Treatment of motor disorders in glucose transporter type 1 deficiency syndrome without inducing ketosis

Abstract

This invention relates to the treatment of glucose transporter type 1 deficiency syndrome (Glut1-DS). In particular, the invention relates to specific medium-chain triglyceride compositions, enriched for C10 (decanoic acid), for use in treating movement disorders in Glut1-DS patients.

Description

[0001] TREATMENT OF MOTOR DISORDERS IN GLUCOSE TRANSPORTER TYPE 1 DEFICIENCY SYNDROME WITHOUT INDUCING KETOSIS

[0002] FIELD OF THE INVENTION

[0003] This invention relates to the treatment of glucose transporter type 1 deficiency syndrome (Glutl-DS). In particular, the invention relates to specific medium-chain triglyceride compositions, enriched for CIO (decanoic acid), for use in treating movement disorders in Glutl-DS patients, especially those without concomitant epilepsy when treatment is initiated.

[0004] BACKGROUND OF THE INVENTION

[0005] Glucose transporter type 1 (Glutl) deficiency syndrome (Glutl-DS) is a brain energy deficiency syndrome caused by impaired glucose transport into the brain. Active glucose diffusion is facilitated by transporters including Glutl. Patients may be treated with ketogenic diet therapies (KDT) that provide ketone bodies as a supplemental fuel for brain energy metabolism (J. Klepper et al. (2020) Epilepsia Open, 5:354-365).

[0006] Patients classically present with infantile-on-set epilepsy, deceleration of head growth, impaired neurological growth and development, and complex movement disorders. Symptoms develop in an age-specific pattern with paroxysmal eye-head movements and seizures being presenting features in infancy. Developmental impairment becomes increasingly apparent and is followed by ataxia, paroxysmal exertion-induced dystonia, and further movement abnormalities that develop over time often becoming the major symptoms in adolescents and adult Glutl-DS patients. Older patients, such as adolescents and adults, can present with movement disorders without concomitant epilepsy. It is unclear if the movement disorders without concomitant epilepsy can be treated using the same treatments that show efficacy when epilepsy is present. The natural history of the disease is poorly characterised and, even then, symptoms can remit and relapse without clinical intervention in individual patients (S. Olivotto et al. (2022) Orphanet J Rare Dis,' 17:365). So, short-term disappearance of a single symptom in a single patient cannot confirm a therapeutic effect.

[0007] Many rare diseases present with both movement disorders and epilepsy, but it is unclear to what extend the symptoms are linked, partially overlap or are driven by distinct mechanisms (A. Papandreou et al. (2019) Dev Med Child Neurol,' 62: 178-191).

[0008] Initial diagnosis of Glutl-DS typically occurs biochemically (a cerebrospinal fluid (CSF)-to-blood glucose ratio <0.50) or genetically (a mutation in the SLC2A1 gene) (M. Schwantje et al. (2019) J Inherit Metab Dis,' 43:216-222). Where no mutation is identified, 3-O-methyl-D-glucose uptake in erythrocytes can be performed with values below 74% of controls being diagnostic of Glutl-DS (D. Wang et al. Glucose Transporter Type 1 Deficiency Syndrome. 2002 Jul 30 [Updated 2018 Mar 1], In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet], Seattle (WA): University of Washington, Seattle; 1993-2023). Therefore, whilst most patients carry a mutation in the SLC2A1 gene, this is not necessarily the case (O. Sanchez-Lijarcio et al. (2022) Clin Genet, 102:40-55).

[0009] Most patients have autosomal dominant de novo heterozygous mutations in SLC2A1 as the cause of the Glutl-DS. KDTs provide a supplemental metabolic fuel for the brain and control seizures effectively in some patients. The beneficial effects on developmental delay and movement abnormalities, unfortunately, appear to be less striking (J. Klepper et al. (2020) Epilepsia Open,' 5:354-365).

[0010] According to one review article, “The ketogenic diet is the mainstay of therapy in Glutl DS” (T. Pearson (2013) Curr Neurol Neurosci Rep,' 13:342). However, the efficacy of different KDTs in different patient subtypes is unpredictable. As mentioned above, the therapeutic effect of KDTs in Glutl-DS is attributed to the production of ketone bodies, derived from the hepatic metabolism of fatty acids, as an alternative energy source for the brain. This common wisdom remains to this day (D. Wang et al. Glucose Transporter Type 1 Deficiency Syndrome. 2002 Jul 30 [Updated 2018 Mar 1]; M. Schwantje et al. (2019) J Inherit Metab Dis,' 43:216-222; and J. Klepper et al. (2020) Epilepsia Open, 5:354-365). Therefore, therapeutic strategies have focused on boosting ketone bodies by inducing “ketosis” by making the patient “ketoic” (P-hydroxybutyrate (BHB) > 1 mmol / L).

[0011] Standard long-chain triglyceride (LCT) diets, standard medium-chain triglyceride (MCT) diets (based on coconut oil) and the modified Atkins diet are known to produce ketone bodies and treat some symptoms of Glutl-DS in certain patients. However, efficacy is unpredictable and can take months until an effect on symptoms is realised, especially in movement and cognitive symptoms (M. Schwantje et al. (2019) J Inherit Metab Dis, 43:216-222). This is consistent with earlier studies demonstrating greater efficacy in the symptoms of epilepsy compared to cognitive and movement disorders (W. Leen et al. (2010) Brain, 133:655-670). Therefore, there is a need for a specialised treatment that can target movement symptoms in Glutl-DS patients, especially at stages of disease where epilepsy has subsided or is absent (i.e., in the absence of concomitant epilepsy). The absence of a clear therapeutic effect for KDTs in treating Glutl-DS was summarised in the recent review article (M. Tang and U. Monani (2021) Neurosci Insights,' 16: 1-7) where the authors concluded “ while ketogenic diets mitigate seizure activity in Glutl DS patients, their effects on cognitive and motor dysfunction in the disease are variable and modest at best” . Furthermore, standard KDT may be associated with osteopenia, osteoporosis, potential cardiovascular risks, and unclear effects on pregnancy (J. Klepper et al. (2020) Epilepsia Open, 5:354-365). Therefore, there is need for a treatment for Glutl-DS that alleviates movement disorders without side effects, in a broad range of Glutl-DS patients, especially those where seizures are absent.

[0012] Specialised fat-based interventions have also been considered for treating certain symptoms of Glutl-DS.

[0013] K.Vita® (MCTs with a C10:C8 ratio of 8:2) is a thickened liquid supplement containing a specific blend of MCTs for the dietary management of drug-resistant epilepsy for use in adults and in children from 3 years of age. The active triglycerides are known to treat epileptic seizures in animal models of epilepsy (WO 2018 / 189113; N. Jancovski et al. (2021) Epilepsia, 00: 1-12) and the K.Vita® product treats drug-resistant epilepsy (N. Schoeler et al. (2021) Brain Comms,' 3 : 1-13). Compared to a standard MCT diet (based on coconut oil), K.Vita® is enriched for CIO (decanoic acid) over C8 (octanoic acid). This is because decanoic acid is believed to be the active ingredient for treating epilepsy (WO 2013 / 186570; P. Chang et al. (2013) Neuropharmacology,' 69: 105-114) via a direct effect on AMPA receptors (P. Chang et al. (2016) Brain, 139:431-443). Octanoic acid is believed to have a secondary effect by preventing decanoic acid oxidation (A. Khabbush et al. (2017) Epilepsia, 58: 1423-1429; WO / 2018189113). In contrast, C8 is more ketogenic than CIO or C12 (V. St-Pierre et al. ( QVE) Front. Nutr., ' 6:46).

[0014] Compositions enriched for decanoic acid are known to enhance mitochondrial function in neuronal cells and fibroblasts (WO 2013 / 186570). However, it is presumed that in epilepsy the effect is driven by an effect on the brain within the central nervous system. It is not clear if decanoic acid can induce a clinically significant effect in the periphery of Glutl- DS patients in the absence of epilepsy, or if the therapeutic effect is specific to the symptoms of epilepsy. This is because, whilst K.Vita® is clearly effective in the treatment of drugresistant epilepsy (N. Schoeler et al. (2021) Brain Comms,' 3: 1-13), its efficacy in Glutl-DS specifically has not been confirmed clinically, especially in symptoms other than epilepsy, especially in the absence of concomitant epilepsy. In a general drug-resistant epilepsy trial, only 4 out of 61 participants were characterised as having Glutl-DS and no diagnostic information was provided (i.e., clinical, metabolic, genetic or biochemical). The metabolic hallmark of Glutl-DS is reduced glucose in the central nervous system, as detected in the CSF. This results in a glucose deficit in the brain. But unlike other fat-based interventions, K.Vita® fails to induce reliable ketosis with only 4 out of 61 participants becoming “ketotic” (BHB > 1 mmol / L). Therefore, K.Vita® is not truly “ketogenic” or a KDT. Given that the canonical view of the mechanism by which KDTs act is by providing ketone bodies as an alternative brain energy supply, K.Vita® might be predicted to be less effective in treating Glutl-DS than fat-based interventions. Its effect might only treat epileptic symptoms. Perhaps for this reason, MCT diets are not commonly used for treating Glutl-DS (M. Schwantje et al. (2019) J Inherit Metab Dis, 43.216-222).

[0015] This is confounded by the fact that octanoic and decanoic acid have structural similarities to the branched medium-chain fatty acid, valproic acid (WO 2012 / 069790), a known anti-epileptic drug believed to inhibit glucose transport and contraindicated for Glutl- DS (H. Wong et al. (2005) J Cell Biochenr, 96:775-785 or A. Brukner et al. (2018) Front Pharmacol,' 9: 1054). Therefore, one or both fatty acids could exasperate Glutl-DS symptoms. It is even possible that the effects might be cell type specific. Therefore, K.Vita® cannot be predicted to treat Glutl-DS, especially symptoms other than epilepsy, especially in the absence of concomitant epilepsy.

[0016] There is also no information on whether K.Vita® treated epilepsy in the Glutl-DS patients (N. Schoeler et al. (2021) Brain Comms,' 3: 1-13). The authors state "one childwith GLUT 1 -DS and gait difficulties, but without current seizures, became free of paroxysmal events’". However, the authors also state “[o]ne child with GLUT1-DS gained 10.8 kg (+14 percentiles, UK-World Health Organization growth charts), due to greater range and quantity of foods available, following recent discontinuation of the KD". Therefore, it is unclear whether the improvements were due to a therapeutic effect of K.Vita®, a short-term effect due to an improvement in general diet or spontaneous remission of symptoms. It is unclear what symptoms were present to be treated. It is unclear if the treatment was effective in any of the other three Glutl-DS patients. Therefore, it remains unclear whether K.Vita® could treat Glutl-DS in humans.

[0017] Whilst anecdotal evidence begins to emerge, such as the individual patient report mentioned above, it is unclear if K.Vita® can provide a clinically relevant therapeutic effect in Glutl-DS patients. There is no information whether K.Vita® can treated movement disorders in Glutl-DS patients, especially without concomitant epilepsy. Based on the fact that K.Vita® has a primary role in the brain where there is a direct effect from decanoic acid, there can be no expectation that K.Vita® will exert a therapeutic effect on movement disorders in Glutl-DS patients without concomitant epilepsy. Any effect for ketogenic diets on movement disorders in Glutl-DS patients without concomitant epilepsy might be entirely driven by ketogenic effects in the periphery rather than a direct pharmacological effect of decanoic acid in the central nervous system when treating epilepsy. This ketogenic effect is absent in patients treated with K.Vita®. Therefore, K.Vita® is not currently indicated for Glutl-DS patients without concurrent epilepsy.

[0018] Animal data suggest that MCT diets at different ratios can treat symptoms relating to seizures (e.g., myoclonic jerks) and movement disorders (delayed dystonia onset). However, models required acute induction of seizures (with insulin or pentylenetetrazol) for movement disorders to be observed and the treatment failed to treat dystonia - only slowing its onset. Therefore, it is unclear if mouse models faithfully recapitulate the human condition, or whether it is applicable to treating movement disorders not causally linked to the epilepsy, such as in a patient without concomitant epilepsy. It is also unclear if the effect on dystonia (induced alongside seizure) is relevant to other human movement disorders such as common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), motor disturbance (e.g., involuntary movements), pyramidal symptoms, spasticity, ataxia, hypotonia, gait disturbances, chorea, tremor, nonepileptic myoclonus (optionally including startle myoclonus, action, and postural myoclonus or weakness / paralysis), dyspraxia (e.g., oculomotor dyspraxia and oro-buccal dyspraxia) or paroxysmal non-motor episodes (e.g., migraines, behavioural disturbances, cyclical vomiting, and sleep episodes, as well as confusion, lethargy, somnolence dysphoria, hemiparesis, cataplexy and total body paralysis). It is also unclear if acute mouse models are relevant for persistent movement disorders seen in humans.

