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Karin Borges - One of the best experts on this subject based on the ideXlab platform.
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Triheptanoin alters u 13c6 glucose incorporation into glycolytic intermediates and increases tca cycling by normalizing the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase in a chronic epilepsy mouse model
Journal of Cerebral Blood Flow and Metabolism, 2020Co-Authors: Tanya S Mcdonald, Mark P Hodson, Ilya Bederman, Michelle Puchowicz, Karin BorgesAbstract:Triheptanoin is anticonvulsant in several seizure models. Here, we investigated changes in glucose metabolism by Triheptanoin interictally in the chronic stage of the pilocarpine mouse epilepsy mod...
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Triheptanoin alters [U-13C6]-glucose incorporation into glycolytic intermediates and increases TCA cycling by normalizing the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase in a chronic epilepsy mouse model.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2019Co-Authors: Tanya S Mcdonald, Mark P Hodson, Ilya Bederman, Michelle Puchowicz, Karin BorgesAbstract:Triheptanoin is anticonvulsant in several seizure models. Here, we investigated changes in glucose metabolism by Triheptanoin interictally in the chronic stage of the pilocarpine mouse epilepsy model. After injection of [U-13C6]-glucose (i.p.), enrichments of 13C in intermediates of glycolysis and the tricarboxylic acid (TCA) cycle were quantified in hippocampal extracts and maximal activities of enzymes in each pathway were measured. The enrichment of 13C glucose in plasma was similar across all groups. Despite this, we observed reductions in incorporation of 13C in several glycolytic intermediates compared to control mice suggesting glucose utilization may be impaired and/or glycogenolysis increased in the untreated interictal hippocampus. Triheptanoin prevented the interictal reductions of 13C incorporation in most glycolytic intermediates, suggesting it increased glucose utilization or - as an additional astrocytic fuel - it decreased glycogen breakdown. In the TCA cycle metabolites, the incorporation of 13C was reduced in the interictal state. Triheptanoin restored the correlation between 13C enrichments of pyruvate relative to most of the TCA cycle intermediates in "epileptic" mice. Triheptanoin also prevented the reductions of hippocampal pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase activities. Decreased glycogen breakdown and increased glucose utilization and metabolism via the TCA cycle in epileptogenic brain areas may contribute to Triheptanoin's anticonvulsant effects.
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Randomized trial of add-on Triheptanoin vs medium chain triglycerides in adults with refractory epilepsy.
Epilepsia open, 2019Co-Authors: Karin Borges, Neha Kaul, Jack Germaine, Patrick Kwan, Terence J. O'brienAbstract:Objective: To investigate the feasibility, safety, and tolerability of add-on treatment of the triglycerides of heptanoate (Triheptanoin) vs the triglycerides of octanoate and decanoate (medium chain triglycerides [MCTs]) in adults with treatment-refractory epilepsy. Methods: After an 8-week prospective baseline period, people with drug-resistant epilepsy were randomized in a double-blind fashion to receive Triheptanoin or MCTs. Treatment was titrated over 3 weeks to a maximum of 100 mL/d to be distributed over 3 meals and mixed into food, followed by 12-week maintenance before tapering. The primary aims were to assess the following: (a) safety by comparing the number of intervention-related adverse events with Triheptanoin vs MCT treatment and (b) adherence, measured as a percentage of the prescribed treatment doses taken. Results: Thirty-four people were randomized (17 to MCT and 17 to Triheptanoin). There were no differences regarding (a) the number of participants completing the study (11 vs 9 participants), (b) the time until withdrawal, (c) the total number of adverse events or those potentially related to treatment, (d) median doses of oils taken (59 vs 55 mL/d, P = 0.59), or (e) change in seizure frequency (54% vs 102%, P = 0.13). Please note that people with focal unaware seizures were underrepresented in the Triheptanoin treatment arm (P = 0.04). The most common adverse events were gastrointestinal disturbances (47% and 62.5% of participants). Five people taking on average 0.73 mL/kg body weight MCTs (0.64 mL/kg median) and one person taking 0.59 mL/kg Triheptanoin showed >50% reduction in seizure frequency, specifically focal unaware seizures. Significance: Add-on treatment with MCTs or Triheptanoin was feasible, safe, and tolerated for 12 weeks in two-thirds of people with treatment-resistant epilepsy. Our results indicate a protective effect of MCTs on focal unaware seizures. This warrants further study.
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Heptanoate is neuroprotective in vitro but Triheptanoin post-treatment did not protect against middle cerebral artery occlusion in rats.
