diagnosis), mutation of the SLC2A1 gene (genetic diagnosis), or impaired 3-O-methyl-D-glucose uptake in erythrocytes (biochemical diagnosis).

[0108] In a more preferred embodiment, the patient diagnosed with Glut1-DS has a (confirmed) diagnosis and has symptoms (clinical diagnosis), low CSF glucose (metabolic diagnosis), and a mutation in the SLC2A1 gene (genetic diagnosis) and / or impaired 3-O-methyl-D-glucose uptake in erythrocytes (biochemical diagnosis).

[0109] Clinical diagnosis

[0110] Clinical diagnosis should generally be made by experienced clinicians, and treatment may include the steps involved in making a clinical diagnosis.

[0111] In one implementation, the patient is diagnosed with symptoms selected from the group consisting of: eye-head movement abnormalities, seizures, neurodevelopmental impairment, slowed head circumference growth, and motor dysfunction. The symptoms used for diagnosis may change after diagnosis. Specifically, seizures may subside, and motor dysfunction may become more prevalent or dominant. Therefore, in a preferred implementation, all seizures have subsided, and the patient still has motor dysfunction but no accompanying seizures before initiating the treatment claimed for protection.

[0112] The following symptoms are taken from J. Klepper et al. (2020) Epilepsia Open; 5:354–365, which is incorporated herein by reference.

[0113] Epilepsy and / or seizures: Drug-resistant seizures are often the first symptom of Glut1-DS. Any type of seizure can be observed. Generalized seizures are more frequent than focal seizures. Early-onset absence epilepsy (onset before age 4) and epilepsy with myoclonic-atonic seizures (Doose syndrome) are associated with pathogenic variants of SLC2A1. Any epilepsy associated with motor disorders should be considered for Glut1-DS. Epilepsy is often the primary clinical problem in infants and young children with Glut1-DS, while seizures tend to decrease or disappear in late childhood, adolescence, and adulthood.

[0114] Motor disturbances: In early infancy, paroxysmal eye-head movements, second only to seizures, are the second most common initial symptom of Glut1-DS. Attacks are usually involuntary and brief. Eye movements are repetitive, multidirectional, saccades, often synkinetic, and frequently accompanied by head movements in the same direction. Other paroxysmal events may occur later in childhood, but their severity varies greatly. Clinical presentations typically involve some type of motor abnormality, such as involuntary movements, ataxia, or weakness / paralysis. Consciousness is usually preserved. In adulthood, the clinical symptoms of paroxysmal events usually improve gradually, with a decrease in frequency and severity. Paroxysmal nonmotor seizures include migraines, behavioral disturbances, periodic vomiting, and sleep attacks.

[0115] Motor disturbances are typically characteristic of Glut1-DS. Severity ranges from mild to severe. These movements can be persistent or paroxysmal, usually occurring before meals and subsiding after eating. Persistent motor disturbances include spasticity, ataxia, and dystonia, often leading to gait abnormalities, followed by chorea and tremor. Ataxia becomes increasingly apparent in late infancy as the child stands and begins to walk. Ataxia is more often manifested as truncal symptoms than limb symptoms. Chorea is usually mild and involves the face and distal upper limbs. Terminal intention tremor is common and is often accompanied by other signs of cerebellar dysfunction. Myoclonus is usually epileptic; non-epileptic myoclonus is less common and includes startle myoclonus, action myoclonus, and postural myoclonus. Motor dysfunctions are not well recognized and include oculomotor and oro-cheek dysfunctions. Paroxysmal kinetic disorders affect approximately 75% of patients and typically include paroxysmal eye-head movements, paroxysmal movement-induced kinetic disorders (PED), paroxysmal events presenting as severe motor dysfunction, and paroxysmal events with complex neurological symptoms (J. Klepper et al., (2020) Epilepsia Open; 5:354–365). These motor abnormalities are frequent and often triggered by fasting and exercise. Potential triggers include emotional stress, fever, fatigue, insufficient ketosis, sleep deprivation, temperature changes, and medications.

[0116] Developmental and / or cognitive impairments: Glut1-DS is associated with mild to severe intellectual disability, with severity proportional to overall disease severity. Microcephaly may appear in infancy, with varying degrees of severity and may correlate with clinical severity. Dysarthria is observed in all affected individuals, accompanied by varying degrees of language impairment. Social adaptation is a remarkably prominent strength. Performance skills impairment is often more pronounced than verbal skills impairment, accompanied by visuospatial and visuomotor deficits. The timing of KDT introduction is a predictor of cognitive outcomes. Early dietary intervention is associated with better intellectual and social adaptation skills (J. Klepper et al., (2020) Epilepsia Open; 5:354–365).

[0117] Atypical presentations: Rare features described in Glut1-DS include writer's cramp, intermittent ataxia, generalized paralysis, sudden falls, Parkinson's disease, and nocturnal muscle spasms in the legs. Individual patients have been described as having alternating hemiplegia in children, hemiplegic migraine, periodic vomiting, and stroke-like episodes with paroxysmal hemiplegia, dysarthria, or aphasia. Other rare features include hemolytic anemia associated with PED, hepatosplenomegaly, periventricular calcification, brain atrophy, pseudohyperkalemia, cataracts, and retinal dysfunction.

[0118] Symptoms of Adult-onset Glut1-DS: Data on adult-onset Glut1-DS are only beginning to emerge. The long-term prognosis and long-term adverse effects of KDT remain largely unknown. Symptom changes over time include a shift from epilepsy with infancy-childhood seizures to motor disorders with juvenile-adult seizures, including PED. Assessment and treatment of adult-onset Glut1-DS also differ from those for childhood Glut1-DS. Expanded metabolic assessment may not be necessary, and for women of childbearing age, pregnancy testing should be considered before initiating KDT, given the unknown risk of teratogenicity. Initiating KDT in adults is controversial due to the side effects described in drug-resistant childhood epilepsy, including osteopenia, osteoporosis, potential cardiovascular risks, and unclear effects on pregnancy. Furthermore, a fully developed brain requires less energy and nutrients than a developing brain. Generally, the modified Atkins diet (MAD) is considered a reasonable alternative for treating poorly controlled seizures and paroxysmal motor disorders in adolescents and adults.

[0119] As can be clearly seen from the overview above (J. Klepper et al., (2020) Epilepsia Open; 5:354-365), patients may present with different symptoms at different ages and with varying disease severity. For example, in infancy, paroxysmal eye-head movements may occur alongside seizures, but it is unlikely that movement-induced motor disturbances will be detected. In late childhood, adolescence, or adulthood, paroxysmal movement-induced motor disturbances may occur alongside motor abnormalities without seizures.

[0120] Therefore, in one embodiment, the patient suffers from one or more symptoms selected from the group consisting of epilepsy and / or seizures, motor disorders, developmental and / or cognitive impairments, atypical presentations, and / or adult-onset Glut1-DS. Preferably, the patient suffers from one or more symptoms selected from the group consisting of motor disorders, developmental and / or cognitive impairments, atypical presentations, and / or adult-onset Glut1-DS; more preferably, motor disorders, atypical presentations, and / or adult-onset Glut1-DS; even more preferably, motor disorders and / or adult-onset Glut1-DS; most preferably, motor disorders. Preferably, one or more symptoms have been present for at least 4 weeks, more preferably at least 3 months, and most preferably at least 1 year.

[0121] In a preferred embodiment, the patient does not exhibit epilepsy or seizures, but does indeed suffer from one or more symptoms selected from the group consisting of motor disorders, developmental and / or cognitive impairments, atypical presentations, and / or adult-onset Glut1-DS; more preferably motor disorders, atypical presentations, and / or adult-onset Glut1-DS; even more preferably motor disorders and / or adult-onset Glut1-DS; most preferably motor disorders. Preferably, the patient has exhibited the above-mentioned symptoms without accompanying epilepsy or seizures for at least 4 weeks, more preferably at least 3 months, and most preferably at least 1 year.

[0122] Epilepsy and / or seizures can be selected from the group consisting of: generalized seizures, focal seizures, early-onset absence epilepsy (onset before age 4), epilepsy with myoclonic-atonic seizures (Doose syndrome), and epilepsy associated with movement disorders. Preferably, epilepsy and / or seizures are selected from the group consisting of: generalized seizures and epilepsy associated with movement disorders. In a most preferred embodiment, all types of seizures and epilepsy are absent when the patient begins treatment.

[0123] Motor disorders can be selected from the following groups: common paroxysmal motor disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events presenting with severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), motor abnormalities (e.g., involuntary movements), pyramidal tract symptoms, spasticity, ataxia, dystonia, hypotonia, gait abnormalities, chorea, tremor, non-epileptic myoclonus (optionally including startle myoclonus, action myoclonus, and postural myoclonus or weakness / paralysis), agility disorders (e.g., oculomotor agility disorders and orofacial-cheek agility disorders), and paroxysmal nonmotor seizures (e.g., migraine, behavioral abnormalities, periodic vomiting and sleep attacks, as well as confusion, somnolence, somnolence-induced irritability, mild hemiparesis, cataplexy, and generalized paralysis).