[0019] Triheptanoin (UX007; Ultragenyx Pharmaceuticals, Novato, USA) is the most advanced treatment for Glutl-DS having been tested up to phase III in humans (NCT02960217). The active ingredient is a medium odd-chain triglyceride containing three 7-carbon fatty acids. A small open-label pilot study in 6 patients with missense mutations reported a significant increase in ketone bodies and hinted to an improvement in this type of patient (F. Mochel et al. (2016) J Neurol Neurosurg Psychiatry, 87:550-553). Missense mutations account for -40% of all cases who generally have the mildest phenotypes (T. Pearson et al. (2013) Curr Neurol Neurosci Rep, 13:342). However, Ultragenyx Pharmaceuticals issued a press release on 26 October 2018 confirming the phase III trial (NCT02960217) was prematurely terminated because it failed to meet its primary endpoint (statistically significant reduction in the frequency of paroxysmal movement events) or secondary end points “zn patients with glucose transporter type-1 deficiency syndrome (Glutl DS) experiencing disabling paroxysmal movement disorders’". Triheptanoin was also less efficacious than standard MCT oil in adults with drugresistant epilepsy (K. Borges et al. (2019) Epilepsia Open, 4: 153-163). There was also a hint that triheptanoin had a short-term effect on drug-resistant epilepsy in children previously treated with a standard ketogenic diet. However, this was also a small open-labelled study. This reinforces the fact that a composition that treats epilepsy in one patient population cannot be assumed to treat Glutl -DS or vice versa. Furthermore, a preliminary effect observed in a small open-labelled study cannot confirm a therapeutic effect in Glutl-DS.

[0020] Perhaps due to the failures of fat-based interventions in treating Glutl-DS, the latest clinical trials are considering alternative treatments, such as sodium lactate (NCT04112862). Again, this is expected to exert an effect in the brain (L van Gemert et al. (2023) Neuropediatrics,' 54:365-370).

[0021] The failure to identify an effective treatment for Glutl-DS and its movement symptoms might be related to the fact that most clinical trials are not designed or powered to demonstrate efficacy in Glutl-DS specifically. Generally, Glutl-DS patients account for -10% of patients in drug-resistant epilepsy trials (N. Schoeler et al. (2021) Brain Comms,' 3: 1-13) or Glutl-DS status is not disclosed (M. Cervenka et al. (2017) Neurology,' 88: 938- 943). As an exception, the triheptanoin phase III trial aimed to enrol 44 Glutl-DS patients but was halted prematurely due to lack of efficacy (NCT02960217). There is a need for an active ingredient with efficacy in late-phase clinical trials with defined Glutl-DS patient populations, especially one that can upregulate relevant pathways in Glutl-DS cells and treat movement disorders in Glutl-DS patients without concomitant epilepsy.

[0022] Generally, there is a need for a therapeutic intervention for Glutl-DS that provides improved treatment of movement disorders in patients compared to standard KDTs and that is effective in a broad range of Glutl-DS patients, especially those where seizures are absent.

[0023] SUMMARY OF THE INVENTION

[0024] The present inventors predict that specific medium-chain triglyceride (MCT) compositions with enhanced levels of decanoic acid (CIO) may provide a targeted therapeutic effect for movement disorders in Glutl-DS patients even without concomitant epilepsy. Based on the fact that valproic acid, a known anti-epileptic drug with structural similarities to decanoic acid and octanoic 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 assessed the effect of decanoic acid and octanoic acid on GLUT1 (SLC2AP) expression in U251 human glioblastoma astrocytoma cells. Decanoic acid and octanoic acid are known to affect astrocyte-derived cells differently and are considered suitable for assessing effects of different fatty acids in the brain (F. Damiano et al (2020) Front. Neurosci.,' 14:783). Surprisingly, decanoic acid caused a significant decrease in GLUT1 expression in this central nervous system cell type (Figure 1 A). Even more surprisingly, octanoic acid did not have the same effect and induced a moderate increase in GLUT1 expression (SLC2AF, Figure 1 A). The effect of octanoic acid was able to partly offset the reduction in GLUT1 expression by decanoic acid such that the reduction was no longer significant when a combinatory decanoic: octanoic acid (8:2) treatment was added (Figure 1 A).

[0025] The inventors extended the study to consider other genes involved in glucose metabolism, fatty acid metabolism, the citric acid cycle (including citrate synthase) and oxidative phosphorylation (including mitochondrial genes encoding subunits of the enzyme NADH dehydrogenase (ubiquinone)). Overall, the data suggest decanoic acid downregulates glucose metabolism in astrocytes (Figure 1 A) resulting in a switch to fatty acid metabolism (Figure 2A). A combinatory decanoic:octanoic acid (8:2) treatment ensures enhanced fatty acid metabolism without a significant reduction in GLUT1 expression.

[0026] The inventors extended the study to pluripotent stem cells (iPSCs) derived from fibroblasts from a Glutl-DS patient (GM27896 iPSCs from the Coriell Institute, USA: K. Meyer et al. (2018) Cell, 175:239-253). This model is more specific to Glutl-DS patients and suitable for assessing effects driven by cell types found outside the central nervous system. Surprisingly, expression effects were different in iPSCs compared to the astrocyte cell line. In Glutl-DS iPSCs, there was an upregulation of genes involved in both glucose metabolism (Figure IB) and fatty acid metabolism (Figure 2B) for combinatory decanoic:octanoic acid (8:2) treatment, suggesting these compositions are particularly suitable for treating deficits in glucose metabolism and fatty acid metabolism in the cells of Glutl-DS not adapted to the central nervous system (i.e., in the periphery).

[0027] This suggests these fatty acids have specific - and distinct - direct effects on cells containing Glutl-DS mutations that are not seen in non-Glutl-DS -mutated cell lines found in the central nervous system. For example, CPT1B - the isoform of carnitine palmitoyltransferase I (CPT1) found in muscle - was upregulated in Glutl-DS iPSCs, but not in non-Glutl-DS astrocytes. CPT1B is the rate-controlling enzyme of the long-chain fatty acid beta-oxidation pathway in muscle mitochondria, and therefore energy provision to muscle (J. McGarry et al. (1977) J. Clin. Invest., ' 60:265). The data suggest that combinatory decanoic :octanoic acid (8:2) treatment (i.e., compositions enriched for decanoic acid compared to standard MCTs) might exert a direct effect in cells containing Glutl-DS mutations, especially if they are not from a type found in the central nervous system. That the decanoic acid-enriched treatments upregulated genes relating to glucose and fatty acid metabolism in Glutl-DS cells suggests they could overcome inhibition in GLUT1 function that might be attributed to decanoic acid. The combinatory decanoic :octanoic acid (8:2) treatment could be particularly effective in Glutl-DS cells in the periphery, for example, in muscle cells. This provides evidence that the effects on movement disorders might decouple from symptoms linked to the primary role in the brain, such as epilepsy.

[0028] The apparently opposite effects of decanoic and octanoic acid on GLUT1 expression in U251 cells caused the inventors to predict that specific MCT compositions enriched for decanoic acid but containing a minor proportion of octanoic acid, such as K.Vita®, might maintain greater GLUT1 function in the brain, compared to decanoic acid alone. The unexpected discovery that decanoic acid upregulates many genes involved in glucose metabolism and fatty acid metabolism in Glutl-DS iPSCs should ensure it is effective in the periphery of Glutl-DS patients, even in the absence of ketosis. Such compositions might be suitable for treating movement disorders in Glutl-DS patients even without concomitant epilepsy. This is despite the established view is that KDTs treat Glutl-DS by inducing “ketosis”. That the compositions described herein can treat Glutl-DS without inducing ketosis should minimise side effects of ketosis including low blood pressure, kidney stones, constipation, nutrient deficiencies and an increased risk of heart disease. Furthermore, there is evidence that a fatty acid with similar numbers of carbon atoms, valproic acid, inhibits 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 if decanoic acid and octanoic acid might have similar effects. The specific medium-chain fatty acid (MCFA) and MCT compositions with enhanced levels of decanoic acid but maintaining some octanoic acid appear to inhibit GLUT1 function less than decanoic acid alone or valproic acid.

[0029] It might be that decanoic acid generally enhances glucose metabolism in Glutl-DS cells suggesting MCFA and MCT compositions enriched with decanoic acid might be particularly suitable for treating Glutl-DS, especially its motor symptoms. Accordingly, in a first general embodiment, the invention provides a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, for use in the treatment of movement disorders in a Glutl-DS patient in need thereof.

[0030] In a second general embodiment, the invention provides the use of a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, in the manufacture of a medicament for the treatment of movement disorders in a Glutl-DS patient in need thereof.

[0031] In a third general embodiment, the invention provides a method of treating Glutl-DS movement disorders comprising administering a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, to a Glutl-DS patient in need thereof.

[0032] In a highly favoured embodiment related to the first, second and third general embodiments, the Glutl-DS patient is a human with a mutation in the SLC2A1 gene who suffers from movement disorders without concomitant epilepsy, prior to initiation of the treatment (e.g., a period of at least 4 weeks prior to initiation of the treatment). Most preferably, the Glutl-DS patient has a confirmed mutation in the SLC2A1 gene, and the method of treatment includes the step of identifying a mutation in the SLC2A1 gene.

[0033] BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The invention will now be described in detail with reference to the accompanying drawings, in which:

[0035] Figure 1 shows the expression data (based on transcriptional change) for genes related to glucose metabolism in astrocytes (A) and Glutl-DS patient derived iPSCs (B). Down-regulated genes are surrounded by boxes ( — ) with an ' symbol at the top of each box to aid understanding to the heat maps in grey scale. The change represents gene expression change (log2 (fold change)).

[0036] Figure 2 shows the expression data (based on transcriptional change) for genes related to fatty acid metabolism in astrocytes (A) and Glutl-DS patient derived iPSCs (B). Down-regulated genes are surrounded by boxes ( — ) with an ' symbol at the top of each box to aid understanding to the heat maps in grey scale. The change represents gene expression change (log2 (fold change)). DETAILED DESCRIPTION OF THE INVENTION

[0037] A. Definitions

[0038] The following definitions apply to the terms used throughout this specification, unless otherwise limited in specific instances.

[0039] The terms “treat”, “treating” or “treatment” relates to the full or partial treatment of one or more symptom of Glutl-DS, described below. Equally, “treat”, “treating” or “treatment” may relate to the prevention of a known symptom of Glutl-DS that the patient does not yet suffer from, but is expected to suffer from, based on their age or disease severity.

[0040] The term “manage”, “managing” and “management”, particularly in the context of “dietarily manage”, “dietarily managing” and “dietary management”, refer to the prevention or reduction in severity or frequency of one or more symptom of a disease or condition, including ameliorating one or more existing symptoms of a disease or condition, preventing one or more existing symptoms of disease or condition, preventing one or more underlying causes of a disease or condition, ameliorating one or more underlying cause 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 will be understood to include stabilising a disease or condition and preventing progression of a disease or condition. The skilled person will be familiar with the diagnosis and management, more specifically dietary management, of such diseases or conditions (see, e.g. Commission Directive 1999 / 21ZEC including modifications thereto; Commission Notice on the classification of Food for Special Medical Purposes (2017 / C 401 / 01); Commission Delegated Regulation (EU) 2016 / 128 of 25 September 2015 supplementing Regulation (EU) No 609 / 2013 of the European Parliament and of the Council).

[0041] The term “dietary intervention” is defined as the addition of a composition as herein described to a diet of an individual having Glutl-DS in order manage (specifically dietarily manage), prevent and / or treat one or more symptoms of Glutl-DS. The composition is preferably in the form of a medical food, a tube feed, a nutritional composition or a nutritional supplement.

[0042] The term “glucose transporter type 1 deficiency syndrome” or “Glutl-DS” is a condition diagnosed clinically, metabolically, genetically or biochemically (J. Klepper et al. (2020) Epilepsia Open,' 5:354-365). As described below, two of a clinical, metabolic or genetic diagnosis are sufficient for diagnosis. Genetic diagnosis is preferred. In the absence of a genetic diagnosis, a biochemical diagnosis will suffice. The term “medical food” refers to a food product formulated for the dietary management of a medical disease or condition, where the medical food reduces one or more symptoms of a specific disease or condition. For example, the medical disease or condition may have distinctive nutritional needs that cannot be met by normal diet alone. The medical food may be administered under medical supervision. The medical food may be for enteral administration, including oral administration or tube administration.

[0043] The term “movement disorder” refers to a group of conditions that cause abnormal movements. In the context of the current application, the movement disorders are those known to be associated with Glutl-DS, outlined below. These are known to the skilled clinician (J. Klepper et al. (2020) Epilepsia Open: 5:354-365). However, the definition excludes epileptic and seizure-induced seizures that might affect movement, for example, myoclonic jerks.

[0044] The term “movement disorders without concomitant epilepsy” therefore relates to a movement disorder when epilepsy and / or seizures have subsided or are absent. In general, epilepsy will have subsided or have been absent for a period of at least 4 weeks, more preferably at least 3 months, most preferably at least 1 year prior to the initiation of treatment with the claimed composition.

[0045] The term “epilepsy” relates to a group of conditions caused by hyperexcitability of synapses in the brain resulting in epileptiform activity and seizures. These are known to the skilled clinician (J. Klepper et al. (2020) Epilepsia Open,' 5:354-365). In Glutl-DS, epilepsy it is linked to a low level of glucose in the brain.