Neuroscience letters, 2018Co-Authors: Kah Ni Tan, Karin Borges, Catalina Carrasco-pozo, Rebecca J. Hood, Kirby Warren, Debbie Pepperall, Silvia Manzanero, Neil J. SprattAbstract:Triheptanoin, the medium-chain triglyceride of heptanoate, has been shown to be anticonvulsant and neuroprotective in several neurological disorders. In the gastrointestinal tract, Triheptanoin is cleaved to heptanoate, which is then taken up by the blood and most tissues, including liver, heart and brain. Here we evaluated the neuroprotective effects of heptanoate and its effects on mitochondrial oxygen consumption in vitro. We also investigated the neuroprotective effects of Triheptanoin compared to long-chain triglycerides when administered after stroke onset in rats. Heptanoate pre-treatment protected cultured neurons against cell death induced by oxygen glucose deprivation and N-methyl-D-aspartate. Incubation of cultured astrocytes with heptanoate for 2 h increased mitochondrial proton leak and also enhanced basal respiration and ATP turnover, suggesting that heptanoate protects against oxidative stress and is used as fuel. However, continuous 72 h infusion of Triheptanoin initiated 1 h after middle cerebral artery occlusion in rats did not alter stroke volume at 3 days or neurological deficit at 1 and 3 days relative to long-chain triglyceride control treatment.
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Triheptanoin protects against status epilepticus induced hippocampal mitochondrial dysfunctions, oxidative stress and neuronal degeneration
Journal of neurochemistry, 2018Co-Authors: Kah Ni Tan, David G. Simmons, Catalina Carrasco-pozo, Karin BorgesAbstract:Triheptanoin, the triglyceride of heptanoate, is anaplerotic (refills deficient tricarboxylic acid cycle intermediates) via the propionyl-CoA carboxylase (PCC) pathway. It has been shown to be neuroprotective and anticonvulsant in several models of neurological disorders. Here, we investigated the effects of Triheptanoin against changes of hippocampal mitochondrial functions, oxidative stress and cell death induced by pilocarpine-induced status epilepticus (SE) in mice. Ten days of Triheptanoin pre-treatment did not protect against SE, but it preserved hippocampal mitochondrial functions including state 2, state 3 ADP, state 3 uncoupled respiration, respiration linked to ATP synthesis along with the activities of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex 24 h post-SE. Triheptanoin prevented the SE-induced reductions of hippocampal mitochondrial superoxide dismutase activity and plasma antioxidant status as well as lipid peroxidation. It also reduced neuronal degeneration in hippocampal CA1 and CA3 regions three days after SE. In addition, heptanoate significantly reduced hydrogen peroxide-induced cell death in cultured neurons. In situ hybridization localized the enzymes of the PCC pathway, specifically Pccα, Pccβ and methylmalonyl-CoA mutase to adult mouse hippocampal pyramidal neurons and dentate granule cells, indicating that anaplerosis may occur in neurons. In conclusion, Triheptanoin appears to have anaplerotic and antioxidant effects which contribute to its neuroprotective properties. This article is protected by copyright. All rights reserved.
Fanny Mochel - One of the best experts on this subject based on the ideXlab platform.
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Triheptanoin for the treatment of brain energy deficit: A 14-year experience
Journal of Neuroscience Research, 2017Co-Authors: Fanny MochelAbstract:Triheptanoin is an odd-chain triglyceride with anaplerotic properties—that is, replenishing the pool of metabolic intermediates in the Krebs cycle. Unlike even-chain fatty acids metabolized to acetyl-CoA only, Triheptanoin can indeed provide both acetyl-CoA and propionyl-CoA, two key carbon sources for the Krebs cycle. Triheptanoin was initially used in patients with long-chain fatty acid oxidation disorders. The first demonstration of the possible benefit of Triheptanoin for brain energy deficit came from a patient with pyruvate carboxylase deficiency, a severe metabolic disease that affects anaplerosis in the brain. In an open-label study, Triheptanoin was then shown to decrease nonepileptic paroxysmal manifestations by 90% in patients with glucose transporter 1 deficiency syndrome, a disease that affects glucose transport into the brain. 31 P magnetic resonance spectroscopy studies also indicated that Triheptanoin was able to correct bioen-ergetics in the brain of patients with Huntington disease, a neurodegenerative disease associated with brain energy deficit. Altogether, these studies indicate that tri-heptanoin can be a treatment for brain energy deficit related to altered anaplerosis and/or glucose metabolism .