[0124] Preferably, the movement disorder is selected from the group consisting of: common paroxysmal movement disorders (e.g., paroxysmal eye-head movement, paroxysmal PED, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), pyramidal tract symptoms, ataxia, hypotonia, and chorea.

[0125] Movement disorders, especially paroxysmal movement disorders, can be characterized by symptoms that trigger them. In one implementation, a movement disorder is defined as a disorder triggered by one or more of the following groups: fasting, exercise, emotional stress, fever, fatigue, insufficient ketosis, insomnia, temperature changes, and / or medications.

[0126] In one preferred implementation, a motor disorder exists when the patient begins treatment.

[0127] Developmental and / or cognitive impairments may be selected from the group consisting of: microcephaly, mild to severe intellectual disability, dysarthria, visuospatial impairment, and visuomotor impairment. Preferably, the developmental and cognitive impairment is microcephaly.

[0128] Atypical presentations can be selected from the following groups: writer's cramp, intermittent ataxia, sudden collapse, generalized paralysis, Parkinson's disease, nocturnal muscle spasms in the legs, alternating hemiplegia in children, hemiplegic migraine, periodic vomiting, stroke-like episodes (e.g., paroxysmal hemiplegia, dysarthria, or aphasia), hemolytic anemia associated with PED, hepatosplenomegaly, periventricular calcification, brain atrophy, pseudohyperkalemia, cataracts, and retinal dysfunction.

[0129] In some implementations, adult-onset Glut1-DS symptoms are motor disorders (e.g., PED) that occur in adolescents to adults.

[0130] Different combinations of symptoms can be grouped according to phenotype (W. Leen et al., (2010) Brain; 133:655-670): (i) classic phenotype of intellectual disability and epilepsy with or without motor impairment (84%), subdivided into early-onset (52 years) (65%) and late-onset (18%); (ii) non-classical phenotype of intellectual disability and motor impairment (excluding paroxysmal exertion-induced motor impairment) but without epilepsy (15%); and (iii) non-classical phenotype of paroxysmal PED and / or (absence) epilepsy or a mild phenotype (approximately 1%). The preferred combination of symptoms present at the start of treatment is the non-classical phenotype of intellectual disability and motor impairment (excluding paroxysmal exertion-induced motor impairment) but without epilepsy; and / or the non-classical phenotype of paroxysmal PED but without epilepsy or with a mild phenotype.

[0131] Metabolic diagnosis

[0132] Metabolic diagnosis can be performed by an experienced clinical biochemist, and treatment may include procedures for metabolic diagnosis. The metabolic marker of Glut1-DS is a reduction in glucose in the central nervous system in the presence of normal glucose levels, as detected in the CSF via lumbar puncture. This is known as cerebrospinal fluid hypoglycemia. Typically, the cutoff value for cerebrospinal fluid hypoglycemia is 2.2 mmol / L (40 mg / dL), but in milder cases it can be between 2.2 mmol / L and 2.9 mmol / L (41 mg / dL to 52 mg / dL).

[0133] Given that CSF glucose levels vary with age, a more robust diagnostic approach is to compare CSF glucose levels with blood glucose levels, as the CSF-to-blood glucose ratio has been observed to remain stable at approximately 0.8 across all age groups. In patients with Glut1-DS, the CSF-to-blood glucose ratio ranges from 0.19 to 0.59, with ratios of 0.5 and below considered diagnostically significant. Ratios of 0.4 and below are common in more severe or atypical phenotypes (W. Leen et al., (2013) JAMA Neurol; 70:1440–1444).

[0134] Therefore, in one embodiment, the patient exhibits a CSF glucose concentration of 2.9 mmol / L (52 mg / dL) or lower. Preferably, the patient exhibits a CSF glucose concentration of 2.2 mmol / L (40 mg / dL) or lower.

[0135] In a preferred embodiment, the patient exhibits a CSF to blood glucose ratio of 0.59 or lower, more preferably 0.5 or lower, and most preferably 0.4 or lower.

[0136] Genetic diagnosis

[0137] Genetic diagnosis can be performed by experienced geneticists, and treatment may include the steps of genetic diagnosis. The type of genetic mutation is generally related to the severity of the phenotype: missense variants (mild to moderate severity); splice sites and nonsense variants, as well as insertions, deletions, and exon deletions (moderate to severe severity); and complete gene microdeletions or deletions (severe severity).

[0138] A missense variant is a point mutation in which a single nucleotide of the SLC2A1 gene is altered, producing a codon encoding a different amino acid. In one embodiment, a patient carries a missense mutation in the SLC2A1 gene. Preferably, the missense or nonsense mutation results in a point mutation occurring at a site selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Ser113, Arg126, Gly130, Arg153, Arg212, Arg218, Lys256, Arg264, Thr295, Ala155, Arg330, Arg333, Pro485, and Arg468 of the GLUT1 protein. The composition is predicted to provide more effective treatment for missense variants, and these patients may experience milder symptoms.

[0139] Splice sites and nonsense variants, as well as insertions, deletions, and exon deletions, result in significant changes to the expressed genes and proteins. In one embodiment, the patient carries a splice site mutation, nonsense mutation, one or more insertions, one or more deletions, or one or more exon deletions in the SLC2A1 gene. Preferably, the mutation is selected from the group consisting of: missense, insertion, splice site, nonsense, oligonucleotide deletion, and large intragenic deletion.

[0140] Complete microdeletions or deletions result in large areas (1 megabase or more) of deletion. In one implementation, the patient has complete microdeletions, complete deletions, or consecutive deletions.

[0141] Biochemical Diagnostics

[0142] Biochemical diagnosis can be performed by an experienced biochemist, and treatment methods may include steps for performing biochemical diagnosis. In the absence of a pathogenic SLC2A1 variant, impaired 3-O-methyl-D-glucose uptake in erythrocytes, ranging from 35% to 74% in the control group, is diagnostically significant. In one embodiment, the patient's erythrocyte O-methyl-D-glucose uptake is less than 74% of the control value.

[0143] The directly defined patient criteria (age, severity, and different diagnostic criteria) described above can be combined to form specific patient groups, but there is an obvious premise that an individual patient cannot simultaneously possess more than one age, more than one disease severity, and the same specific symptom cannot be both present and absent in the same patient. However, the treatments described herein can be applied to more than one age, severity, and diagnostic criterion, and when one symptom is absent, a subtype of another symptom may exist (e.g., when paroxysmal PED is absent, paroxysmal eye-head movements may exist).

[0144] Symptoms and Treatment

[0145] The symptoms being treated can be frequent (e.g., daily), occasional (e.g., weekly), or rare (e.g., monthly or less).

[0146] The compositions described herein can be used to treat Glut1-DS in general, or one or more patient groups (as described above, such as patients with motor disorders but without accompanying epilepsy) with one or more symptoms (as described above, such as motor disorders). When symptoms are present, “treatment” or “management” involves completely or partially treating one or more of the aforementioned symptoms of Glut1-DS. When symptoms are absent, “treatment” or “management” involves preventing known symptoms of Glut1-DS that the patient does not yet have but is expected to have based on their age or the severity of the disease. Generally, patients who had epilepsy in childhood but do not have epilepsy later in life are not expected to have epilepsy.

[0147] Therefore, in one embodiment, the composition is used to treat symptoms of one or more selected groups consisting of motor disorders, developmental and / or cognitive disorders, atypical presentations, and / or adult-onset Glut1-DS, with motor disorders being the most preferred.

[0148] Motor disorders can be selected from the following groups: common paroxysmal motor disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events presenting with severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), motor abnormalities (e.g., involuntary movements), pyramidal tract symptoms, spasticity, ataxia, dystonia, hypotonia, gait abnormalities, chorea, tremor, non-epileptic myoclonus (optionally including startle myoclonus, action myoclonus, and postural myoclonus or weakness / paralysis), agility disorders (e.g., oculomotor agility disorders and orofacial-cheek agility disorders), and paroxysmal nonmotor seizures (e.g., migraine, behavioral abnormalities, periodic vomiting and sleep attacks, as well as confusion, somnolence, somnolence-induced irritability, mild hemiparesis, cataplexy, and generalized paralysis).

[0149] Preferably, the movement disorder is selected from the group consisting of: common paroxysmal movement disorders (e.g., paroxysmal eye-head movement, paroxysmal PED, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), pyramidal tract symptoms, ataxia, hypotonia, and chorea.

[0150] In a preferred embodiment, movement disorder is a symptom present when the patient begins treatment.

[0151] Developmental and / or cognitive impairments may be selected from the group consisting of: microcephaly, mild to severe intellectual disability, dysarthria, visuospatial impairment, and visuomotor impairment. Preferably, the developmental and cognitive impairment is microcephaly.