[0046] The term “a mutation in the SLC2A1 gene” relates to a known or suspected pathogenic mutation in the SLC2A1 gene than is identified in a patient with other symptoms of Glutl-DS.

[0047] The term “development and / or cognitive disorders” linked to Glutl-DS are known to the skilled clinician (J. Klepper et al. (2020) Epilepsia Open,' 5:354-365) and are associated with mild-to-severe intellectual disability.

[0048] The term “atypical manifestations” of Glutl-DS are rare symptoms described in GlutlDS known to the skilled clinician (J. Klepper et al. (2020) Epilepsia Open, 5:354-365) that do not fit into the standard groups of epilepsy, movement disorders or development and / or cognitive disorders. They are explicitly listed below.

[0049] The term “adult GlutlDS” refers to symptoms that emerge later in life in a patient with GlutlDS and are known to the skilled clinician (J. Klepper et al. (2020) Epilepsia Open, 5:354-365). They are explicitly listed below. The term “common paroxysmal movement disorders” is defined as paroxysmal movement disorders (i.e., rather than persistent movement disorders) that are assessed as prevalent in Glutl-DS patients by the skilled clinician (J. Klepper et al. (2020) Epilepsia Open 5:354-365). In particular, “common” or “prevalent” symptoms are those affecting 20% or more, preferably 40% or more, more preferably 60% or more, of the defined patient population (for example, see R. Pons et al. (2010) Movement Disorders,' 25:275-281.

[0050] The term “child” refers to a human under the age of 18 years.

[0051] The term “an infant” means a human child aged 2 years or less, preferably 1 year or less.

[0052] The term “an adolescent” means a human child during or after the onset of puberty. The term generally means children aged 11 to 17 years.

[0053] The term “adult” refers to a human aged 18 years and over.

[0054] The term “ratio of C10:C8” refers to the weight to weight ratio (wt:wt) of decanoic acid (CIO) to octanoic acid (C8), or C10:C8 ratio. In the case of triglycerides, this relates to the weight ratio of the fatty acids once cleaved from the glycerol backbone. For the avoidance of doubt, the experimental examples include an 80:20 mokmol ratio of decanoic acid:octanoic acid, which relates to a 83: 17 or 8:2 weight to weight ratio (wt:wt) of C8:C10.

[0055] The term “homotriglyceride” refers a glycerol molecule esterified with three of the same fatty acid molecules (e.g., 3 decanoic acids molecules or 3 octanoic acid molecules). Homotriglycerides can be mixed to provide the required proportion of C10:C8.

[0056] The term “heterotriglyceride” refers a glycerol molecule esterified with different fatty acid (e.g., decanoic acids molecules and octanoic acid molecules). Heterotriglycerides with the required proportion of C10:C8 are formed by esterifying the required proportion of C10:C8 with glycerol.

[0057] The term “substantially free” means less than 2% by weight of the composition (i.e., less than 2g / 100 g), preferably less than 1% by weight of the composition (i.e., less than lg / 100 g).

[0058] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. B. Treatment of Glutl-DS with a composition comprising a mixture of decanoic acid (CIO) to octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90:10

[0059] In a first general embodiment, the invention provides a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, for use in the treatment of movement disorders in a Glutl-DS patient in need thereof.

[0060] In a second general embodiment, the invention provides the use of a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, in the manufacture of a medicament for the treatment of movement disorders in a Glutl-DS patient in need thereof.

[0061] In a third general embodiment, the invention provides a method of treating Glutl-DS movement disorders comprising administering a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, to a Glutl-DS patient in need thereof.

[0062] In a highly favoured embodiment related to the first, second and third general embodiments, the Glutl-DS patient is a human with a mutation in the SLC2A1 gene who suffers from movement disorders without concomitant epilepsy prior to initiation of the treatment (e.g., a period of at least 4 weeks prior to initiation of the treatment). Most preferably, the Glutl-DS patient has a confirmed mutation in the SLC2A1 gene, and the method of treatment includes the step of identifying a mutation in the SLC2A1 gene.

[0063] These general embodiments can be readily combined with the specific compositions, patient populations and symptoms described below.

[0064] Compositions

[0065] The composition according to the invention comprises a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt.

[0066] In a preferred embodiment, the composition according to the invention comprises a mixture of CIO (decanoic acid) to C8 (octanoic acid) with a C10:C8 ratio of from 75:25 to 85: 15, more preferably about 8:2 wt:wt, most preferably about 80:20 wt:wt. Surprisingly, the data in Section E, below, confirm that compositions enriched for decanoic acid but retaining some octanoic acid can upregulate specific genes, such as CPT1B - the isoform of carnitine palmitoyltransferase I (CPT1) found in muscle - whilst potentially offsetting reductions in GLUT1 expression in astrocytes caused by decanoic acid alone. CPT1B is the ratecontrolling enzyme of the long-chain fatty acid beta-oxidation pathway in muscle mitochondria, and therefore energy provision to muscle (J. McGarry et al. (1977) J. Clin. Invest.,' 60:265).

[0067] Whilst the decanoic acid and octanoic acid are generally in the form of triglycerides when used to treat patients, the cellular effects demonstrated in the application confirm an effect for free fatty acids, or salts (e.g., sodium or potassium) or prodrugs (e.g., methyl or succinyl esters) thereof.

[0068] In one embodiment, the decanoic acid and octanoic acid are in the form of heterotriglycerides re-esterified with glycerol from free fatty acids (in the wt:wt ratios described above) such that there is a random distribution of CIO and C8 in the SN1 (peripheral) and SN2 (central) positions, as described in WO 2017 / 093449. These triglycerides may form part of a composition described herein. Such heterotriglycerides are relatively simple to produce.

[0069] In a preferred embodiment, the decanoic acid and octanoic acid are in the form of homotriglycerides re-esterified with glycerol from free fatty acids and then combined (in the wt:wt ratios described above) such that there is a homogeneous distribution of decanoic acid or octanoic acid on all positions, as described in WO 2017 / 093449. These triglycerides may form part of a composition described herein. Such homotriglycerides increase the proportions of ketones and CIO fatty acids in the bodily fluids (such as plasma or CSF) than the corresponding heterotriglycerides.

[0070] In another embodiment, the decanoic acid and octanoic acid make up at least 80%, preferably 85%, more preferably 90%, even more preferably 95% or most preferably 99% of the total fatty acid content of the composition by weight.

[0071] In another embodiment, the composition is substantially free of mono- or polyunsaturated fatty acids.

[0072] In another embodiment, the composition is substantially free of carbohydrate.

[0073] In another embodiment, the composition is substantially free of protein.

[0074] In another embodiment, the composition is in the form of an oil-in-water emulsion.

[0075] In another embodiment, the composition is packaged.

[0076] In another embodiment, the composition is self-stable at room temperature for at least 3 months.

[0077] In another embodiment, the composition is in the form of a medical food, a tube feed, a nutritional composition or a nutritional supplement.

[0078] In a preferred embodiment, the composition 25 to 40 g / 100 mL, preferably 30 to 35 g / 100 mL, most preferably about 33.5 g / 100 mL of decanoic acid and octanoic acid triglycerides in the forms described above. This ensures the required dosage is administered per pack (e.g., per 120 mL pack). It is predicted that these dosages will achieve a therapeutic effect in Glutl-DS patients without causing significant “ketosis”.

[0079] Dosages

[0080] The compositions described herein may be given in an effective amount to treat Glutl-DS. Preferably, the dosages are administered to a human patient. The dosage can be titrated by the skilled clinician. In a preferred embodiment, the composition is administered in an amount of 60 to 480 mL per day. In a preferred embodiment, the composition is administered in an amount of 240 mL per day (e.g., 2 x 120 mL packs containing 33.5 g / 100 mL of decanoic acid and octanoic acid triglycerides in the forms described above). This amount is especially suitable for an adult patient. In a more preferred embodiment, the composition is administered in an amount of 240 mL per day (e.g., 4 x 60 mL containing 33.5 g / 100 mL of decanoic acid and octanoic acid triglycerides in the forms described above). This dosage regimen ensures good tolerance in patients, whilst maintaining good efficacy, in spite of lower maximum predicted plasma concentrations of decanoic acid.

[0081] In another preferred embodiment, the composition is administered in an amount of 120 mL per day (e.g., 1 x 120 mL pack containing 33.5 g / 100 mL of decanoic acid and octanoic acid triglycerides in the forms described above). This amount is especially suitable for a child patient.

[0082] Alternative, the dosage (in grams) may be based on the weight of the patient (in kilograms). The inventors have identified a dosage of about 1 g / kg / day to be suitable across a broad range of weights. Therefore, in a preferred embodiment, the composition is administered in an amount of 0.5 to 2.5 g / kg / day, more preferably 0.8 to 1.5 g / kg / day, most preferably about 1.0 g / kg / day. This amount is especially suitable the general patient population. Preferably, the daily dosage is split into 2 to 4, more preferably 4 daily separate dosages (e.g., 4 x 60 mL containing 33.5 g / 100 mL of decanoic acid and octanoic acid triglycerides in the forms described above).

[0083] The dosages described directly above can readily be combined with the compositions described above. Patient population

[0084] The composition is for use in treating a Glutl-DS patient, most preferably the Glutl- DS patient is a human with a mutation in the SLC2A1 gene who suffers from movement disorders without concomitant epilepsy prior to initiation of the treatment.

[0085] Age

[0086] In one embodiment, the patient may be defined by their age. For example, the patient may be an infant, a child, an adolescent or an adult. Preferably, the patient is a child (e.g., over the age of 3 years), an adolescent or an adult. As the composition is predicted to show good efficacy in treating movement disorders in Glutl-DS patients even without concomitant epilepsy, and epilepsy and / or seizures generally subside with age whilst certain movement disorders appear with age, the composition detailed above is more preferably for treating an adolescent or an adult, even more preferably an adult.

[0087] As explained above, the Glutl-DS patient most preferably suffers from movement disorders without concomitant epilepsy prior to initiation of the treatment (e.g., 4 weeks prior to the initiation of treatment).

[0088] Movement disorders often develop when a Glutl-DS patient is aged 3 years or older and K.Vita® is currently recommended for use in adults and in children from 3 years of age.

[0089] Previous treatments and dietary interventions

[0090] The patient may be defined by their previous treatments.

[0091] In one embodiment, the patient may have previously been treated with one or more KDT selected from the group consisting of standard LCT diet, standard MCT diet (based on coconut oil with a -40:60 C10:C8 wt:wt ratio) and modified Atkins diet. In another embodiment, the patient undergoes concurrent treatment with one or more KDT selected from the group consisting of standard LCT diet and modified Atkins diet. In a preferred embodiment, the patient discontinued one or more KDT (selected from the group consisting of standard LCT diet, standard MCT diet (based on coconut oil) and modified Atkins diet) prior to starting treatment (e.g., due to a lack of efficacy or unacceptable side effects). In a more preferred embodiment, the patient did not respond to one or more KDT (selected from the group consisting of standard LCT diet, standard MCT diet (based on coconut oil) and modified Atkins diet). In another embodiment, the patient has not previously been treated with one or more KDT selected from the group consisting of standard LCT diet, standard MCT diet (based on coconut oil) and modified Atkins diet.

[0092] In another embodiment, the patient is not currently following a low-carbohydrate diet (defined as <26% of calories per day from carbohydrate in R. Feinman et al. (2015) Nutrition,' 31 : 1-13).

[0093] Disease severity

[0094] In another embodiment, the patient may be defined by their disease severity according to the Columbia Neurological Score (CNS) into 4 groups: Minimal (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 epileptic phenotype fall into the moderate to severe range in this classification system. Disease severity generally corelates with specific types of SLC2A1 mutation (described in detail below): Missense mutations were detected predominantly in individuals with mild to moderate clinical syndromes. Splice site and nonsense mutations and insertions, deletions, and exonic deletions were associated with moderate to severe clinical syndromes. Complete gene deletions clustered in the severe clinical category.

[0095] Diagnosis

[0096] According to recent recommendations, Glutl-DS is diagnosed (J. Klepper et al. (2020) Epilepsia Open,' 5:354-365): a) clinically as having symptoms selected from the group consisting of eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders; b) metabolically as having a cerebrospinal fluid (CSF)-to-blood glucose ratio <0.50; c) genetically as having a mutation in the SLC2A1 gene; and / or d) biochemically as 3-O-methyl-D-glucose uptake in erythrocytes less than 74% of controls.

[0097] Therefore, in an embodiment, the patient that has been diagnosed with Glutl-DS has a (possible) diagnosis confirmed by at least one of the groups selected from symptoms (clinical diagnosis), low CSF glucose (metabolic diagnosis), a mutation in the SLC2A1 gene (genetic diagnosis) and impaired 3-O-methyl-D-glucose uptake in erythrocytes (biochemical diagnosis).

[0098] Generally, two of a) to c) are sufficient for diagnosis, at which point treatment with KDT should be considered. In the absence of a pathogenic SLC2A1 variant, d) is diagnostic in lieu of c).