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Triheptanoin for the treatment of brain energy deficit: A 14‐year experience
Journal of neuroscience research, 2017Co-Authors: Fanny MochelAbstract:Triheptanoin is an odd-chain triglyceride with anaplerotic properties-that is, replenishing the pool of metabolic intermediates in the Krebs cycle. Unlike even-chain fatty acids metabolized to acetyl-CoA only, Triheptanoin can indeed provide both acetyl-CoA and propionyl-CoA, two key carbon sources for the Krebs cycle. Triheptanoin was initially used in patients with long-chain fatty acid oxidation disorders. The first demonstration of the possible benefit of Triheptanoin for brain energy deficit came from a patient with pyruvate carboxylase deficiency, a severe metabolic disease that affects anaplerosis in the brain. In an open-label study, Triheptanoin was then shown to decrease nonepileptic paroxysmal manifestations by 90% in patients with glucose transporter 1 deficiency syndrome, a disease that affects glucose transport into the brain. 31 P magnetic resonance spectroscopy studies also indicated that Triheptanoin was able to correct bioenergetics in the brain of patients with Huntington disease, a neurodegenerative disease associated with brain energy deficit. Altogether, these studies indicate that Triheptanoin can be a treatment for brain energy deficit related to altered anaplerosis and/or glucose metabolism. © 2017 Wiley Periodicals, Inc.
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Triheptanoin for the treatment of brain energy deficit a 14 year experience
Journal of Neuroscience Research, 2017Co-Authors: Fanny MochelAbstract:Triheptanoin is an odd-chain triglyceride with anaplerotic properties-that is, replenishing the pool of metabolic intermediates in the Krebs cycle. Unlike even-chain fatty acids metabolized to acetyl-CoA only, Triheptanoin can indeed provide both acetyl-CoA and propionyl-CoA, two key carbon sources for the Krebs cycle. Triheptanoin was initially used in patients with long-chain fatty acid oxidation disorders. The first demonstration of the possible benefit of Triheptanoin for brain energy deficit came from a patient with pyruvate carboxylase deficiency, a severe metabolic disease that affects anaplerosis in the brain. In an open-label study, Triheptanoin was then shown to decrease nonepileptic paroxysmal manifestations by 90% in patients with glucose transporter 1 deficiency syndrome, a disease that affects glucose transport into the brain. 31 P magnetic resonance spectroscopy studies also indicated that Triheptanoin was able to correct bioenergetics in the brain of patients with Huntington disease, a neurodegenerative disease associated with brain energy deficit. Altogether, these studies indicate that Triheptanoin can be a treatment for brain energy deficit related to altered anaplerosis and/or glucose metabolism. © 2017 Wiley Periodicals, Inc.
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Triheptanoin dramatically reduces paroxysmal motor disorder in patients with glut1 deficiency
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Fanny Mochel, Elodie Hainque, Samantha Caillet, Domitille Gras, Isaac M. Adanyeguh, Romain Valabregue, Bénédicte Héron, Agathe Roubertie, Elsa Kaphan, Daisy RinaldiAbstract:Objective On the basis of our previous work with Triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional 31 P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with Triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when Triheptanoin was withdrawn. Conclusions Treatment with Triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. Trial registration number NCT02014883.
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Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Fanny Mochel, Elodie Hainque, Samantha Caillet, Isaac Adanyeguh, Domitille Gras, Romain Valabregue, Bénédicte Héron, Agathe Roubertie, Elsa Kaphan, Daisy RinaldiAbstract:Objective On the basis of our previous work with Triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional 31P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with Triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when Triheptanoin was withdrawn. Conclusions Treatment with Triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.
Elodie Hainque - One of the best experts on this subject based on the ideXlab platform.