[0152] Atypical presentations can be selected from the following groups: writer's cramp, intermittent ataxia, sudden collapse, generalized paralysis, Parkinson's disease, nocturnal muscle spasms in the legs, alternating hemiplegia in children, hemiplegic migraine, periodic vomiting, stroke-like episodes (e.g., paroxysmal hemiplegia, dysarthria, or aphasia), hemolytic anemia associated with PED, hepatosplenomegaly, periventricular calcification, brain atrophy, pseudohyperkalemia, cataracts, and retinal dysfunction.

[0153] In some implementations, adult-onset Glut1-DS symptoms are motor disorders (e.g., PED) that occur in adolescents to adults.

[0154] Different combinations of symptoms can be grouped according to phenotype (W. Leen et al., (2010) Brain; 133: 655-670): (i) classic phenotype of intellectual disability and epilepsy with or without motor impairment (84%), subdivided into early-onset (52 years) (65%) and late-onset (18%); (ii) non-classical phenotype of intellectual disability and motor impairment (excluding paroxysmal exertion-induced motor impairment) but without epilepsy (15%); and (iii) non-classical phenotype of paroxysmal PED and / or (absence) epilepsy or mild phenotype (approximately 1%). The preferred combination of symptoms to be treated is the non-classical phenotype of intellectual disability and motor impairment (excluding paroxysmal exertion-induced motor impairment) but without epilepsy; and / or the non-classical phenotype of paroxysmal PED but without epilepsy or with mild phenotype.

[0155] The above-described embodiments and preferred embodiments are equally applicable to the use of the compositions described at the beginning of Part B in the preparation of a medicament, and to methods of treating Glut1-DS in subjects of need. Treatment methods may include additional steps for diagnosis.

[0156] Based on the prediction that the compositions described herein can treat Glut1-DS independently of the presence of epilepsy and / or seizures, the compositions detailed above are particularly suitable for treating Glut1-DS-related motor disorders in patients who do not exhibit one or more symptoms selected from the group consisting of epilepsy and seizures (i.e., do not have concomitant epilepsy).

[0157] Given that epilepsy and / or seizures typically subside with age, and that certain motor disorders may develop with age, the compositions detailed above are particularly suitable for treating common paroxysmal motor disorders associated with Glut1-DS (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events with complex neurological symptoms), pyramidal tract symptoms, ataxia, hypotonia, and / or chorea.

[0158] C. Preparations

[0159] While decanoic acid and caprylic acid are preferably used in the form of triglycerides when treating patients, the cellular effects demonstrated in this application confirm the role of free fatty acids or their salts (e.g., sodium or potassium salts) or prodrugs (e.g., methyl esters or succinyl esters).

[0160] In a preferred embodiment, the composition is a formulation in which decanoic acid and caprylic acid are present in a ratio of about 8:2 (C10:C8), and 99% of the fat is decanoic acid and caprylic acid.

[0161] K.Vita used in previous clinical trials ® The formulations are shown in Table 1:

[0162] per 100mL 120mL per package Energy (kcal) 308 370 Fat (g) 34 41 Saturated fat (g) 31 37 Medium-chain triglycerides (MCT) (g) 33.5 40 Caprylic acid (C8:0) (g) 6.2 7.6 Decanoic acid (C10:0) (g) 24.5 29 Carbohydrates (g) 0.42 0.5 Sugar (g) 0 0 Protein (g) 0 0 Salt (g) 0.11 0.13 Sodium (mg) 46 55 Chlorine (mg) 56 67

[0163] Osmotic pressure: 85 mOsm / kg

[0164] Ingredients: Water, medium-chain triglycerides (MCT), oil, emulsifiers (E472c, E471), thickeners (E415), flavoring agents, sodium chloride, coloring (E120), acidity regulators (E296), artificial sweetener (sucralose).

[0165] Triglycerides

[0166] The composition or formulation may contain a standard heteroglyceride containing decanoic acid and caprylic acid randomly distributed along the glycerol backbone (caprylic acid / decanoic acid triglyceride). This has been used in K. Vita ® The prior art is disclosed. Preferably, the composition or formulation may contain a mixture of homoglycerides containing tri-C8 triglycerides (caprylic triglyceride) and tri-C10 triglycerides (decanoic triglyceride) in the claimed proportions as used in WO 2017 / 093449. The inventors predict that this will be particularly effective in treating motor symptoms in patients with Glut1-DS.

[0167] D. Additional beneficial effects

[0168] Preferably, when administered as part of a treatment, the composition or formulation does not induce ketosis. This reduces the risk of hyperketosis and eliminates the need for daily ketosis testing.

[0169] Preferably, the composition or formulation does not cause a decrease in GLUT1 expression in muscle compared to before treatment, as determined by Western blotting or expression analysis of muscle biopsies using standard transcriptomic methods. Suitable methods for Western blotting and expression analysis are described below. A decrease in expression may mean a 20% reduction in expression compared to before treatment.

[0170] Alternatively, the composition or formulation does not cause a decrease in glucose levels in the central nervous system, as measured by a further decrease in the cerebrospinal fluid (CSF) / glucose ratio, compared to before the start of treatment. A decrease in the CSF / glucose ratio can mean a 20% reduction compared to before the start of treatment (a 20% reduction in the ratio value, e.g., from 0.5 to 0.4). Methods for quantifying CSF and glucose levels are known to those skilled in the art (M. Schwantje et al., (2019) J. Inherit. Metab. Dis.; 43:216–222).

[0171] Preferably, the composition or formulation is used to increase or maintain GLUT1 levels in the brains of patients with Glut1-DS.

[0172] E. Cellular transcriptional studies of astrocytes and iPSCs derived from Glut1-DS patients.

[0173] As mentioned above, one possible reason for the failure to identify effective treatments for Glut1-DS (including movement disorders) is the lack of biochemical data in the relevant cell models, making it impossible to measure symptoms associated with epilepsy.

[0174] Therefore, the inventors tested the effects of decanoic acid (C10), caprylic acid (C8), and an 8:2 mixture of C10:C8 on gene expression related to glucose metabolism, fatty acid metabolism, the citric acid cycle (including citrate synthase), and oxidative phosphorylation (including mitochondrial genes encoding the NADH dehydrogenase (ubiquinone) subunit). The inventors compared astrocytes (associated with generalized epilepsy and belonging to the central nervous system cell type) with induced pluripotent stem cells (iPSCs) derived from fibroblasts of Glut1-DS patients (associated with Glut1-DS, especially cells that have not yet differentiated for the central nervous system environment).

[0175] Surprisingly, the decanoic acid-rich composition disrupts glucose metabolism in iPSCs carrying the Glut1DS mutation. Figure 1 Fatty acid metabolism ( Figure 2A number of genes associated with Glut1-DS, including citrate cycle (including citrate synthase) (data not shown), and oxidative phosphorylation (data not shown), were upregulated, while caprylic acid did not show the same effect on iPSCs. Similarly, the combination rich in capric acid did not upregulate genes associated with glucose metabolism in U251 cells. This suggests that caprylic acid and capric acid have specific and unique direct effects on cells carrying the Glut1-DS mutation, which are not observed in non-mutant cell lines present in the central nervous system. For example, CPT1B (an isotype of carnitine palmitoyltransferase I (CPT1) present in muscle) is upregulated in Glut1-DS iPSCs but not in non-Glut1-DS astrocytes. Figure 2 CPT1B is a rate-controlling enzyme in the long-chain fatty acid β-oxidation pathway in muscle mitochondria, and therefore plays a crucial role in muscle energy supply (J. McGarry et al., (1977) J. Clin. Invest.; 60:265). Indeed, glucose metabolism generally increases when decanoic acid (or an 8:2 C10:20 mixture) is added to Glut1-DS iPSCs. Figure 1 B), but the opposite effect was observed in astrocytes ( Figure 1 A). Data indicate that decanoic acid-rich compositions may have a direct effect on cells carrying the Glut1-DS mutation, even if these cells are not derived from cell types present in the central nervous system. Furthermore, data confirm that decanoic acid alone downregulates the Glut1 gene (SLC2A1 gene) in both astrocytes and Glut1-DS iPSCs. Surprisingly, caprylic acid has the opposite effect on brain-derived astrocytes. This leads the inventors to predict specific MCT compositions (such as K. Vita) rich in decanoic acid but containing a small amount of caprylic acid. ® This combination of decanoic acid and caprylic acid may be suitable for treating motor disorders in patients with Glut1-DS. Since decanoic acid may inhibit GLUT1 function in the brain, it is predicted that containing a small amount of caprylic acid will counteract this negative effect. Although Glut1-DS is generally believed to be treated with KDTs that induce "ketosis," certain MCT compositions rich in decanoic acid but containing a small amount of caprylic acid (such as K. Vita) are actually effective. ® It can even treat movement disorders in Glut1-DS patients without epilepsy.

[0176] experiment

[0177] chemicals

[0178] Decanoic acid and octanoic acid were purchased from Alfa Aesar (A14788 and A11149, respectively). Dimethyl sulfoxide (DMSO) was purchased from VWR (MFCD00002089).