[0099] In a preferred embodiment, the patient that has been diagnosed with Glutl-DS has a (probable) diagnosis with symptoms (clinical diagnosis) and at least one of low CSF glucose (metabolic diagnosis), a mutation in the SLC2A1 gene (genetic diagnosis) or impaired 3-O- methyl-D-glucose uptake in erythrocytes (biochemical diagnosis).

[0100] In a more preferred embodiment, the patient that has been diagnosed with Glutl-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).

[0101] Clinical diagnosis

[0102] The clinical diagnosis should generally be performed by a skilled clinician and the method of treatment may include the step of performing a clinical diagnosis.

[0103] In one embodiment, the patient is diagnosed with symptoms selected from the group consisting of eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. The symptoms used for diagnosis can change after the diagnosis. In particular, seizures may subside and movement disorders may become more prevalent or dominant. Therefore, in a preferred embodiment, any seizures have subsided and the patient maintains movement disorders without concomitant epilepsy prior to initiating the claimed treatment.

[0104] The symptoms below are taken from J. Klepper et al. (2020) Epilepsia Open: 5:354- 365, which is incorporated herein by reference.

[0105] Epilepsy and / or seizures: Pharmaco-resistant seizures are frequently the first sign of Glutl-DS. Any type of seizure can be observed. Generalized seizures are more frequent than focal seizures. Early-onset absence epilepsy (onset prior to age 4 years) and epilepsy with myoclonic-atonic seizures (Doose syndrome) have been associated with SLC2A1 pathogenic variants. Any epilepsy associated with movement disorders should suggest Glutl-DS.

[0106] Epilepsy tends to be the major clinical problem in infants and young children with Glutl-DS, whereas seizures tend to decline or disappear in later childhood, adolescence, and adulthood. Movement disorders: In early infancy, distinctive paroxysmal eye-head movements are the second most common initial sign of Glutl-DS, after seizures. Episodes are typically involuntary and brief. The eye movements are repeated, multidirectional, saccadic, usually conjugate, and often accompanied by a head movement in the same direction. Later in childhood, other paroxysmal events emerge but the severity is highly variable. Presentation often involves some type of motor disturbance such as involuntary movements, ataxia, or weakness / paralysis. Awareness is generally preserved. Gradual clinical improvement, decreased frequency, and decreased severity of paroxysmal events are typical in adult life. Paroxysmal nonmotor episodes include migraines, behavioural disturbances, cyclical vomiting, and sleep episodes.

[0107] In general, movement disorders are characteristic of Glutl-DS. Severity ranges from minimal to severe. The movements can be persistent or paroxysmal, classically present pre- prandially, and are mitigated by meals. Persistent movement disorders include spasticity, ataxia, and dystonia often producing disturbances of gait, followed by chorea and tremor. Ataxia is increasingly evident in late infancy as the child stands and starts to walk. Ataxia is more truncal than appendicular. Chorea is often mild and involves the face and the distal upper limbs. A terminal intention tremor is frequent and often associated with other signs of cerebellar dysfunction. Myoclonus is generally epileptic; nonepileptic myoclonus is less common and includes startle myoclonus, action, and postural myoclonus. Dyspraxia is underrecognised and includes oculomotor dyspraxia and oro-buccal dyspraxia. Paroxysmal movement disorders affect approximately 75% of patients and commonly include paroxysmal eye-head movements, paroxysmal exercise-induced dyskinesia (PED), paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms (J. Klepper et al. (2020) Epilepsia Open,' 5:354-365). These movement abnormalities are frequent and often precipitated by fasting and exercise. Potential triggers are emotional stress, fever, fatigue, insufficient ketosis, sleep deprivation, temperature changes, and drugs.

[0108] Development and / or cognitive disorders: Glutl-DS is associated with mild-to- severe intellectual disability, with the degree of severity being proportional to the overall disease severity. Microcephaly may be acquired during infancy and is of varying degree likely correlating with clinical severity. Dysarthria, with varying degrees of speech impairment, is observed in all affected individuals. Social adaptive behaviour is an exceptional strength. Performance skills usually are more affected than verbal skills, with prominent deficiencies in visuospatial and visuomotor abilities. Timing of KDT introduction is a predictive factor for cognitive outcome. Early dietary treatment correlates with better intellectual and social adaptive skills (J. Klepper et al. (2020) Epilepsia Open; 5:354-365).

[0109] Atypical manifestations: Rare features described in Glutl-DS include writer's cramp, intermittent ataxia, total body paralysis, cataplexy, Parkinsonism, and nocturnal painful muscle cramps in the legs. Alternating hemiplegia of childhood, hemiplegic migraine, cyclic vomiting, and stroke-like episodes with paroxysmal hemiparesis, dysarthria, or aphasia have been described in individual patients. Other rare features include hemolytic anemia associated with PED, hepatosplenomegaly, periventricular calcifications, brain atrophy, pseudohyperkalemia, cataracts, and retinal dysfunction.

[0110] Adult Glutl-DS symptoms: Data on adult Glutl-DS are just emerging. Long-term prognosis and long-term adverse effects of KDT largely remain unknown. Changes in symptomatology over time include a shift from infantile-childhood onset epilepsy to adolescent-adult onset movement disorders including PED. Evaluation and treatment of adult Glutl-DS also differ from paediatric Glutl-DS. An extended metabolic evaluation may not be necessary, and for women of childbearing age, a pregnancy test should be considered prior to a KDT given that the risks of teratogenicity are unknown. Initiation of a KDT in adults is controversial given the side effects described in drug-resistant childhood epilepsy including osteopenia, osteoporosis, potential cardiovascular risks, and unclear effects on pregnancy. Also, energy and nutritional requirements in the mature brain are less than in the developing brain. In general, the modified Atkins diet (MAD) is considered a reasonable alternative for adolescents and adults when treating poorly controlled seizures and paroxysmal movement disorders.

[0111] It is clear from the summary above (J. Klepper et al. (2020) Epilepsia Open,' 5:354- 365), that patients can present with different symptoms at different ages and disease severities. For example, in infancy, paroxysmal eye-head movements may be present alongside seizures, but exercise-induced dyskinesia is unlikely to be detected. In later childhood, adolescence or adulthood, paroxysmal exercise-induced dyskinesia alongside motor disturbance may present without seizures.

[0112] Therefore, it one embodiment, the patient suffers from one or more of the symptoms selected from the group consisting of epilepsy and / or seizures, movement disorders, development and / or cognitive disorders, atypical manifestations, and / or adult Glutl-DS. Preferably, the patient suffers from one or more of the symptoms selected from the group consisting of movement disorders, development and / or cognitive disorders, atypical manifestations, and / or adult Glutl-DS; more preferably movement disorders, atypical manifestations, and / or adult Glutl-DS; even more preferably movement disorders and / or adult Glutl-DS; most preferably movement disorders. Preferably, the one or more of the symptoms has been present for at least 4 weeks, more preferably at least 3 months, most preferably at least 1 year.

[0113] In a preferred embodiment, the patient does not display epilepsy or seizures, and does suffer from one or more of the symptoms selected from the group consisting of movement disorders, development and / or cognitive disorders, atypical manifestations, and / or adult Glutl-DS; more preferably movement disorders, atypical manifestations, and / or adult Glutl- DS; even more preferably movement disorders and / or adult Glutl-DS; most preferably movement disorders. Preferably, the patient has displayed the above symptoms without concomitant epilepsy or seizures for at least 4 weeks, more preferably at least 3 months, most preferably at least 1 year.

[0114] The epilepsy and / or seizures may be selected from the group consisting of generalised seizures, focal seizures, early-onset absence epilepsy (onset prior to age 4 years), epilepsy with myoclonic-atonic seizures (Doose syndrome), and epilepsy associated with movement disorders. Preferably, epilepsy and / or seizures is selected from the group consisting of generalised seizures and epilepsy associated with movement disorders. In a most preferred embodiment, all types of seizures and epilepsy are absent when the patient starts treatment.

[0115] The movement disorders may be selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), motor disturbance (e.g., involuntary movements), pyramidal symptoms, spasticity, ataxia, dystonia, hypotonia, gait disturbances, chorea, tremor, nonepileptic myoclonus (optionally including startle myoclonus, action, and postural myoclonus or weakness / paralysis), dyspraxia (e.g., oculomotor dyspraxia and oro-buccal dyspraxia) and paroxysmal non-motor episodes (e.g., migraines, behavioural disturbances, cyclical vomiting, and sleep episodes, as well as confusion, lethargy, somnolence dysphoria, hemiparesis, cataplexy and total body paralysis).

[0116] Preferably, the movement disorder is selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), pyramidal symptoms, ataxia, hypotonia, and chorea.

[0117] The movement disorders, especially paroxysmal movement disorders, may be characterised by the conditions that trigger them. In one embodiment, the movement disorder is defined as one triggered by one or more selected from the group consisting of fasting, exercise, emotional stress, fever, fatigue, insufficient ketosis, sleep deprivation, temperature changes, and / or medication.

[0118] In a most preferred embodiment, the movement disorders are present when the patient starts treatment.

[0119] The development and / or cognitive disorders may be selected from the group consisting of microcephaly, mild-to-severe intellectual disability, dysarthria, deficiencies in visuospatial abilities and deficiencies in visuomotor abilities. Preferably, the development and cognitive disorder is microcephaly.

[0120] The atypical manifestations may be selected from the group consisting of writer's cramp, intermittent ataxia, cataplexy, total body paralysis, Parkinsonism, nocturnal painful muscle cramps in the legs, alternating hemiplegia of childhood, hemiplegic migraine, cyclic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with PED, hepatosplenomegaly, periventricular calcifications, brain atrophy, pseudohyperkalemia, cataracts, and retinal dysfunction.

[0121] The adult Glutl-DS symptoms may be adolescent-adult onset movement disorders (e g., PED).

[0122] Different combinations of symptoms can be grouped phenotypically (W. Leen et al. (2010) Brain, 133:655-670): (i) the classical phenotype of intellectual disability and epilepsy with or without a movement disorder (84%), subdivided into early-onset (52 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder (other than paroxysmal exertion-induced dyskinesia), without epilepsy (15%); and (iii) a non-classical phenotype of paroxysmal PED and / or (absence) epilepsy or a minimal phenotype (~1%). A preferred combination of symptoms present as treatment is initiated is a non-classical phenotype, with mental retardation and movement disorder (other than paroxysmal exertion-induced dyskinesia), without epilepsy; and / or a non-classical phenotype of paroxysmal PED without epilepsy or with a minimal phenotype.

[0123] Metabolic diagnosis

[0124] The metabolic diagnosis may be performed by a skilled clinical biochemist and the method of treatment may include the step of performing a metabolic diagnosis. The metabolic hallmark of Glutl-DS is reduced glucose in the central nervous system, as detected in the CSF by lumbar puncture, in the presence of normoglycemia. This is known as hypoglycorrhachia. Generally, the cut-off for hypoglycorrhachia is 2.2 mmol / L (40 mg / dL), but can be 2.2 to 2.9 mmol / L (41-52 mg / dL) in milder case.

[0125] Given that CSF glucose levels vary with age, a more robust diagnosis compares the CSF glucose level to the blood glucose level because a consistent CSF to blood glucose ratio of ~0.8 is seen in all age groups. CSF to blood glucose ratios ranged from 0.19 to 0.59 in Glutl-DS patients with ratios of 0.5 and below being considered diagnostic. Ratios of 0.4 and below are often seen to more severe or atypical phenotypes (W. Leen et al. (2013) JAMA Neurol,- 70: 1440-1444).

[0126] Therefore, it one embodiment, the patient displays a CSF glucose concentration of 2.9 mmol / L (52 mg / dL) or less. Preferably, the patient displays a CSF glucose concentration of 2.2 mmol / L (40 mg / dL) or less.

[0127] In a preferred embodiment, the patient displays CSF to blood glucose ratio of 0.59 or less, more preferably 0.5 or less, most preferably 0.4 or less.

[0128] Genetic diagnosis

[0129] The genetic diagnosis may be performed by a skilled geneticist and the method of treatment may include the step of performing a genetic diagnosis. The type of genetic mutation often correlates with phenotypic severity: missense variants (mild and moderate severity); splice site and nonsense variants and insertions, deletions, and exon deletions (moderate and severe severity); and complete gene microdeletions or deletions (severe severity).

[0130] A missense variant is a point mutation in which a single nucleotide changes in the SLC2A1 gene results in a codon that codes for a different amino acid. In an embodiment, the patient has a missense mutation in the SLC2A1 gene. Preferably, missense or non-sense mutation results in a point mutation that occurs at a site selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Seri 13, Argl26, Glyl30, Argl53, Arg212, Arg218, Lys256, Arg264, Thr295, Alai 55, Arg330, Arg333, Pro485 and Arg468 of the GLUT1 protein. It is predicted that the composition will have stronger treatments on missense variants, where the symptoms may be milder.

[0131] Splice site and nonsense variants and insertions, deletions, and exon deletions result in larger changes to the gene and protein expressed. In an embodiment, the patient has a splice site mutation, nonsense mutation, one or more insertion, one or more deletion, or one or more exon deletion the SLC2A1 gene. Preferably, the mutations are selected from the group consisting of missense, insertion, splice site, nonsense, oligonucleotide deletions and intragenic large deletions.

[0132] Complete gene microdeletions or deletions result in large (1 Megabase or greater) deletions. In an embodiment, the patient has a complete gene microdeletion, complete gene deletion or contiguous gene deletion.

[0133] Biochemical diagnosis

[0134] The biochemical diagnosis may be performed by a skilled biochemist and the method of treatment may include the step of performing a biochemical diagnosis. In the absence of pathogenic SLC2A1 variants, an impaired 3-O-methyl-D-glucose uptake in erythrocytes between 35% and 74% of controls is diagnostic. In an embodiment, the patient has a O- methyl-D-glucose uptake in their erythrocytes less than 74% of control values.

[0135] The definitions of the patient (age, severity and different diagnostic criteria) defined directly above may be combined to form specific patient populations with the obvious exception that an individual patient cannot have more than one age, more than one disease severity and the same specific symptom cannot be present and absent in the same patient at the same time. However, the treatment described herein can apply to more than one age, severity and diagnostic criteria, and one sub-type of symptom may be present when another is absent (e.g., paroxysmal eye-head movements may be present when paroxysmal PED is absent).

[0136] Symptoms and their treatment

[0137] The symptoms treated may be frequent (e.g., daily), occasional (e.g., weekly) or rare (e.g., monthly or less).

[0138] The compositions described herein may be for use in treating Glutl-DS in general, or one or more of the symptoms (described above, such as movement disorders) in one or more of the patient groups (described above, such as a patient with movement disorders without concomitant epilepsy). When a symptom is present, “treat” or “manage” relates to the full or partial treatment of one or more symptom of Glutl-DS, described above. When a symptom is absent, “treat” or “manage” relates to the prevention of a known symptom of Glutl-DS that the patient does not yet suffer from, but is expected to suffer from based on their age or disease severity. Generally, a patient who suffered from epilepsy in childhood, but no longer suffers from epilepsy in later life, would not be expected to suffer from epilepsy. Therefore, it one embodiment, the composition is for use in treating one or more of the symptoms selected from the group consisting of movement disorders, development and / or cognitive disorders, atypical manifestations, and / or adult Glutl-DS, most preferably movement disorders.

[0139] The movement disorders may be selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), motor disturbance (e.g., involuntary movements), pyramidal symptoms, spasticity, ataxia, dystonia, hypotonia, gait disturbances, chorea, tremor, nonepileptic myoclonus (optionally including startle myoclonus, action, and postural myoclonus or weakness / paralysis), dyspraxia (e.g., oculomotor dyspraxia and oro-buccal dyspraxia) and paroxysmal non-motor episodes (e.g., migraines, behavioural disturbances, cyclical vomiting, and sleep episodes, as well as confusion, lethargy, somnolence dysphoria, hemiparesis, cataplexy and total body paralysis).

[0140] Preferably, the movement disorder is selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), pyramidal symptoms, ataxia, hypotonia, and chorea.

[0141] In a most preferred embodiment, the movement disorders are a current symptom when the patient starts treatment.

[0142] The development and / or cognitive disorders may be selected from the group consisting of microcephaly, mild-to-severe intellectual disability, dysarthria, deficiencies in visuospatial abilities and deficiencies in visuomotor abilities. Preferably, the development and cognitive disorder is microcephaly.

[0143] The atypical manifestations may be selected from the group consisting of writer's cramp, intermittent ataxia, cataplexy, total body paralysis, Parkinsonism, nocturnal painful muscle cramps in the legs, alternating hemiplegia of childhood, hemiplegic migraine, cyclic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with PED, hepatosplenomegaly, periventricular calcifications, brain atrophy, pseudohyperkalemia, cataracts, and retinal dysfunction.

[0144] The adult Glutl-DS symptoms may be adolescent-adult onset movement disorders (e g., PED).

[0145] Different combinations of symptoms can be grouped phenotypically (W. Leen et al. (2010) Brain, 133: 655-670): (i) the classical phenotype of intellectual disability and epilepsy with or without a movement disorder (84%), subdivided into early-onset (52 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder (other than paroxysmal exertion-induced dyskinesia), without epilepsy (15%); and (iii) a non-classical phenotype of paroxysmal PED and / or (absence) epilepsy or a minimal phenotype (~1%). A preferred combination of symptoms treated is a non-classical phenotype, with mental retardation and movement disorder (other than paroxysmal exertion-induced dyskinesia), without epilepsy; and / or a non-classical phenotype of paroxysmal PED without epilepsy or with a minimal phenotype.

[0146] The embodiments and preferred embodiments described above apply equally for the use of the composition in the manufacture of a medicament and the method of treating Glutl- DS in a patient in need thereof described at the top of Section B. The methods of treatment may include an additional step of performing a diagnosis.

[0147] Based on the prediction that the composition described herein can treat Glutl-DS independently of the presence of epilepsy and / or seizures, the composition detailed above is particular suitable for treating Glutl-DS related movement disorders in a patient who does not display one or more of the symptoms selected from the group consisting of epilepsy and seizures (i.e., does not suffer from concomitant epilepsy).

[0148] Given that epilepsy and / or seizures generally subside with age and certain movement disorders appear with age, the composition detailed above is particular suitable for treating Glutl-DS related common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal PED, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), pyramidal symptoms, ataxia, hypotonia, and / or chorea.

[0149] C. Formulations

[0150] Whilst the decanoic acid and octanoic acid are preferably in the form of triglycerides when used to treat patients, the cellular effects demonstrated in the application confirm an effect for free fatty acids, or salt (e.g., sodium or potassium) or prodrugs (e.g., methyl or succinyl esters) thereof.

[0151] In a preferred embodiment, the composition is a formulation described below wherein both decanoic acid and octanoic acid are present in a ratio of about 8:2 (C10:C8) and 99% of the fat is decanoic acid and octanoic acid. The formulation of K. Vita® used in previous clinical trials is shown in Table 1:

[0152] Osmolality: 85 mOsm / kg

[0153] Ingredients: Water, Medium Chain Triglyceride (MCT) Oil, Emulsifiers (E472c, E471), Thickener (E415), Flavourings, Sodium Chloride, Colour (E120), Acidity Regulator (E296), Artificial Sweetener (Sucralose).

[0154] Triglycerides

[0155] The composition or formulation may contain standard heterotriglycerides with a random distribution of both decanoic and octanoic acid on the glycerol backbones (caprylic / capric triglyceride). This has been used in the prior art disclosures of K. Vita®. Preferably, the composition or formulation may contain mixtures of homotriglycerides containing tri-C8 triglycerides (caprylic triglyceride) and tri-ClO triglycerides (capric triglyceride), as used in WO 2017 / 093449, in the claimed proportions. The inventors predict this will be particularly effective in treating movement symptoms in a patient with Glutl-DS.

[0156] D. Additional benefits

[0157] Preferably, the composition or formulation does not induce ketosis when administered as part of the treatment. This reduces the risk of hyperketosis and eliminates the onerous task of daily ketone testing. Preferably, the composition or formulation does not cause reduced expression of GLUT1 in muscle, as determined by Western blotting or expression analysis of muscle biopsy by standard transcriptomic methods, compared to before treatment was initiated. Suitable methods for Western blotting and expression analysis are described below. Reduced expression may mean a reduction in expression of 20% compared to before treatment was initiated.

[0158] Alternatively, the composition or formulation does not cause reduced glucose levels in the central nervous system, as determined by a further reduction in cerebrospinal fluid [CSF] / blood glucose ratio, compared to before treatment was initiated. Reduced cerebrospinal fluid [CSF] / blood glucose ratio may mean a reduction of 20% compared to before treatment was initiated ( a reduction of 20% in ratiometric value, e.g., from 0.5 to 0.4). Methods of quantifying CSF and blood glucose levels are known to the skilled person (M. Schwantje et al. (2019) J. Inherit. Metab. Dis., ' 43:216-222).

[0159] Preferably, the composition or formulation is for use in increasing or maintaining GLUT1 levels in the brain of a patient with Glutl-DS.

[0160] E. Cellular transcription studies in astrocytes and Glutl-DS patient derived iPSCs

[0161] As described above, one possible reason for the failure to identify an efficacious treatment for Glutl-DS (including movement disorders) is the lack of biochemical data in relevant cell models that do not measure symptoms linked to concomitant epilepsy.

[0162] Therefore, the inventors tested the effects of decanoic acid (CIO), octanoic acid (C8) and an 8:2 mixture of C10:C8 on the expression of genes related to glucose metabolism, fatty acid metabolism, the citric acid cycle (including citrate synthase) and oxidative phosphorylation (including mitochondrial genes encoding subunits of the enzyme NADH dehydrogenase (ubiquinone)). The inventors compared astrocytes (relevant for general epilepsy being a central nervous system cell type) and induced pluripotent stem cells (iPSCs) derived from fibroblasts from a Glutl-DS patient (relevant for Glutl-DS, especially for cells not differentiated for the central nervous system environment).

[0163] Surprisingly, the compositions enriched with decanoic acid upregulate an array of genes in GlutlDS-containing iPSCs that are relevant to glucose metabolism (Figure 1), fatty acid metabolism (Figure 2), the citric acid cycle including citrate synthase (data not shown) and oxidative phosphorylation (data not shown) whereas octanoic acid does not have the same effect in iPSCs. Likewise, decanoic acid enriched compositions did not upregulate genes related to glucose metabolism in U251 cells. This suggests that octanoic acid and decanoic acid have specific - and distinct - direct effects on cells containing Glutl-DS mutations that are not seen non-mutated cell lines found in the central nervous system. For example, CPT1B - the isoform of carnitine palmitoyltransferase I (CPT1) found in muscle - was upregulated in Glutl-DS iPSCs, but not in non-Glutl-DS astrocytes (Figure 2). CPT1B is the rate-controlling enzyme of the long-chain fatty acid beta-oxidation pathway in muscle mitochondria, and therefore energy provision to muscle (J. McGarry et al. (1977) J. Clin. Invest., - 60:265). In fact, there was a general increase in glucose metabolism when decanoic acid (or the 8:2 C10:20 mixture) was added to Glutl-DS iPSCs (Figure IB) whereas the opposite effect was seen in astrocytes (Figure 1 A). The data suggest that compositions enriched for decanoic acid might exert a direct effect in cells containing Glutl-DS mutations even if they are not from a type found in the central nervous system. Furthermore, the data confirm that decanoic acid alone downregulates the Glutl gene (SI.C2A 1) gene in both astrocytes and Glutl-DS iPSCs. Surprisingly, octanoic acid has the opposite effect in brain- derived astrocytes. The causes the inventors to predict that specific MCT compositions enriched for decanoic acid but containing a minor proportion of octanoic acid, such as K.Vita®, might be suitable for treating movement disorders in Glutl-DS patients. As pure decanoic acid might inhibit GLUT1 function in the brain, including of a small proportion of octanoic acid is predicted to offset this negative effect. Indeed, specific MCT compositions enriched for decanoic acid but containing a minor proportion of octanoic acid, such as K.Vita®, might even treat movement disorders in Glutl-DS patients without concomitant epilepsy, despite the prevailing view that KDTs treat Glutl-DS by inducing “ketosis”.

[0164] Experimental

[0165] Chemicals

[0166] Decanoic and octanoic acid were purchased from Alfa Aesar (A14788, Al 1149 respectively). Dimethyl sulphoxide (DMSO) was purchased from VWR (MFCD00002089).

[0167] Cell culture

[0168] GLUT1 deficient fibroblast derived iPSCs were obtained from Coriell Institute (GM27896). Cells originate from a skin biopsy of a patient with GLUT1 deficiency syndrome due to a mutation from C to T at the base pair 1454 in the SLC2A1 gene inducing a P485L mutation in the GLUT1 protein. Cells were stored in liquid nitrogen and grown in either 25 cm2or 75 cm2cell culture flasks (Corning, 430639 / 430641U) coated with hESC- qualified Matrigel (Corning, #354277) in mTeSR-1 medium (Stem Cell Technologies, # 85850) for no more than 10 passages containing high glucose levels (A. Chen et al. (2021) Int. J. Mol. Set., - 22: 10729). Cells were maintained at 37 °C, 5% CO2, passaged using StemPro Accutase (Thermo Fisher, Al 110501) and seeded at a concentration of 2.5-3.104 cells / cm2with 10 pM of ROCK inhibitor Y-27632 for the first 24 h (Abeam, abl20129). mTeSR-1 medium was changed every 24 h to prevent cell differentiation and allow optimal growth.

[0169] U251 human astrocyte-derived cells were obtained from ECACC (U-373MG, Cat. 080619010). Cells were stored in liquid nitrogen and taken from storage to be grown for no more than 10 passages. Cells were cultivated at 37 °C, 5% CO2 in either 25 cm2or 75 cm2cell culture flasks (Corning, 430639 / 430641U) in Minimum Essential Medium Eagle (Merck, M4655) with non-essential amino acids (Merck, M7145), Sodium pyruvate (Merck, S8636), 10 % Foetal Bovine Serum (Merck, F7524), 1% Penicillin / Streptomycin and 5.6 mM glucose. At 80% confluency, cells were trypsinised (Thermo Fisher, 25300054) and split to be seeded at 3.104 cells / cm2in a new flask.