[0179] Cell culture

[0180] The iPSCs derived from GLUT1-deficient fibroblasts were obtained from the Coriell Institute (GM27896). The cells were derived from skin biopsies of patients with GLUT1 deficiency syndrome, caused by a C-to-T mutation at base pair 1454 of the SLC2A1 gene, which induces the P485L mutation in the GLUT1 protein. The cells were stored in liquid nitrogen and encapsulated in 25 cm³ containers coated with hESC-certified Matrigel (Corning, #354277). 2 Or 75cm 2 Cells were cultured in Corning (430639 / 430641U) flasks in mTeSR-1 medium (Stem Cell Technologies, #85850) with a high glucose level, and passaged no more than 10 times (A. Chen et al., (2021) Int. J. Mol. Sci.; 22:10729). Cells were maintained at 37°C and 5% CO2, passaged using StemPro Accutase (Thermo Fisher, A1110501), and cultured at a rate of 2.5–3.104 cells / cm². 2 Cells were seeded at a high density, with initial treatment with 10 μM ROCK inhibitor Y-27632 (Abcam, ab120129) for the first 24 hours. The mTeSR-1 medium was changed every 24 hours to prevent cell differentiation and allow for optimal growth.

[0181] U251 human astrocyte-derived cells were obtained from ECACC (U-373MG, Cat.080619010). Cells were stored in liquid nitrogen and, upon removal from the storage device, passaged no more than 10 times. Cells were incubated at 37°C and 5% CO2 at a depth of 25 cm⁻¹. 2 Or 75cm 2 Cells were cultured in Eagle's minimum essential culture (Merck, M4655) in cell culture flasks (Corning, 430639 / 430641U). This medium contained non-essential amino acids (Merck, M7145), sodium pyruvate (Merck, S8636), 10% fetal bovine serum (Merck, F7524), 1% penicillin / streptomycin, and 5.6 mM glucose. When confluence reached 80%, cells were digested with trypsin (Thermo Fisher, 25300054) and passaged at a concentration of 3.104 cells / cm³. 2 The density of the inoculation was increased and the culture was inoculated into new culture flasks.

[0182] RNA sequencing

[0183] Cells derived from GLUT1-deficient iPSCs or U251 human astrocytes were cultured at a concentration of 2.1 cells / cm³. 2 The samples were seeded at a density in T25 culture flasks and treated for 4 days with physiologically relevant concentrations (150 μM) of decanoic acid or caprylic acid, or 120 μM decanoic acid / 30 μM caprylic acid (8:2 C10:C8 ratio). The culture medium was changed every 48 hours. Total RNA was extracted from the samples using the RNeasy kit (Qiagen, 74104), and the samples were diluted to 20 ng / μl for sequencing analysis.

[0184] mRNA from total RNA was sequenced and pathway enrichment analyzed using Novogene. mRNA was purified from total RNA using magnetic beads, and the resulting samples were fragmented into 50 bp mRNA fragments. cDNA was synthesized from mRNA fragments linked to adaptors, amplified using real-time PCR, and sequenced on an Illumina platform. The original reads were cleaned by removing reads containing adaptors, poly-N reads, and low-quality reads using FastP software. Reads were aligned to known genomes using Hisat2, and gene expression was quantified using FeatureCounts. Differential gene expression was assessed using the DESeq2 R package, and gene set enrichment analysis (GSEA) was performed. http: / / www.broadinstitute.org / gsea / index.jsp A. Subramanian et al., (2005) Proc. Natl. Acad. Sci. USA; 102:15545-15550; L. Mootha et al., (2003) Nature Genetics; 34:267–273) and the Kyoto Encyclopedia of Genetics and Genomes (KEGG) database ( https: / / www.genome.jp / kegg / ; M. Kanehisa and S. Goto (2000) Nucleic Acids Res.; 28:27-30; M. Kanehisa et al. (2023) Nucleic Acids Res.; 51:D587-D592) conducted differential pathway analysis.

[0185] Protein blot

[0186] U251 or GLUT1-deficient iPSC lysates were prepared using RIPA buffer (Thermo Fisher, 89900) containing a protease inhibitor (Thermo Fisher, 87786). Protein quantification was performed using the Pierce BCA protein assay (Thermo Fisher, 23227). The lysates were dissolved in Laemmli buffer (Thermo Fisher, J61337.AC) and heated at 70°C for 5 minutes, then 6 μg was loaded onto an 8% acrylamide gel. Following the manufacturer's protocol, the proteins were transferred to a 0.45 μM PVDF membrane (Millipore, IPFL00010) in transfer buffer using a Trans-blotTurbo transfer system (Bio-Rad, 1704150). After incubating for 1 hour with Intercept blocking buffer (Li-COR, 927-70001), the membrane was incubated overnight at 4°C with antibodies against Vinculin and GLUT1 (1:1000) (Cell Signalling technology, 13901, 73015) in Intercept blocking buffer. The membrane was washed in TBST and incubated for 1 hour with Odyssey goat anti-rat IR DYE 800 diluted 1:10000 (LI-COR Biosciences, UK) in Intercept blocking buffer containing 0.1% SDS (Sigma, L5750) and 0.1% Tween (Thermo Scientific, 10776834). The blot was washed in TBST and visualized using an Odyssey CLx imager (LI-COR) according to the manufacturer's protocol.

[0187] result

[0188] Preliminary screening of astrocyte-derived cells

[0189] The inventors investigated the effects of MCFA on human astrocyte-derived glioblastoma cells (U251) previously used for glucose and fatty acid metabolism analysis (P. Weightman Potter et al., (2019) Diabetologia; 62:187–198). In these experiments, astrocyte-derived cells were treated with decanoic acid or caprylic acid (150 μM) or a combination of decanoic acid / caprylic acid (120 μM / 30 μM), at concentrations equivalent to those obtained with K. Vita ®Blood concentrations were measured in epilepsy patients during treatment (N. Schoeler et al., (2021) Brain Comms; 3:1–13). Cells were treated for 4 days to allow time for metabolic changes to occur following prolonged dietary therapy (C. Harvey et al., (2018) J. Nutr. Metab.; 2630565). Transcriptional regulation was initially selected to monitor metabolic changes after treatment, with key modifications validated by Western blot analysis.

[0190] Decanoate treatment significantly upregulated 15 KEGG pathways and downregulated 75 KEGG pathways in U251 cells. Of the 15 most significantly upregulated pathways, 5 involved fatty acid metabolism and signal transduction (including fatty acid degradation p < 0.001; fatty acid metabolism p < 0.001; peroxisome p = 0.001; PPARα p = 0.002; and butyrate metabolism p = 0.033). Conversely, caprylic acid treatment provided relatively smaller significant changes, with caprylic acid significantly upregulating 10 KEGG pathways and downregulating 4 pathways, with smaller changes in fatty acid or glucose metabolism. Treatment with a combination of decanoic acid:caprylic acid (8:2) downregulated 14 pathways, including four involved in glucose uptake and metabolism (HIF-1 signaling p < 0.001; glycolysis p = 0.001; fructose / mannose metabolism p = 0.011; galactose metabolism p = 0.016; starch / sucrose metabolism p = 0.02) and three involved in cell signaling (PI3K-AKT signaling p = 0.003; MAPK signaling p = 0.02 and AMPK signaling p = 0.01). The decanoic acid:caprylic acid combination significantly upregulated one pathway. This analysis suggests that decanoic acid-containing treatment plays a crucial role in enhancing fatty acid metabolism and downregulating glucose metabolism in astrocyte-derived cells after long-term treatment.

[0191] To identify the relative contribution of each fatty acid in regulating transcriptional changes, the inventors examined the total number of genes significantly regulated by each treatment. In summary, the expression of 4172 genes was significantly altered under all conditions, with 6.5% (270 genes) of these genes altered under all three conditions (decanoic acid, caprylic acid, and combined treatments), indicating that most transcriptional changes are associated with the action of specific fatty acids. Decanoic acid treatment regulated the largest proportion of genes (63%, 2626 genes), with 60% (1534 genes) altered only after decanoic acid treatment. Caprylic acid treatment significantly altered the expression of 1869 genes, with 52% (991 genes) of these genes being specific to caprylic acid treatment. Of the 3844 genes significantly upregulated or downregulated after treatment with one or another MCFA, only 17% (651 genes) were shared by decanoic acid and caprylic acid, indicating that these fatty acids have different mechanisms of action and provide different roles. Interestingly, the combination of the two fatty acids significantly altered the expression of 1266 genes, with 74% (938 genes) sharing the same effect as either decanoic acid or caprylic acid treatment, but also specifically inducing significant changes in the expression of 328 other unique genes (26%). Therefore, decanoic acid and caprylic acid treatments primarily provide different roles in gene transcription, and the combined treatment provides specific alterations to gene transcription rather than an "average" of the individual effects of their components.