[0170] RNA sequencing

[0171] GLUT1 deficient iPSCs or U251 human astrocyte-derived cells were seeded at 2.1 cells / cm2in T25 flasks and treated with physiologically relevant concentrations (150 pM) of either decanoic or octanoic acid, or 120 / 30 pM decanoic / octanoic acid (8:2 C10:C8 ratio), for 4 days. Media was changed every 48 h. Total RNA from samples was extracted using the RNeasy kit (Qiagen, 74104) and samples were diluted to 20 ng / pl to be analysed by sequencing.

[0172] Sequencing of mRNA from total RNA and pathway enrichment analysis was carried out by Novogene. mRNA was purified from total RNA using magnetic bead, and the obtained samples were fragmented in 50 bp mRNA fragments. cDNA was synthesised from mRNA fragments ligated with adapters, amplified using real-time PCR and sequenced on an Illumina platform. Raw reads were cleaned by removing reads containing adapter, read containing poly-N and low-quality reads using fastp software. Reads were aligned to a known genome using Hisat2, and quantification of genes expression was carried out using FeatureCounts. Differential gene expression was assessed by using the DESeq2 R package, and differential pathway analysis was carried out using Gene Set Enrichment Analysis (GSEA; 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) with the Kyoto Encyclopaedia of Genes 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).

[0173] Western Blotting

[0174] U251 or GLUT1 deficient iPSC lysates were prepared using RIPA buffer (Thermo Fisher, 89900) containing protease inhibitor (Thermo Fisher, 87786). Protein quantification was carried out using Pierce BCA protein Assay (Thermo Fisher, 23227) and lysates were heated at 70 °C for 5 mins in Laemmli buffer (Thermo Fisher, J61337.AC) before being loading 6 pg on an 8% acrylamide gel. Proteins were transferred to a 0.45 pM PVDF membrane (Millipore, IPFL00010) in transfer buffer using a Trans-blot Turbo Transfer System according to the manufacturer’s protocols (Bio-Rad, 1704150). After incubation with Intercept blocking buffer (Li-COR, 927-70001) for 1 hour, the membrane was incubated in Intercept blocking buffer with antibodies (1 : 1000) against Vinculin and GLUT1 (Cell Signalling technology, 13901, 73015) at 4°C overnight. Membranes were washed in TBST and incubated with a 1 : 10000 dilution of odyssey goat anti -rat IR DYE 800 (LI-COR Biosciences, UK) in Intercept blocking buffer with 0.1% SDS (Sigma, L5750) and 0.1% Tween (Thermo Scientific, 10776834) for Ih. Blots were washed in TBST and visualised using the Odyssey CLx imager (LI-COR) according to the manufacturer’s protocols.

[0175] Results

[0176] Initial screen in astrocyte derived astrocyte-derived cells

[0177] The inventors investigated the effects of MCFAs on a human-derived astrocyte- derived glioblastoma cell (U251), previously used in 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 either decanoic or octanoic acid (150 pM), or a combination of decanoic / octanoic acids (120 / 30 pM) that are equivalent to blood concentration found in epileptic patients during treatment with K.Vita® (N. Schoeler et al. (2021) Brain Comms,' 3 : 1-13). Cells were treated for 4 days to enable time for metabolic changes to occur following extended dietary treatment (C. Harvey et al. (2018) J. Nutr. Metab., ' 2630565). Transcriptional regulation was initially chosen to monitor metabolic changes following treatment, with key modifications validated by western analysis. Decanoic acid treatment significantly upregulated 15 KEGG pathways and downregulated 75 KEGG pathways in U251 cells. Of the 15 most significantly upregulated pathways, five were involved in fatty acid metabolism and signalling (including fatty acid degradation p<0.001; fatty acid metabolism p<0.001; peroxisome p=0.001; PPARy p=0.002; butanoate metabolism p=0.033). In contrast, octanoic acid treatment provided relatively few significant changes, with 10 KEGG pathways significantly upregulated by octanoic acid and four downregulated with few changes to fatty acid or sugar metabolism. Following combinatory decanoic:octanoic acid (8:2) treatment, 14 pathways were downregulated, including four pathways involved in sugar uptake and metabolism (HIF-1 signalling 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 pathways in cell signalling (PI3K-AKT signalling p=0.003; MAPK signalling p=0.02 and AMPK signalling p=0.01). One pathway was significantly upregulated by combinatory decanoic: octanoic acid. This analysis suggests a significant role for decanoic acid containing treatments in enhancing fatty acid metabolism and downregulating sugar-metabolism in astrocyte-derived cells following chronic treatment.

[0178] To identify the relative contribution of each fatty acid in regulating transcriptional changes, the inventors examined the total number of gene significantly regulated with each treatment. In total, the expression of 4172 genes were significantly modified in any condition, with 6.5% (270 genes) of these genes altered in all three conditions (decanoic, octanoic and combinatory treatment) suggesting that the majority of transcription changes were related to specific fatty acid effects. Decanoic acid treatment regulated the largest proportion of genes (63%, 2626 genes), where 60% of these genes (1534) were modified with decanoic acid only treatment. Octanoic acid treatment significantly modified the expression of 1869 genes, where 52% of these genes (991) were unique to octanoic acid. Decanoic: octanoic acid shared only 17% (651 genes) of the 3844 genes significantly up or downregulated following treatment with one or the other MCFA, suggesting that the mechanisms of action of these fatty acids are distinct, providing different effects. Interestingly, the combination of both fatty acids significantly modified the expression of 1266 genes, of which 74% (938 genes) shared an effect with either decanoic or octanoic treatment conditions, but also specifically induced a significant change in expression of 328 other unique genes (26%). Thus, decanoic and octanoic acid treatment provided mainly distinct effects on gene transcription, and combinatory treatment provided specific alteration of gene transcription rather than an “average” of their components. Speci fic transcriptional changes induced by medium chain fatty acid treatment

[0179] As decanoic acid-containing treatments reduce expression of several related KEGG pathways relating to transport and metabolism of glucose in astrocyte-derived cells, the inventors investigated genes with significant changes in expression levels that are involved in sugar transport, glycolysis and gluconeogenesis (Fig. 1 A). Heat map comparison of significant altered gene expression following different MCFAs treatments indicate one gene to be strongly increased in expression phosphoenolpyruvate carboxykinase (PCK2) in decanoic acid only treatment, controlling the rate limiting step in gluconeogenesis and TCA flux (S. Burgess et al. (2007) Cell Metab., - 5:313-320). However, decanoic acid and combinatory decanoic:octanoic acid (8:2) treatment provided a broad decrease in expression of carbohydrate uptake and glycolytic related genes following treatment, which was absent following octanoic acid treatment (Fig. 1 A). Here, decanoic acid enriched treatment significantly decreased the expression of the gene encoding astrocytic GLUT1 (SLC2A1) and reduced expression of genes relating to 10 of the 11 steps of glycolysis (Fig. 1 A). In contrast, octanoic acid treatment significantly reduced expression of one gene, ENO2, involved in the end of the glycolytic process. Combinatory decanoic: octanoic acid treatment (8:2) provided a decrease in seven genes involved in glycolysis, with several of these genes shown in decanoic acid-only treatment. Crucially, combinatory decanoic: octanoic acid treatment (8:2) did not significantly decreased the expression of the gene encoding astrocytic GLUT1 (SLC2A1).

[0180] Changed protein levels of GLUT1 in U251 cells was investigate by Western blotting analysis. Decanoic acid treatment significantly reduced GLUT1 level compared to control condition (p=0.005), but octanoic acid did not, validating the transcriptional analysis.

[0181] The inventors also analysed genes involved in fatty acid metabolic processes (Fig. 2A). Heat map comparison of significant altered gene expression involved in B-oxidation, including acyl-CoA formation, identified a broad increase in expression of these genes following decanoic acid and combinatory decanoic: octanoic acid treatment (8:2), which was absent following octanoic acid treatment (Fig. 2A).

[0182] Next, the inventors identified genes with significant changes in expression levels that are involved in sugar transport, glycolysis and gluconeogenesis of Glut 1-DS -derived iPSCs (Fig. IB). Heat map comparison of significantly altered gene expression following different MCFAs treatments indicated Glut 1-DS -derived iPSCs compared to astrocyte-derived cells. In particular, more genes involved in glucose metabolism were upregulated following decanoic acid-enriched treatments. Among the 12 genes involved in both glycolysis and gluconeogenesis were upregulated while 5 were downregulated and among the 3 genes involved only in glycolysis, two were downregulated (PFKP, PGM1) and one was upregulated (PGM2). Interestingly, lactate dehydrogenase (LDHD) was also strongly downregulated in expression, where inhibition of LDH (Y. Inoue et al. (2021) Epilepsy Res. ; 176: 106705) provides a mechanism for seizure control. Furthermore, 4 of the 6 genes involved in gluconeogenesis that showed significant modification were upregulated (GOT2, SLC25A13, SLC25A12, PC), and 2 were downregulated (FBP1, GOT1). These data therefore suggest that decanoic acid-enriched treatment in GLUT1 deficient cells stimulates gluconeogenesis while inhibiting glycolysis.

[0183] Expression of numerous genes encoding energy-related mitochondrial metabolism proteins were also altered following decanoic treatments, including genes relating to fatty acid and ketone metabolism (Fig. 2B). Of particular interest in fatty acid beta oxidation, the CPT1B protein is the rate-controlling enzyme of the long-chain fatty acid beta-oxidation pathway in muscle mitochondria, and therefore energy provision to muscle (J. McGarry et al. (1977) J. Clin. Invest. ; 60:265) that was upregulated following decanoic acid-enriched treatments. Furthermore, CPT2 functions in the mitochondria to remove the carnitine from the acyl-carnitine to allow beta oxidation, thus upregulation of CPT1B in conjunction with CPT2 strengthens the likelihood of enhanced energy provision in muscle. In addition, the first step in metabolism of 12-22 carbons is through ACADVL, where expression of the encoding gene is upregulated following these treatments. ECHS1 is a mitochondrial protein that catalyses the hydration of medium- and short-chained fatty enoyl-CoA thioesters from 4 carbons long (C4) up to C16 and this gene is upregulated following treatment. HMGCS1 is cytosolic form of the ketogenic enzyme HMGCS2 (F. Hegardt (1999) Biochem. J; 338:569- 582) and catalyses the same reaction (need to see if ketones are made following treatment). In addition, expression of OXCT2 is reduced, where the encoded protein (SCOT) catalyses the first, rate-limiting step of ketone body utilisation (N. Shafqat et al. (2013) J. Inherit. Metab. Dis. ; 36:983-987), suggesting metabolic sparing of produced ketones in these cells following treatment. Other genes encoding beta oxidation proteins that showed increased expression following decanoic acid-enriched treatments included ACOX1 that controls the initial and rate-limiting step of peroxisomal beta-oxidation of straight-chain saturated and unsaturated very-long-chain fatty acids and ACOX3, a peroxisomal protein that functions to oxidize the CoA-esters of 2-methyl-branched fatty acids. ACSBG1 catalyses the conversion of fatty acids such as long-chain and very long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation. Thus, these changes in fatty acid metabolism are consistent with enhanced fatty acid metabolism to provide energy in Glutl-DS derived iPSCs.

[0184] The inventors performed provisional experiments on expression of genes relating to the citric acid cycle including citrate synthase (data not shown) and oxidative phosphorylation (data not shown) in both U251 and Glutl-DS derived iPSCs. Only six citric acid cycle genes were affected by decanoic acid in U251 cells, four of which were upregulated and two of which were downregulated (including citrate synthase). Expression of a wide range of genes encoding citric acid cycle and oxidative phosphorylation proteins were enhanced following decanoic acid-enriched treatments of Glutl-DS derived iPSCs (data not shown). Genes encoding thirteen citric acid cycle-related mitochondrial proteins were increased in expression, consistent with an increase in mitochondrial load following treatment in Glutl-DS derived iPSCs. These included ACLY that catalyses the cleavage of citrate into oxaloacetate and acetyl-CoA and the generation of ATP, and citrate synthase that is used as a marker for mitochondrial content and has been demonstrated to increase following decanoic acid treatments. In addition, 20 genes encoding oxidative phosphorylation proteins showed significantly increased expression in Glutl-DS derived iPSCs. Importantly, these increases in citric acid cycle and oxidative phosphorylation related genes were not seen following equivalent treatment of a human astrocyte-derived cell line (U251), indicating a potential disease specific mechanism for K.vita® on GlutlDS cells to enhance energy provision.

[0185] Expression of two genes encoding pentose phosphate pathway (PPP) enzymes were elevated following decanoic acid-enriched treatments (data not shown). This pathway provides energy through the formation of NADPH and additionally reduces reactive oxygen species (ROS). Both, G6PD, which catalyses the rate-limiting step of the oxidative pentosephosphate pathway and generates NADPH, and PGD, which also generates NAPDH, that enable the removal of ROS were elevated. Enhanced expression of these two proteins may provide a mechanism for reducing ROS production arising from increased mitochondrial load.

[0186] It is hypothesised that combinatory decanoic :octanoic acid treatment (8:2) might be less toxic to GlutlDS cells than decanoic acid or octanoic acid alone.

[0187] Thus, in summary, the effect of MCFAs, in particular a combinatory decanoic: octanoic acid treatment (8:2), on GlutlDS cells is to reduce expression of genes encoding glucose uptake and glycolysis, and to increase expression of genes encoding some gluconeogenesis and fatty acid metabolism proteins (including muscle specific genes), suggesting a metabolic switch of energy supply from glucose metabolism to glucose catabolism and fatty acid metabolism.

[0188] In addition, combinatory decanoic :octanoic acid treatment (8:2) broadly enhanced expression of many citric acid cycle and oxidative phosphorylation associated genes, consistent with elevated mitochondrial and enhanced energy provision. Equivalent changes were not found following treatment of U251 cells, suggesting disease specificity for these changes relevant for Glutl-DS.

[0189] In addition, combinatory decanoic :octanoic acid treatment (8:2) increased PPP -related gene expression, likely leading to reduce ROS levels associated with enhanced mitochondrial load. These mechanisms therefore provide a unique set of metabolic signalling changes that will likely reduce the detrimental effect of lower glucose uptake in Glutl-DS, including in the periphery. These data support a peripheral effect for combinatory decanoic:octanoic acid treatment (8:2) that might allow treatment of Glutl-DS patients that suffer from movement disorders, even those without concomitant epilepsy prior to treatment.

[0190] F. Planned clinical protocols

[0191] Based on the discovery that octanoic acid and decanoic acid have opposite effects on GLUT1 expression, and that combinatory decanoic: octanoic acid treatment (8:2) has a distinct effect on iPSCs, as detailed in Section E, above, the inventors planned a clinical trial to be carried out in a well-characterised Glutl-DS patient population.

[0192] Clinical trial design

[0193] An interventional study with a duration of about 6 months and continued participant follow-up evaluating the use of K.Vita® as a pharmaceutical intervention (e.g., in the form of homotriglycerides) or dietary intervention, in the management of children and adults with glucose transporter type 1 deficiency syndrome (Glutl-DS).

[0194] Subjects consist of adults and children with Glutl-DS, with a confirmed diagnosis and current symptoms of epilepsy and / or movement disorder, who are not currently following or adhering to ketogenic diet therapy (KDT), or that are following a standard long- chain triglyceride (LCT) ketogenic diet or a modified Atkins diet. Subjects following a standard medium-chain triglyceride (MCT) diets (based on coconut oil) or who regularly consume MCT at screening will be excluded. The dietary intake of the subject should remain stable for the trial period, with the exception of the addition of K.Vita®. 20 to 40 participants are required for this study to detect a change from 10% to 50% in the primary outcome, with acceptable power.

[0195] The sample size is also reflective of the rarity of the condition and anticipated attrition rate.

[0196] The study will open in multiple sites to recruit the required number of participants in the required timeframe.

[0197] Objectives

[0198] Primary: To investigate the clinical efficacy of K.Vita® as a pharmaceutical intervention (e.g., in the form of homotriglycerides), or dietary intervention when used alongside no dietary restrictions or minimal restrictions (avoidance of foods containing simple sugars), or following a standard long-chain triglyceride (LCT) ketogenic diet or a modified Atkins diet, in the management of Glutl-DS with epilepsy and / or movement disorder symptoms. To be measured alongside Neuro QoL scale and ambulatory EEG.

[0199] Planned secondary, including: i) To measure relevant biomarkers and their correlation with efficacy. ii) To investigate the effect of dietary intervention with K.Vita® on quality of life (Neuro QoL scale) in participants with Glutl-DS and caregiver burden. iii) To determine long-term (e.g., up to 26 weeks) acceptance, compliance and tolerance of K.Vita® in participants with Glutl-DS. iv) To evaluate use of participant and healthcare professional K.Vita® resources and support, and to compare participant / carer experience of K.Vita® compared to KDT. v) To determine effect on depression, as measured by Neurological Disorders Depression Inventory in Epilepsy (NIDDI-E).

[0200] Parameters

[0201] Primary: Daily seizure for each (countable) seizure and / or movement disorders (e.g., measured by dyskinesia impairment scale), in the 30-days prior to 3- and 6-month follow-up compared to a 30-day baseline period, assessed by paper or electronic diary.

[0202] Planned secondary for participants with epilepsy: i) Number of prolonged seizures, use of emergency medication and seizure-related hospital admissions during the 6-month intervention period, compared to the 6 months prior to study enrolment. Frequency collected via patient / carer report during baseline, 3- and 6-month study visits by study Investigators. ii) Seizure Severity Questionnaire (1), completed at baseline, 3- and 6-month study visits.

[0203] Planned secondary for participants with movement disorder: i) Number of paroxysmal episodes involving impairment of motor control in the 30- days prior to 3- and 6-month follow-up compared to a 30-day baseline period, and whether there were any precipitating factors for the episodes, assessed by paper or electronic diary. ii) Length of paroxysmal episodes, for each (countable) episode type, in the 30-days prior to 3- and 6-month follow-up compared to a 30-day baseline period, assessed by paper or electronic diary. iii) Wearable device / activity watch to assess degree of activity. iv) Gait analysis using GAITRite® electronic walkway system (CIR Systems, Inc., New Jersey, USA) conducted at baseline, 3- and 6-month study visits as part of 6-minute walk test: used to calculate gait speed, cadence, stride length, heel-to-heel base of support, and percentage time spent in double support.

[0204] Planned secondary for all participants:

[0205] Assessment of Quality of Life

[0206] To be completed at baseline and at the end of 6 months:

[0207] - PedsQL™ Generic Core Scales, age-appropriate version: Toddlers (2-4 years of age), Young Child (5-7 years of age), Child (8-12 years of age), Adolescent (13-18 years of age), Young Adult (18-25 years of age) and Adults (>26 years of age), completed at baseline, 3- and 6-month study visits. A free text box will be added for patients / carers to input their own comments regarding quality of life (QoL). At the 3- and 6-month study visits, patients / carers will be asked to refer to any comments they inputted at baseline and how they have been impacted.

[0208] - Zarit Burden Interview 6-item version (2), to assess caregiver burden, completed at baseline, 3- and 6-month study visits.

[0209] Planned assessment of acceptance, compliance, and tolerance - Diet Satisfaction Score (3) at 3- and 6-month reviews.

[0210] - Ad hoc recording of non-compliance (if amount of K. Vita® taken is different to the recommended intake) via patient diary or app, and review of compliance at 3- and 6- month reviews with Investigator.

[0211] - 24-hour diet recall at baseline, 3- and 6-month study visits: to calculate percentage energy intake from fat, carbohydrate (starch and sugars) and carbohydrate.

[0212] - Ad hoc recording of gastro-intestinal symptoms via patient diary or app, and review of gastro-intestinal tolerance at baseline, 3- and 6-month study visits with Investigator.

[0213] - Height and weight measurement at baseline, 3- and 6-month study visits.

[0214] Clinical biochemistry testing, at baseline, 3- and 6-month study visits:

[0215] Blood spot free and acylcamitine profile

[0216] Glucose (mmol / L)

[0217] Triglycerides (mmol / L)

[0218] NEFA (mmol / L)

[0219] Total cholesterol (mmol / L)

[0220] Beta-hydroxybutyrate (mmol / L)

[0221] Sodium (mmol / L)

[0222] Potassium (mmol / L)

[0223] Urea (mmol / L)

[0224] Creatinine (pmol / L)

[0225] Calcium (mmol / L)

[0226] Magnesium (mmol / L)

[0227] Phosphate (mmol / L)

[0228] 25-hydroxyvitamin D (nmol / L)

[0229] ALT (U / L)

[0230] ALP (U / L)

[0231] Bilirubin (pmol / L)

[0232] Albumin (g / L)

[0233] Urate (pmol / L)

[0234] Total CO2 (mmol / L)

[0235] C8 (pmol / L)

[0236] CIO (pmol / L) Urine dipstick: pH, specific gravity, protein, glucose, ketones, bilirubin, infection, blood.

[0237] Urine organic acids (at baseline only)

[0238] Urine urate and calcium: creatinine ratio

[0239] Planned evaluation of use of K. Vita® resources and support and comparison of experience to previous KDT

[0240] - Investigator-designed short questionnaire asking for participants’ / carers’ opinions on K.Vita® resources, introduction schedules and perceived need for clinical / dietetic support, and how their experience has differed from when they followed KDT alone previously or prior to initiating K.Vita®, completed at 3- and 6-month study visits.

[0241] - Investigator-designed short questionnaire asking for the opinions of healthcare professionals involved in managing participants taking K.Vita® on the resources used (both aimed at healthcare professionals and participants / carers) and the amount of clinical / dietetic time required for managing participants taking K.Vita®, completed at 3-6 months after study initiation.

[0242] Reminders will be sent to participants to complete seizure / episode diaries and to record non-compliance and gastro-intestinal symptoms.

[0243] Rave eCOA and integrated tools, such as patient cloud and sensor cloud, will be used to collect questionnaire data electronically.

[0244] Patients / carers will be given the option to complete all follow-up questionnaires online prior to the study visit.

[0245] Planned inclusion criteria

[0246] Subjects are eligible to be included in the study only if all the following criteria apply:

[0247] 1) Confirmed genetic (SIX'2A 1) or biochemical (reduced cerebrospinal fluid [CSF] / blood glucose ratio) diagnosis of Glutl-DS and symptomatic of Glutl- DS, e.g. seizures / paroxysmal episodes.

[0248] 2) Not currently following or adhering to KDT, in the opinion of the referring dietitian or clinician, or defined as no dietary restrictions with the exception of avoidance of foods and beverages containing simple sugars. Alternatively, currently following a standard long-chain triglyceride (LCT) ketogenic diet or a modified Atkins diet. 3) Aged 3 years and above (may be amended based on tolerance).

[0249] 4) Absence of any metabolic or mitochondrial disorder that precludes the use of medium chain triglyceride (MCT).

[0250] 5) Willingly given, written, informed consent from the patient or parent / carer.

[0251] 6) Willingly given, written assent (if appropriate).

[0252] Planned exclusion criteria

[0253] Subjects are excluded from the study if any of the following criteria apply:

[0254] 1) Aged under 3 years (may be amended based on tolerance).

[0255] 2) Newly diagnosed Glutl-DS or diagnosed Glutl-DS not following the standard of care treatment.

[0256] 3) Currently fully or partially compliant with KDT and no symptoms of Glutl- DS, e.g. seizures / paroxysmal episodes.

[0257] 4) Inability to comply with the study protocol, in the opinion of the Investigator.

[0258] 5) Other concurrent medical or psychiatric condition, which, in the opinion of the Investigator, would place the subject at increased risk, preclude obtaining voluntary consent / assent or compliance with required study procedures, or would confound the objectives of study.

[0259] 6) Participants who are pregnant / breastfeeding at the start of the study or planning to become pregnant during the study period. Participants of childbearing potential will be required to undergo pregnancy test prior to enrolment.

[0260] 7) Allergy to any ingredient present in the study product.

[0261] 8) Is participating in any other interventional study and has started any other investigational drug, product or device within 30 days prior to screening or are taking part in a non-medication study which, in the opinion of the Investigator, would interfere with study compliance or outcome assessments.

[0262] 9) Following a standard medium-chain triglyceride (MCT) diets (based on coconut oil) or regularly consuming MCT at screening.

[0263] Planned dosage

[0264] Adults will receive four 60 mL dosages per day and children will aim to achieve <35% energy requirements from K.Vita® with a predicted dosage of 120 mL per day.

[0265] Statistical methods Statistical analysis will be performed in an appropriate manner known to the skilled clinical statistician.

[0266] G. Sub-group analysis in patients with movement disorders without concomitant epilepsy

[0267] Sub-group analysis will be performed in Glutl-DS patient without concomitant epilepsy to assess whether an effect is seen in their symptoms. In particular, sub-group analysis will be performed in Glutl-DS patient without concomitant epilepsy to assess whether an effect is seen in their movement symptoms. Furthermore, sub-group analysis will be performed in Glutl-DS patient without concomitant epilepsy to assess whether an effect is seen on individual movement disorders. Furthermore, sub-group analysis will be performed in Glutl-DS patient without concomitant epilepsy to assess whether an effect is seen without occurrence or recurrence of epilepsy or seizures.

[0268] H. Service evaluation in a sub-group of patients with movement disorders without concomitant epilepsy

[0269] The applicant is currently carrying out a service evaluation into the use of decanoic acid and octanoic acid (80:20 ratio as an FSMP - K. Vita®) in a group of patients in the UK based on the planned dosage described in Section F, above. Amongst this group is a cohort of 7 Glutl-DS patients who have movement disorder without accompanying seizures. Symptom frequency has been collected at 3,6 and 12 months after commencing K.Vita®:

[0270] • All 7 patients reached the 3 -month timepoint and, of these, 4 reported a reduction in movement disorder.

[0271] • 6 of these 7 patients reached the 6-month timepoint and all 6 reported a reduction in movement disorder.

[0272] • 4 of these 7 patients reached the 12-month timepoint and all 4 maintained the reduction in movement disorder.