[0192] Specific transcriptional changes induced by medium-chain fatty acid treatment

[0193] Because treatment with decanoic acid reduces the expression of several KEGG pathways related to glucose transport and metabolism in astrocyte-derived cells, the inventors investigated genes involved in glucose transport, glycolysis, and gluconeogenesis whose expression levels were significantly altered. Figure 1 A). A heatmap comparison of genes whose expression levels changed significantly after different MCFA treatments showed that, with decanoate treatment alone, the expression of phosphoenolpyruvate carboxylase (PCK2) was strongly increased. This gene controls the rate-limiting step of gluconeogenesis and the TCA cycle (S. Burgess et al., (2007) Cell Metab.; 5:313-320). However, decanoate and the combination of decanoate:caprylic acid (8:2) treatments significantly reduced the expression of genes related to carbohydrate uptake and glycolysis after treatment, but this effect did not appear after caprylic acid treatment ( Figure 1 A). Here, treatment rich in decanoic acid significantly reduced the expression of the gene encoding GLUT1 in astrocytes (SLC2A1) and reduced the expression of genes associated with 10 of the 11 steps of glycolysis. Figure 1A). Conversely, caprylic acid treatment significantly reduced the expression of the ENO2 gene, which is involved in the final stage of glycolysis. Combined capric acid:caprylic acid (8:2) treatment reduced the expression of seven genes involved in glycolysis, several of which also showed reductions when treated with capric acid alone. Crucially, combined capric acid:caprylic acid (8:2) treatment did not significantly reduce the expression of the gene encoding astrocyte GLUT1 (SLC2A1).

[0194] Western blot analysis was used to investigate changes in GLUT1 protein levels in U251 cells. Compared with control conditions, decanoic acid treatment significantly reduced GLUT1 levels (p=0.005), but caprylic acid did not show this effect, validating the transcriptional analysis.

[0195] The inventors also analyzed genes involved in fatty acid metabolism. Figure 2 A). A heatmap comparison of genes involved in β-oxidation (including acyl-CoA formation) showing significant changes in expression levels revealed that decanoic acid and the combination of decanoic acid:octanoic acid (8:2) treatments greatly increased the expression of these genes, but this effect did not appear after octanoic acid treatment. Figure 2 A).

[0196] Next, the inventors identified genes whose expression levels were significantly altered in Glut1-DS-derived iPSCs involved in sugar transport, glycolysis, and gluconeogenesis. Figure 1 B). A heatmap comparison of genes whose expression levels changed significantly after different MCFA treatments showed that, compared with astrocyte-derived cells, Glut1-DS-derived iPSCs showed significant changes. Specifically, after treatment with decanoic acid-rich MCFA, more genes involved in glucose metabolism were upregulated. Of the 12 genes involved in both glycolysis and gluconeogenesis, 5 were upregulated, while of the 3 genes involved in glycolysis only, 2 (PFKP, PGM1) were downregulated and 1 (PGM2) was upregulated. Interestingly, lactate dehydrogenase (LDHD) expression was also strongly downregulated, and inhibition of LDH (Y. Inoue et al., (2021) Epilepsy Res.; 176:106705) provides a mechanism for controlling epileptic seizures. Furthermore, four of the six genes involved in gluconeogenesis that showed significant changes (GOT2, SLC25A13, SLC25A12, and PC) were upregulated, while two genes (FBP1 and GOT1) were downregulated. Therefore, these data indicate that decanoic acid-rich treatment of GLUT1-deficient cells can stimulate gluconeogenesis while inhibiting glycolysis.

[0197] The expression of many genes encoding energy-related mitochondrial metabolism proteins was also altered after decanoate treatment, including genes related to fatty acid and ketone metabolism. Figure 2 (B) Of particular interest in fatty acid β-oxidation is the CPT1B protein, a rate-controlling enzyme in the long-chain fatty acid β-oxidation pathway in muscle mitochondria, which plays a crucial role in muscle energy supply (J. McGarry et al., (1977) J. Clin. Invest.; 60:265), which is upregulated upon treatment with decanoic acid-rich solutions. Furthermore, CPT2 acts in mitochondria to remove carnitine from acyl-carnitine, thus allowing β-oxidation; therefore, the co-upregulation of CPT1B and CPT2 increases the likelihood of enhanced energy supply in muscle. Additionally, the first step in the metabolism of 12 to 22 carbon atoms is mediated by ACADVL, in which the expression of the gene encoding it is upregulated upon these treatments. ECHS1 is a mitochondrial protein that catalyzes the hydration of medium- and short-chain fatty acyl-CoA thioesters from 4 carbon atoms (C4) to C16, and this protein is upregulated upon treatment. HMGCS1 is the cytoplasmic form of the ketogenic enzyme HMGCS2 (F. Hegardt (1999) Biochem.J.; 338:569–582) and catalyzes the same reaction (it is necessary to observe whether ketones are produced after treatment). Furthermore, decreased expression of OXCT2, the protein it encodes (SCOT), catalyzes the first rate-limiting step of ketone body utilization (N. Shafqat et al., (2013) J. Inherit. Metab.Dis.; 36:983-987), indicates metabolic ketone saving in these cells after treatment. Other genes encoding β-oxidation proteins showed increased expression after treatment with decanoate-rich esters, including ACOX1, which controls the initial and rate-limiting steps of peroxisome β-oxidation of linear saturated and unsaturated very long-chain fatty acids, and ACOX3, a peroxisome protein that functions to oxidize the CoA-ester of 2-methyl-branched fatty acids. ACSBG1 catalyzes the conversion of fatty acids (such as long-chain and very long-chain fatty acids) into their active form, acyl-CoA, for use in cellular lipid synthesis and degradation via β-oxidation. Therefore, these changes in fatty acid metabolism are consistent with an enhancement of fatty acid metabolism, thereby providing energy for iPSCs derived from Glut1-DS.

[0198] The inventors conducted preliminary experiments on the expression of genes related to the citrate cycle in U251 and Glut1-DS-derived iPSCs, including citrate synthase (data not shown) and oxidative phosphorylation (data not shown). In U251 cells, only six citrate cycle genes were altered by decanoate, with four genes upregulated and two genes downregulated (including citrate synthase). In Glut1-DS-derived iPSCs, after treatment with decanoate-rich mitochondrial cells, the expression of multiple genes encoding citrate cycle and oxidative phosphorylation proteins was enhanced (data not shown). The expression of genes encoding thirteen citrate cycle-related mitochondrial proteins increased, consistent with the increased mitochondrial load in Glut1-DS-derived iPSCs after treatment. These proteins include ACLY, which catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA to produce ATP, and citrate synthase, which serves as a marker of mitochondrial content, and whose expression was shown to increase after decanoate treatment. Furthermore, 20 genes encoding oxidative phosphorylation proteins showed significantly increased expression in Glut1-DS-derived iPSCs. Importantly, these increases in citrate cycling and oxidative phosphorylation-related genes were not observed after equivalent treatment of the human astrocyte-derived cell line (U251), indicating that *K. vita*... ® It has a potential disease-specific mechanism to enhance energy supply in Glut1DS cells.

[0199] Following treatment with decanoate-rich solutions, the expression of two genes encoding pentose-phosphate pathway (PPP) enzymes was increased (data not shown). This pathway provides energy by generating NADPH and incidentally reduces reactive oxygen species (ROS). Both G6PD, which catalyzes the rate-limiting step of the pentose-phosphate pathway and produces NADPH, and PGD, which also produces NAPDH and removes ROS, were increased. This enhanced expression of the two proteins could provide a mechanism for reducing ROS generated by increased mitochondrial load.

[0200] It is hypothesized that the combined treatment of decanoic acid:caprylic acid (8:2) may be less toxic to Glut1DS cells than decanoic acid or caprylic acid alone.

[0201] Therefore, in summary, the effects of MCFA, especially the combined decanoic acid:octanoic acid (8:2) treatment on Glut1DS cells are to reduce the expression of genes encoding glucose uptake and glycolysis, and to increase the expression of genes encoding some gluconeogenic and fatty acid metabolism proteins (including muscle-specific genes), indicating a shift in the metabolic pattern of energy supply from glucose metabolism to glucose catabolism and fatty acid metabolism.

[0202] Furthermore, the combined decanoic acid:caprylic acid (8:2) treatment significantly enhanced the expression of many genes related to the citric acid cycle and oxidative phosphorylation, consistent with increased mitochondrial load and enhanced energy supply. No equivalent changes were observed after treatment with U251 cells, suggesting that these changes associated with Glut1-DS are disease-specific.

[0203] Furthermore, the combined decanoate:caprylic acid (8:2) treatment increased the expression of PPP-related genes, which may have reduced ROS levels associated with increased mitochondrial load. Therefore, these mechanisms provide a unique set of metabolic signaling changes that could potentially mitigate the detrimental effects of lower glucose uptake in Glut1-DS, including in the peripheral zone. These data support the peripheral effects of the combined decanoate:caprylic acid (8:2) treatment, which may allow for the treatment of Glut1-DS patients with movement disorders, even those without prior epilepsy.

[0204] F. Planned Clinical Protocol

[0205] Based on the findings that caprylic acid and decanoic acid have opposite effects on GLUT1 expression and that the combined decanoic acid:caprylic acid (8:2) treatment has a significant effect on iPSCs, as detailed in Section E above, the inventors plan to conduct clinical trials on a well-characterized Glut1-DS patient population.

[0206] Clinical trial design

[0207] An intervention study lasting approximately 6 months, with ongoing follow-up of participants, aimed to evaluate the use of K. Vita. ® Use as a pharmacological intervention (e.g., in the form of homoglycerides) or dietary intervention in the management of children and adults with glucose transporter deficiency syndrome type 1 (Glut1-DS).

[0208] Subjects consisted of adults and children with Glut1-DS, a confirmed diagnosis and current symptoms of epilepsy and / or motor disorders, who were not currently following or adhering to a ketogenic diet (KDT), or who were following a standard long-chain triglyceride (LCT) ketogenic diet or a modified Atkins diet. Subjects following a standard medium-chain triglyceride (MCT) diet (based on coconut oil) or who regularly consumed MCT at the time of screening were excluded. In addition to adding K. Vita ® In addition, the subjects' dietary intake should remain stable throughout the trial period.

[0209] This study requires 20 to 40 participants to detect changes in the primary outcome ranging from 10% to 50% with acceptable statistical power.

[0210] The sample size also reflects the rarity of the disease and the expected loss to follow-up rate.

[0211] This study will be conducted at multiple locations to recruit the required number of participants within a specified timeframe.

[0212] Target

[0213] Main objective: To study K. Vita ® Clinical efficacy of Glut1-DS in managing symptoms of epilepsy and / or movement disorders, as a pharmacological intervention (e.g., in the form of homoglycerides) or dietary intervention, when used with no dietary restrictions or minimal dietary restrictions (avoiding foods containing monosaccharides), or when used with a standard long-chain triglyceride (LCT) ketogenic diet or a modified Atkins diet. Measured in conjunction with the NeuroQoL scale and dynamic EEG.

[0214] The plan's secondary objectives include:

[0215] i) The aim is to measure relevant biomarkers and their correlation with efficacy.

[0216] ii) The aim is to study K. Vita ® The impact of dietary intervention on the quality of life (Neuro QoL scale) and caregiver burden of participants with Glut1-DS.

[0217] iii) The aim was to determine the efficacy of K. Vita in participants with Glut1-DS. ® Long-term (e.g., up to 26 weeks) acceptance, compliance, and tolerability.

[0218] iv) aimed at assessing the participation of participants and healthcare professionals regarding K. Vita ® The use of resources and support, and the participants / caregivers' assessment of K.Vita ® The experience is compared with KDT.

[0219] v) The aim is to measure the effect on depression, such as by the Neurological Disorders of Epilepsy Depression Scale (NIDDI-E).

[0220] parameter

[0221] Key parameters: Daily seizure count and / or motor impairment (e.g., measured by a motor impairment scale) of each (countable) seizure in the 30 days prior to the 3-month and 6-month follow-ups, as assessed by a paper or electronic diary, compared to the 30-day baseline period.

[0222] Secondary parameters for participants with epilepsy as part of the plan:

[0223] i) The number of seizures, use of emergency medications, and seizure-related hospitalizations was prolonged during the 6-month intervention period compared to the 6 months prior to study enrollment. This was measured by the frequency of patient / caregiver reports collected by the study investigator during baseline, 3-month, and 6-month study visits.

[0224] ii) Seizure Severity Questionnaire (1), completed at baseline, 3-month and 6-month study visits.

[0225] Secondary parameters of the plan for participants with movement disorders:

[0226] i) The number of paroxysmal seizures involving impaired motor control, as assessed by paper or electronic diaries, in the 30 days prior to the 3-month and 6-month follow-up periods, compared to the 30-day baseline period, and the presence of any triggering factors for the seizures.

[0227] ii) Duration of paroxysmal seizures of each (countable) seizure type, assessed by paper or electronic diary, within 30 days prior to the 3-month and 6-month follow-up periods, compared to the 30-day baseline period.

[0228] iii) Wearable devices / activity watches for assessing activity levels.

[0229] iv) Use GAITRite at baseline, 3-month, and 6-month study visits. ® The Electronic Walking System (CIRSystems, Inc., New Jersey, USA) performs gait analysis as part of a 6-minute walk test: it calculates walking speed, cadence, stride length, heel-to-heel support base, and the percentage of time spent on both feet.

[0230] Secondary parameters of the plan for all participants:

[0231] Quality of life assessment

[0232] Completed at baseline and at the end of 6 months:

[0233] -PedsQL ™ The universal core scale, with versions suitable for the corresponding age groups: toddlers (2-4 years), preschoolers (5-7 years), children (8-12 years), adolescents (13-18 years), young adults (18-25 years), and adults (≥26 years), will be completed at baseline, 3-month, and 6-month study visits. Free text boxes will be added for patients / caregivers to enter their own comments on quality of life (QoL). At the 3-month and 6-month study visits, patients / caregivers will be asked to refer to any comments they entered at baseline and explain how those comments were influenced.

[0234] -Zarit Caregiver Burden Interview 6-item version (2), designed to assess caregiver burden, was conducted at baseline, 3-month and 6-month study visits.

[0235] Assessment of the plan's acceptance, compliance, and tolerability

[0236] - Dietary satisfaction scores at 3-month and 6-month reviews (3).

[0237] - Make temporary records of poor adherence through a patient diary or app (if K.Vita is being taken). ® (The amount was inconsistent with the recommended intake), and adherence was reviewed with the researchers at 3 and 6 months.

[0238] - Conduct 24-hour dietary recall at baseline, 3-month, and 6-month study visits: calculate the percentage of energy intake from fat, carbohydrates (starch and sugar), and carbohydrates.

[0239] - Temporarily record gastrointestinal symptoms through patient diaries or applications, and review gastrointestinal tolerance with researchers at baseline, 3-month, and 6-month study visits.

[0240] Height and weight were measured at baseline, 3-month, and 6-month study visits.

[0241] - Clinical biochemical tests were performed at baseline, 3-month, and 6-month study visits:

[0242] Distribution of free carnitine and acylcarnitine in dried blood spots

[0243] Glucose (mmol / L)

[0244] Triglycerides (mmol / L)

[0245] NEFA (mmol / L)

[0246] Total cholesterol (mmol / L)

[0247] β-hydroxybutyrate (mmol / L)

[0248] Sodium (mmol / L)

[0249] Potassium (mmol / L)

[0250] Urea (mmol / L)

[0251] Creatinine (μmol / L)

[0252] Calcium (mmol / L)

[0253] Magnesium (mmol / L)

[0254] Phosphoric acid (mmol / L)

[0255] 25-Hydroxyvitamin D (nmol / L)

[0256] ALT (U / L)

[0257] ALP (U / L)

[0258] Bilirubin (μmol / L)

[0259] Albumin (g / L)

[0260] Urate (μmol / L)

[0261] Total CO2 (mmol / L)

[0262] C8 (μmol / L)

[0263] C10 (μmol / L)

[0264] Urine test strips: pH, specific gravity, protein, glucose, ketones, bilirubin, infection markers, occult blood.

[0265] Urinary organic acids (at baseline only)

[0266] Urate and calcium:creatinine ratio in urine

[0267] The plan is against K.Vita ® An assessment of resource and support usage and a comparison of experience with previous KDTs.

[0268] Researchers designed a short questionnaire asking participants / caregivers about K. Vita. ® Resources, presentation schedules, and opinions on perceived needs for clinical / nutritional support, as well as their experiences compared to those who previously followed KDT alone or started K.Vita. ® What was different before was determined during the 3-month and 6-month study visits.

[0269] Researchers designed a short questionnaire asking participants who were managing their K.Vita use... ® The participants' healthcare professionals' opinions on the resources used (for both healthcare professionals and participants / caregivers), and the management of K. Vita administration. ® The required clinical / nutritional time for participants was determined and completed 3 to 6 months after the start of the study.

[0270] Participants will be reminded to complete a seizure / seizure diary and record instances of poor adherence and gastrointestinal symptoms.

[0271] Rave eCOA and integrated tools such as Patient Cloud and Sensor Cloud will be used to collect questionnaire data electronically.

[0272] Patients / caregivers can choose to complete all follow-up questionnaires online before the study visit.

[0273] Selection criteria for the plan

[0274] Participants are eligible to participate in this study only if they meet all of the following criteria:

[0275] 1) Having a confirmed genetic (SLC2A1) or biochemical (decreased cerebrospinal fluid [CSF] / glucose ratio) diagnosis of Glut1-DS and symptoms of Glut1-DS, such as seizures / paroxysmal seizures.

[0276] 2) Based on the advice of a referring dietitian or clinician, currently not following or adhering to the KDT, or defined as having no dietary restrictions other than avoiding foods and beverages containing simple sugars. Alternatively, currently following a standard long-chain triglyceride (LCT) ketogenic diet or a modified Atkins diet.

[0277] 3) Age 3 years and above (may be adjusted based on tolerability).

[0278] 4) There are no metabolic or mitochondrial barriers that would prevent the use of medium-chain triglycerides (MCTs).

[0279] 5) Written informed consent form voluntarily signed by the patient or their parents / caregivers.

[0280] 6) A voluntary written consent form (if applicable).