[0273] These results suggest that the claimed composition can be used in the treatment and / or dietary management of movement disorders in a Glutl-DS patient, especially a human who suffers from movement disorders without concomitant epilepsy prior to administration of the composition. DIETARY INTERVENTION EMBODIMENTS:

[0274] Embodiment 1. A composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, for use in the dietary management of movement disorders in a Glutl-DS patient.

[0275] Embodiment 2. The composition for use according to embodiment 1, wherein the Glutl-DS patient is a human who suffers from movement disorders without concomitant epilepsy prior to administration of the composition.

[0276] Embodiment 3. The composition for use according to embodiment 1 or embodiment 2, wherein the Glutl-DS patient is a human with a mutation in the SLC2A1 gene, selected from the group consisting of: a point mutation, preferably a point mutation that occurs at a site selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Seri 13, Argl26, Glyl30, Argl53, Arg212, Arg218, Lys256, Arg264, Thr295, Alal55, Arg330, Arg333, Pro485 and Arg468 of the Glucose Transport 1 protein; a splice site mutation; a nonsense mutation; an insertion; a deletion; an exonic deletion; or a complete gene deletion.

[0277] Embodiment 4. The composition for use according to any preceding embodiment, wherein the movement disorder is selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal exercise-induced dyskinesia, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), motor disturbance (e.g., involuntary movements), pyramidal symptoms, spasticity, ataxia, dystonia, hypotonia, gait disturbances, chorea, tremor, nonepileptic myoclonus (optionally including startle myoclonus, action, and postural myoclonus or weakness / paralysis), dyspraxia (e.g., oculomotor dyspraxia and oro- buccal dyspraxia) and paroxysmal non-motor episodes (e.g., migraines, behavioural disturbances, cyclical vomiting, and sleep episodes, as well as confusion, lethargy, somnolence dysphoria, hemiparesis, cataplexy and total body paralysis), preferably the movement disorder is selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal exercise-induced dyskinesia, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), pyramidal symptoms, ataxia, hypotonia, and chorea.

[0278] Embodiment 5. The composition for use according to any preceding embodiment, wherein the patient suffers with one or more of the additional symptoms selected from the group consisting of development and / or cognitive disorders, atypical manifestations, and / or adult Glutl-DS.

[0279] Embodiment 6. The composition for use according to embodiment 5, wherein: the additional symptoms are the development and / or cognitive disorders are selected from the group consisting of microcephaly, mild-to-severe intellectual disability, dysarthria, deficiencies in visuospatial abilities and deficiencies in visuomotor abilities; preferably the development and cognitive disorder is microcephaly; and / or the additional symptoms are the atypical manifestations is selected from the group consisting of writer's cramp, intermittent ataxia, cataplexy, total body paralysis, Parkinsonism, nocturnal painful muscle cramps in the legs, alternating hemiplegia of childhood, hemiplegic migraine, cyclic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with paroxysmal exercise- induced dyskinesia, hepatosplenomegaly, periventricular calcifications, brain atrophy, pseudohyperkalemia, cataracts, and retinal; and / or the additional symptoms are the adult Glutl-DS symptoms is adolescent-adult onset movement disorders; preferably paroxysmal exercise-induced dyskinesia.

[0280] Embodiment 7. The composition for use according to embodiment 5 or embodiment 6, wherein one or more additional symptoms are treated, preferably all additional symptoms are treated.

[0281] Embodiment 8. The composition for use according to any preceding embodiment, wherein the patient is an infant, a child, an adolescent or an adult; preferably an adolescent or an adult; even more preferably an adult. Embodiment 9. The composition for use according to any preceding embodiment, wherein the ratio of C10:C8 is from 75:25 to 85: 15; preferably about 8:2 wt:wt, more preferably about 80:20 wt:wt.

[0282] Embodiment 10. The composition for use according to any preceding embodiment, wherein the decanoic acid and octanoic acid are in the form of triglycerides; preferably in the form of mixtures of homotriglycerides containing mixture of tri-C8 triglycerides (caprylic triglyceride) and tri-ClO triglycerides (capric triglyceride).

[0283] Embodiment 11. The composition for use according to any preceding embodiment, wherein the decanoic acid and octanoic acid make up at least 80%, preferably 85%, more preferably 90%, even more preferably 95% or most preferably 99% of the total fatty acid content of the composition by weight.

[0284] Embodiment 12. The composition for use according to any preceding embodiment, wherein the composition is substantially free of mono- or poly-unsaturated fatty acids, carbohydrate and / or protein.

[0285] Embodiment 13. The composition for use according to any preceding embodiment, wherein the composition is in the form of an oil-in-water emulsion.

[0286] Embodiment 14. The use of a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, in the manufacture of a medical food for

[0287] (a) the treatment of movement disorders in a Glutl-DS patient; and / or

[0288] (b) the dietary management of movement disorders in a Glutl-DS patient. METHOD OF TREATMENT EMBODIMENTS:

[0289] Embodiment 15. A method of treating Glutl-DS movement disorders comprising administering a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, to a Glutl-DS patient in need thereof.

[0290] Embodiment 16. The method according to method embodiment 15, wherein the Glutl- DS patient is a human who suffers from movement disorders without concomitant epilepsy prior to treatment.

[0291] Embodiment 17. The method according to method embodiment 15 or method embodiment 16, wherein the Glutl-DS patient is a human with a mutation in the SLC2A1 gene, selected from the group consisting of: a point mutation, preferably a point mutation that occurs at a site selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Seri 13, Argl26, Glyl30, Argl53, Arg212, Arg218, Lys256, Arg264, Thr295, Alal55, Arg330, Arg333, Pro485 and Arg468 of the Glucose Transport 1 protein; a splice site mutation; a nonsense mutation; an insertion; a deletion; an exonic deletion; or a complete gene deletion.

[0292] Embodiment 18. The method according to any preceding method embodiment, wherein the movement disorder is selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal exercise-induced dyskinesia, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), motor disturbance (e.g., involuntary movements), pyramidal symptoms, spasticity, ataxia, dystonia, hypotonia, gait disturbances, chorea, tremor, nonepileptic myoclonus (optionally including startle myoclonus, action, and postural myoclonus or weakness / paralysis), dyspraxia (e.g., oculomotor dyspraxia and oro- buccal dyspraxia) and paroxysmal non-motor episodes (e.g., migraines, behavioural disturbances, cyclical vomiting, and sleep episodes, as well as confusion, lethargy, somnolence dysphoria, hemiparesis, cataplexy and total body paralysis), preferably the movement disorder is selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal exercise-induced dyskinesia, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), pyramidal symptoms, ataxia, hypotonia, and chorea.

[0293] Embodiment 19. The method according to any preceding method embodiment, wherein the patient suffers with one or more of the additional symptoms selected from the group consisting of development and / or cognitive disorders, atypical manifestations, and / or adult

[0294] Glutl-DS.

[0295] Embodiment 20. The method according to method embodiment 19, wherein: the additional symptoms are the development and / or cognitive disorders are selected from the group consisting of microcephaly, mild-to-severe intellectual disability, dysarthria, deficiencies in visuospatial abilities and deficiencies in visuomotor abilities; preferably the development and cognitive disorder is microcephaly; and / or the additional symptoms are the atypical manifestations is selected from the group consisting of writer's cramp, intermittent ataxia, cataplexy, total body paralysis, Parkinsonism, nocturnal painful muscle cramps in the legs, alternating hemiplegia of childhood, hemiplegic migraine, cyclic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with paroxysmal exercise- induced dyskinesia, hepatosplenomegaly, periventricular calcifications, brain atrophy, pseudohyperkalemia, cataracts, and retinal; and / or the additional symptoms are the adult Glutl-DS symptoms is adolescent-adult onset movement disorders; preferably paroxysmal exercise-induced dyskinesia.

[0296] Embodiment 21. The method according to method embodiment 19 or method embodiment 20, wherein one or more additional symptoms are treated, preferably all additional symptoms are treated.

[0297] Embodiment 22. The method according to any preceding method embodiment, wherein the patient is an infant, a child, an adolescent or an adult; preferably an adolescent or an adult; even more preferably an adult. Embodiment 23. The method according to any preceding method embodiment, wherein the ratio of C10:C8 is from 75:25 to 85:15; preferably about 8:2 wt:wt, more preferably about 80:20 wt:wt.

[0298] Embodiment 24. The method according to any preceding method embodiment, wherein the decanoic acid and octanoic acid are in the form of triglycerides; preferably in the form of mixtures of homotriglycerides containing mixture of tri-C8 triglycerides (caprylic triglyceride) and tri-ClO triglycerides (capric triglyceride).

[0299] Embodiment 25. The method according to any preceding method embodiment, wherein the decanoic acid and octanoic acid make up at least 80%, preferably 85%, more preferably 90%, even more preferably 95% or most preferably 99% of the total fatty acid content of the composition by weight.

[0300] Embodiment 26. The method according to any preceding method embodiment, wherein the composition is substantially free of mono- or poly-unsaturated fatty acids, carbohydrate and / or protein.

[0301] Embodiment 27. The method according to any preceding method embodiment, wherein the composition is in the form of an oil-in-water emulsion.

Claims

CLAIMS:

1. A composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, for use in the treatment of movement disorders in a Glutl-DS patient in need thereof.

2. The composition for use according to claim 1, wherein the Glutl-DS patient is a human who suffers from movement disorders without concomitant epilepsy prior to treatment.

3. The composition for use according to claim 1 or claim 2, wherein the Glutl-DS patient is a human with a mutation in the SLC2A1 gene, selected from the group consisting of: a point mutation, preferably a point mutation that occurs at a site selected from the group consisting of Asn34, Gly91, Arg92, Arg93, Seri 13, Argl26, Glyl30, Argl53, Arg212, Arg218, Lys256, Arg264, Thr295, Alal55, Arg330, Arg333, Pro485 and Arg468 of the Glucose Transport 1 protein; a splice site mutation; a nonsense mutation; an insertion; a deletion; an exonic deletion; or a complete gene deletion.

4. The composition for use 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 exercise-induced dyskinesia, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), motor disturbance (e.g., involuntary movements), pyramidal symptoms, spasticity, ataxia, dystonia, hypotonia, gait disturbances, chorea, tremor, nonepileptic myoclonus (optionally including startle myoclonus, action, and postural myoclonus or weakness / paralysis), dyspraxia (e.g., oculomotor dyspraxia and oro-buccal dyspraxia) and paroxysmal non-motor episodes (e.g., migraines, behavioural disturbances, cyclical vomiting, and sleep episodes, as well as confusion, lethargy, somnolence dysphoria,hemiparesis, cataplexy and total body paralysis), preferably the movement disorder is selected from the group consisting of common paroxysmal movement disorders (e.g., paroxysmal eye-head movements, paroxysmal exercise-induced dyskinesia, paroxysmal events manifested by major motor dysfunction, and paroxysmal events with complex neurological symptoms), pyramidal symptoms, ataxia, hypotonia, and chorea.

5. The composition for use according to any preceding claim, wherein the patient suffers with one or more of the additional symptoms selected from the group consisting of development and / or cognitive disorders, atypical manifestations, and / or adult Glutl-DS.

6. The composition for use according to claim 5, wherein: the additional symptoms are the development and / or cognitive disorders are selected from the group consisting of microcephaly, mild-to-severe intellectual disability, dysarthria, deficiencies in visuospatial abilities and deficiencies in visuomotor abilities; preferably the development and cognitive disorder is microcephaly; and / or the additional symptoms are the atypical manifestations is selected from the group consisting of writer's cramp, intermittent ataxia, cataplexy, total body paralysis, Parkinsonism, nocturnal painful muscle cramps in the legs, alternating hemiplegia of childhood, hemiplegic migraine, cyclic vomiting, stroke-like episodes (e.g., paroxysmal hemiparesis, dysarthria, or aphasia), hemolytic anemia associated with paroxysmal exercise- induced dyskinesia, hepatosplenomegaly, periventricular calcifications, brain atrophy, pseudohyperkalemia, cataracts, and retinal; and / or the additional symptoms are the adult Glutl-DS symptoms is adolescent-adult onset movement disorders; preferably paroxysmal exercise-induced dyskinesia.

7. The composition for use 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 use according to any preceding claim, wherein the patient is an infant, a child, an adolescent or an adult; preferably an adolescent or an adult; even more preferably an adult.

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

10. The composition for use according to any preceding claim, wherein the decanoic acid and octanoic acid are in the form of triglycerides; preferably in the form of mixtures of homotriglycerides containing mixture of tri-C8 triglycerides (caprylic triglyceride) and tri- C10 triglycerides (capric triglyceride).

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

12. The composition for use according to any preceding claim, wherein the composition is substantially free of mono- or poly-unsaturated fatty acids, carbohydrate and / or protein.

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

14. The use of a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, in the manufacture of a medicament for the treatment of movement disorders in a Glutl-DS patient in need thereof.

15. A method of treating Glutl-DS movement disorders comprising administering a composition comprising a mixture of decanoic acid (CIO) and octanoic acid (C8), wherein the ratio of C10:C8 is from 70:30 to 90: 10 wt:wt, to a Glutl-DS patient in need thereof.