[0281] Exclusion criteria for the plan

[0282] Participants will be excluded from this study if they meet any of the following criteria:

[0283] 1) Age under 3 years old (can be adjusted based on tolerance).

[0284] 2) Newly diagnosed Glut1-DS patients or Glut1-DS patients who have been diagnosed but have not followed standard care treatment.

[0285] 3) Currently using KDT fully or partially and without symptoms of Glut1-DS, such as seizures / paroxysmal seizures.

[0286] 4) Subjects whom the researchers believe are unable to comply with the research protocol.

[0287] 5) Having other concurrent medical or psychiatric conditions that researchers believe would increase the risk to the subject, making it impossible to obtain voluntary informed consent / agreement or to follow the procedures prescribed for the study, or would interfere with the achievement of the study objectives.

[0288] 6) Participants who are pregnant / breastfeeding at the start of the study or plan to become pregnant during the study. Participants of childbearing age are required to undergo pregnancy testing before enrollment.

[0289] 7) Allergic to any ingredient present in the research product.

[0290] 8) Currently participating in any other interventional study and having started using any other investigational drug, product, or device within 30 days prior to screening, or currently participating in a non-drug study that the investigator believes will interfere with study adherence or outcome assessment.

[0291] 9) Follow a standard medium-chain triglyceride (MCT) diet (based on coconut oil), or consume MCT regularly during screening.

[0292] Planned dose

[0293] Adults will receive four 60mL doses daily, and the target for children is through K.Vita. ® To achieve ≤35% of energy requirements, with a predicted dose of 120 mL per day.

[0294] Statistical methods

[0295] Statistical analysis will be performed in a manner known to experienced clinical statisticians.

[0296] G. Subgroup analysis of patients with movement disorders but without concurrent epilepsy.

[0297] Subgroup analyses will be conducted on Glut1-DS patients without concomitant epilepsy to assess whether an effect is seen on their symptoms. Specifically, subgroup analyses will be conducted on Glut1-DS patients without concomitant epilepsy to assess whether an effect is seen on their motor symptoms. Additionally, subgroup analyses will be conducted on Glut1-DS patients without concomitant epilepsy to assess whether an effect is seen in the absence of occurrence or recurrence of epilepsy or seizures.

[0298] H. Service assessment of a subgroup of patients with movement disorders but without concurrent epilepsy.

[0299] The applicant is currently administering decanoic acid and caprylic acid (in a ratio of 80:20 as FSMP) to a group of patients in the UK based on the planned dosage described in Part F above – K. Vita ® Service assessment was conducted. Seven patients in this group had Glut1-DS with motor disorders but no accompanying seizures. They started taking K.Vita. ® Symptom frequency was collected at 3, 6, and 12 months:

[0300] • All 7 patients completed the 3-month observation period, and 4 of them reported a reduction in motor dysfunction.

[0301] • Of these 7 patients, 6 completed the 6-month observation period, and all 6 patients reported a reduction in motor dysfunction.

[0302] • Of these 7 patients, 4 completed the 12-month observation period, and all 4 patients maintained the reduction in motor dysfunction.

[0303] These results suggest that the claimed composition may be used to treat and / or manage the movement disorders in patients with Glut1-DS, particularly those who had movement disorders but no accompanying epilepsy prior to the administration of the composition.

[0304] Dietary intervention implementation plan :

[0305] Implementation Scheme 1. A composition for dietary management of movement disorders in patients with Glut1-DS, said composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0306] Implementation Scheme 2. The composition for the purpose according to Implementation Scheme 1, wherein the Glut1-DS patient is a person who had a movement disorder but no accompanying epilepsy before the application of the composition.

[0307] Implementation Scheme 3. The composition for the purpose according to Implementation Scheme 1 or Implementation Scheme 2, wherein the Glut1-DS patient is a person carrying a mutation in the SLC2A1 gene, said mutation being selected from the group consisting of:

[0308] Point mutations are preferred to occur at sites selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Ser113, Arg126, Gly130, Arg153, Arg212, Arg218, Lys256, Arg264, Thr295, Ala155, Arg330, Arg333, Pro485, and Arg468 of type 1 glucose transporters.

[0309] Splice site mutation;

[0310] nonsense mutation;

[0311] insert;

[0312] Missing;

[0313] Exon deletion; or

[0314] Complete gene deletion.

[0315] Implementation Scheme 4. A composition for the purpose according to any of the foregoing embodiments, wherein the movement disorder is selected from the group consisting of: common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal movement-induced movement disorders, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), movement abnormalities (e.g., involuntary movements), pyramidal tract symptoms, spasticity, ataxia, dystonia, hypotonia, gait abnormalities, chorea, tremor, non-epileptic myoclonus (optionally including startle myoclonus, action myoclonus, and postural myoclonus). Or weakness / paralysis), atrophic disorders (e.g., oculomotor and oral-cheek disorders) or paroxysmal nonmotor episodes (e.g., migraine, behavioral abnormalities, periodic vomiting and sleep attacks, as well as confusion, somnolence, somnolence-induced irritability, mild hemiparesis, cataplexy and generalized paralysis); preferably, the motor disorder is selected from the group consisting of: common paroxysmal motor disorders (e.g., paroxysmal eye-head movements, paroxysmal movement-induced motor disorders, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), pyramidal tract symptoms, ataxia, hypotonia and chorea.

[0316] Implementation Scheme 5. The composition for the purpose according to any of the preceding embodiments, wherein the patient suffers from one or more additional symptoms selected from the group consisting of: developmental and / or cognitive impairment, atypical presentation, and / or adult-onset Glut1-DS.

[0317] Implementation Scheme 6. The composition for the said use according to Implementation Scheme 5, wherein:

[0318] The additional symptoms are developmental and / or cognitive impairments selected from the group consisting of: microcephaly, mild to severe intellectual disability, dysarthria, visuospatial impairment, and visuomotor impairment; preferably, the developmental and cognitive impairment is microcephaly; and / or

[0319] The additional symptoms are atypical presentations selected from the following groups: writer's cramp, intermittent ataxia, sudden collapse, generalized paralysis, Parkinson's disease, nocturnal muscle cramps in the legs, alternating hemiplegia in children, hemiplegic migraine, periodic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with paroxysmal motor-induced movement disorders, hepatosplenomegaly, periventricular calcification, cerebral atrophy, pseudohyperkalemia, cataracts, and retinal abnormalities; and / or

[0320] The additional symptom is adult-onset Glut1-DS with symptoms of movement disorder that occurs during adolescence to adulthood; preferably, it is a paroxysmal movement-induced movement disorder.

[0321] Implementation Scheme 7. The composition for the purpose according to Implementation Scheme 5 or Implementation Scheme 6, wherein one or more additional symptoms are treated, preferably all additional symptoms are treated.

[0322] Implementation Scheme 8. The composition for the purpose according to any of the foregoing embodiments, wherein the patient is an infant, child, adolescent or adult; preferably an adolescent or adult; even more preferably an adult.

[0323] Implementation Scheme 9. A composition for the purpose according to any of the preceding embodiments, wherein the C10:C8 ratio is 75:25 to 85:15; preferably about 8:2 wt:wt, more preferably about 80:20 wt:wt.

[0324] Implementation Scheme 10. A composition for the use according to any of the foregoing embodiments, wherein the decanoic acid and caprylic acid are in the form of triglycerides; preferably, in the form of a mixture of homoglycerides containing tri-C8 triglycerides (caprylic triglycerides) and tri-C10 triglycerides (decanoic triglycerides).

[0325] Implementation Scheme 11. A composition for the use according to any of the foregoing embodiments, wherein the decanoic acid and octanoic acid account for at least 80% by weight, preferably 85% by weight, more preferably 90% by weight, even more preferably 95% by weight, or most preferably 99% by weight of the total fatty acid content of the composition.

[0326] Implementation Scheme 12. A composition for the purpose according to any of the foregoing embodiments, wherein the composition is substantially free of monounsaturated or polyunsaturated fatty acids, carbohydrates and / or proteins.

[0327] Implementation Scheme 13. A composition for the purpose according to any of the foregoing embodiments, wherein the composition is in the form of an oil-in-water emulsion.

[0328] Implementation Scheme 14. Use of a composition comprising a mixture of decanoic acid (C10) and octanoic acid (C8) in the preparation of a medicinal food, wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt, for use in the preparation of a medicinal food.

[0329] (a) Treatment of movement disorders in patients with Glut1-DS; and / or

[0330] (b) Dietary management of movement disorders in patients with Glut1-DS.

[0331] Treatment plan :

[0332] Implementation Scheme 15. A method for treating Glut1-DS movement disorder, the method comprising administering to a Glut1-DS patient in need a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

[0333] Implementation Scheme 16. The method according to Implementation Scheme 15, wherein the Glut1-DS patient is a person who had a motor disorder but no accompanying epilepsy prior to treatment.

[0334] Implementation Scheme 17. The method according to Implementation Scheme 15 or Implementation Scheme 16, wherein the Glut1-DS patient is a person carrying a mutation in the SLC2A1 gene, said mutation being selected from the group consisting of:

[0335] Point mutations are preferred to occur at sites selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Ser113, Arg126, Gly130, Arg153, Arg212, Arg218, Lys256, Arg264, Thr295, Ala155, Arg330, Arg333, Pro485, and Arg468 of type 1 glucose transporters.

[0336] Splice site mutation;

[0337] nonsense mutation;

[0338] insert;

[0339] Missing;

[0340] Exon deletion; or

[0341] Complete gene deletion.

[0342] Implementation Scheme 18. The method according to any of the foregoing method implementation schemes, wherein the movement disorder is selected from the group consisting of: common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal movement-induced movement disorders, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), movement abnormalities (e.g., involuntary movements), pyramidal tract symptoms, spasticity, ataxia, dystonia, hypotonia, gait abnormalities, chorea, tremor, non-epileptic myoclonus (optionally including startle myoclonus, action myoclonus, and postural myoclonus or none) The motor dysfunction may include: paralysis / paralysis, dyskinesis (e.g., oculomotor and oral-cheek dysfunction) or paroxysmal nonmotor episodes (e.g., migraine, behavioral abnormalities, periodic vomiting and sleep episodes, as well as confusion, somnolence, somnolence-induced irritability, mild hemiparesis, cataplexy, and generalized paralysis); preferably, the motor dysfunction is selected from the group consisting of: common paroxysmal motor dysfunctions (e.g., paroxysmal eye-head movements, paroxysmal movement-induced motor dysfunctions, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), pyramidal tract symptoms, ataxia, hypotonia, and chorea.

[0343] Implementation Scheme 19. The method according to any of the foregoing method implementation schemes, wherein the patient suffers from one or more additional symptoms selected from the group consisting of: developmental and / or cognitive impairment, atypical presentation and / or adult-onset Glut1-DS.

[0344] Implementation Scheme 20. The method according to Implementation Scheme 19, wherein:

[0345] The additional symptoms are developmental and / or cognitive impairments selected from the group consisting of: microcephaly, mild to severe intellectual disability, dysarthria, visuospatial impairment, and visuomotor impairment; preferably, the developmental and cognitive impairment is microcephaly; and / or

[0346] The additional symptoms are atypical presentations selected from the following groups: writer's cramp, intermittent ataxia, sudden collapse, generalized paralysis, Parkinson's disease, nocturnal muscle cramps in the legs, alternating hemiplegia in children, hemiplegic migraine, periodic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with paroxysmal motor-induced movement disorders, hepatosplenomegaly, periventricular calcification, cerebral atrophy, pseudohyperkalemia, cataracts, and retinal abnormalities; and / or

[0347] The additional symptom is adult-onset Glut1-DS with symptoms of movement disorder that occurs during adolescence to adulthood; preferably, it is a paroxysmal movement-induced movement disorder.

[0348] Implementation Scheme 21. The method according to method implementation scheme 19 or method implementation scheme 20, wherein one or more additional symptoms are treated, preferably all additional symptoms are treated.

[0349] Implementation Scheme 22. The method according to any of the foregoing implementation schemes, wherein the patient is an infant, child, adolescent or adult; preferably an adolescent or adult; even more preferably an adult.

[0350] Implementation Scheme 23. The method according to any of the foregoing method implementation schemes, wherein the C10:C8 ratio is 75:25 to 85:15; preferably about 8:2 wt:wt, more preferably about 80:20 wt:wt.

[0351] Implementation Scheme 24. The method according to any of the foregoing method implementation schemes, wherein the decanoic acid and caprylic acid are in the form of triglycerides; preferably, in the form of a mixture of the following homoglycerides: a mixture of tri-C8 triglycerides (caprylic triglycerides) and tri-C10 triglycerides (decanoic triglycerides).

[0352] Implementation Scheme 25. The method according to any of the foregoing method implementation schemes, wherein the decanoic acid and octanoic acid account for at least 80% by weight, preferably 85% by weight, more preferably 90% by weight, even more preferably 95% by weight, or most preferably 99% by weight of the total fatty acid content of the composition.

[0353] Implementation Scheme 26. The method according to any of the foregoing method embodiments, wherein the composition is substantially free of monounsaturated or polyunsaturated fatty acids, carbohydrates and / or proteins.

[0354] Implementation Scheme 27. The method according to any of the foregoing method implementation schemes, wherein the composition is in the form of an oil-in-water emulsion.

Claims

1. A composition for treating motor disorders in patients with Glut1-DS, the composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

2. The composition for the purpose according to claim 1, wherein the Glut1-DS patient is a person who had a movement disorder but no accompanying epilepsy prior to treatment.

3. The composition for the purpose according to claim 1 or claim 2, wherein the Glut1-DS patient is a person carrying an SLC2A1 gene mutation, said mutation being selected from the group consisting of: Point mutations are preferred to occur at sites selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Ser113, Arg126, Gly130, Arg153, Arg212, Arg218, Lys256, Arg264, Thr295, Ala155, Arg330, Arg333, Pro485, and Arg468 of type 1 glucose transporters. Splice site mutation; nonsense mutation; insert; Missing; Exon deletion; or Complete gene deletion.

4. The composition for the purpose according to any preceding claim, wherein the movement disorder is selected from the group consisting of: common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal movement-induced movement disorders, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), movement abnormalities (e.g., involuntary movements), pyramidal tract symptoms, spasticity, ataxia, dystonia, hypotonia, gait abnormalities, chorea, tremor, non-epileptic myoclonus (optionally including startle myoclonus, action myoclonus, and postural myoclonus or none) The motor dysfunction may include: paralysis / paralysis, dyskinesis (e.g., oculomotor and oral-cheek dysfunction) or paroxysmal nonmotor episodes (e.g., migraine, behavioral abnormalities, periodic vomiting and sleep episodes, as well as confusion, somnolence, somnolence-induced irritability, mild hemiparesis, cataplexy, and generalized paralysis); preferably, the motor dysfunction is selected from the group consisting of: common paroxysmal motor dysfunctions (e.g., paroxysmal eye-head movements, paroxysmal movement-induced motor dysfunctions, paroxysmal events presenting as severe motor dysfunction, and paroxysmal events accompanied by complex neurological symptoms), pyramidal tract symptoms, ataxia, hypotonia, and chorea.

5. The composition for the use according to any of the preceding claims, wherein the patient suffers from one or more additional symptoms selected from the group consisting of: developmental and / or cognitive impairment, atypical presentation, and / or adult-onset Glut1-DS.

6. The composition for the said use according to claim 5, wherein: The additional symptoms are developmental and / or cognitive impairments selected from the group consisting of: microcephaly, mild to severe intellectual disability, dysarthria, visuospatial impairment, and visuomotor impairment; preferably, the developmental and cognitive impairment is microcephaly; and / or The additional symptoms are atypical presentations selected from the following groups: writer's cramp, intermittent ataxia, sudden collapse, generalized paralysis, Parkinson's disease, nocturnal muscle cramps in the legs, alternating hemiplegia in children, hemiplegic migraine, periodic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with paroxysmal motor-induced movement disorders, hepatosplenomegaly, periventricular calcification, cerebral atrophy, pseudohyperkalemia, cataracts, and retinal abnormalities; and / or The additional symptom is adult-onset Glut1-DS with symptoms of movement disorder that occurs during adolescence to adulthood; preferably, it is a paroxysmal movement-induced movement disorder.

7. The composition for the purpose according to claim 5 or claim 6, wherein one or more additional symptoms are treated, preferably all additional symptoms are treated.

8. The composition for the said use according to any of the preceding claims, wherein the patient is an infant, child, adolescent or adult; preferably an adolescent or adult; even more preferably an adult.

9. The composition for the said use according to any of the preceding claims, wherein the C10:C8 ratio is 75:25 to 85:15; preferably about 8:2 wt:wt, more preferably about 80:20 wt:wt.

10. The composition for the use according to any of the preceding claims, wherein the decanoic acid and caprylic acid are in the form of triglycerides; preferably, in the form of a mixture of homoglycerides containing tri-C8 triglycerides (caprylic triglycerides) and tri-C10 triglycerides (decanoic triglycerides).

11. The composition for the use according to any of the preceding claims, wherein the decanoic acid and octanoic acid constitute at least 80% by weight, preferably 85% by weight, more preferably 90% by weight, even more preferably 95% by weight, or most preferably 99% by weight of the total fatty acid content of the composition.

12. A composition for the stated use according to any of the preceding claims, wherein the composition is substantially free of monounsaturated or polyunsaturated fatty acids, carbohydrates and / or proteins.

13. The composition for the said use according to any of the preceding claims, wherein the composition is in the form of an oil-in-water emulsion.

14. Use of a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8) in the preparation of a medicament for treating movement disorders in patients with Glut1-DS in need, wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

15. A method for treating Glut1-DS movement disorder, the method comprising administering to a patient with Glut1-DS in need a composition comprising a mixture of decanoic acid (C10) and caprylic acid (C8), wherein the C10:C8 ratio is 70:30 to 90:10 wt:wt.

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