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Transition from ketogenic diet to Triheptanoin in patients with GLUT1 deficiency syndrome
Journal of neurology neurosurgery and psychiatry, 2019Co-Authors: Elodie Hainque, Marie-pierre Luton, Chris Ottolenghi, Mariana Atencio, Aurélie Méneret, Domitille Gras, Magali Barbier, Anne De Saint Martin, Thierry Billette De Villemeur, Emmanuel RozeAbstract:Glucose transporter type 1 deficiency syndrome (GLUT1-DS) causes cerebral energy deficiency due to altered transport of glucose across the blood brain barrier and into astrocytes.1 Its main phenotype combines developmental delay, permanent motor dysfunction and paroxysmal neurological manifestations.1 In addition, GLUT1-DS may solely consist of paroxysmal manifestations such as seizures or exercise-induced paroxysmal dyskinesia. Ketogenic diet is the primary treatment of GLUT1-DS with clear efficacy on seizures and non-epileptic motor manifestations,1 but it has severe constraints. Ketogenic diet failure has been occasionally reported due to poor tolerance, inefficacy or failure to achieve ketosis,2 emphasising the need for alternative therapeutic options. Triheptanoin is a triglyceride containing three 7-carbon fatty acids, which provides acetyl-coenzyme A (CoA) and propionyl-CoA, two key carbon sources for the Krebs cycle.3 Treatment with Triheptanoin resulted in a dramatic and sustained reduction of non-epileptic paroxysmal events in a group of GLUT1-DS patients who were not on ketogenic diet.4 5 Here, we evaluated the long-term effect of Triheptanoin in four GLUT1-DS patients with persistent paroxysmal manifestations while on ketogenic diet. We enrolled four GLUT1-DS patients (table 1) who reported persistent paroxysmal events while on ketogenic diet (trial registration number NCT02014883). Three adults and one child’s legal guardian signed a written informed consent for participation in this study sponsored by INSERM. View this table: Table 1 Baseline characteristics of GLUT1-DS patients and changes in outcome variables The study was divided into baseline, transition from ketogenic diet to Triheptanoin (transition), short-term evolution (short term) and long-term follow-up (long term) with Triheptanoin. A flow …
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Long-term follow-up in an open-label trial of Triheptanoin in GLUT1 deficiency syndrome: a sustained dramatic effect
Journal of neurology neurosurgery and psychiatry, 2019Co-Authors: Elodie Hainque, Marie-pierre Luton, Chris Ottolenghi, Mariana Atencio, Aurélie Méneret, Domitille Gras, Magali Barbier, Mohamed Doulazmi, Florence Habarou, Emmanuel RozeAbstract:Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by heterozygous mutations in the SLC2A1 gene. Glucose transport is impaired across the blood–brain barrier and into astrocytes. This eventually results in cerebral energy deficiency.1 Typically, GLUT1-DS is associated with developmental delay, permanent motor disorders and paroxysmal manifestations including epileptic and non-epileptic paroxysmal episodes.1 2 The phenotypic spectrum is however much wider: exercise-induced paroxysmal dyskinesia may sometimes be the main or sole manifestation of the disease.3 4 Ketogenic diet is the standard of care in GLUT1-DS,1 5 providing ketone bodies as an alternate source of energy to the brain. Other alternative treatments are needed as many patients have difficulties following the heavy constraints of this diet. Triheptanoin (UX007; Ultragenyx Pharmaceuticals, Novato, USA) is a medium odd-chain triglyceride containing three 7-carbon fatty acids with anaplerotic properties.6–8 Unlike even-chain fatty acids that can only generate acetyl-CoA, Triheptanoin provides indeed both acetyl-CoA and propionyl-CoA, two key carbon sources for the Krebs cycle.9 10 We recently showed that Triheptanoin dramatically reduced by 90% the number of non-epileptic paroxysmal manifestations over 2 months in GLUT1-DS and improved patient’s brain energy profile.9 Here, we wished to evaluate the long-term clinical efficacy of Triheptanoin in children and adults with GLUT1-DS. We extended our study protocol (NCT02014883) based on the striking short-term response with Triheptanoin.9 All participants and/or their legal guardians signed a new informed consent. Among the six patients previously reported who completed the initial …
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A randomized, controlled, double-blind, crossover trial of Triheptanoin in alternating hemiplegia of childhood.
Orphanet journal of rare diseases, 2017Co-Authors: Elodie Hainque, Samantha Caillet, Sandrine Leroy, C. Flamand-roze, Isaac Adanyeguh, Fanny Charbonnier-beaupel, Maryvonne Retail, Benjamin Le Toullec, Mariana Atencio, Sophie Rivaud-péchouxAbstract:Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of Triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. We conducted a randomized, double-blind, placebo-controlled crossover study of Triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. In an intention-to-treat analysis, Triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between Triheptanoin and placebo periods. Triheptanoin was well tolerated. Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.
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A randomized, controlled, double-blind, crossover trial of Triheptanoin in alternating hemiplegia of childhood
Orphanet Journal of Rare Diseases, 2016Co-Authors: Elodie Hainque, Samantha Caillet, Sandrine Leroy, C. Flamand-roze, Isaac Adanyeguh, Fanny Charbonnier-beaupel, Maryvonne Retail, Benjamin Le Toullec, Mariana Atencio, Sophie Rivaud-péchouxAbstract:AbstractBackgroundBased on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of Triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.MethodsWe conducted a randomized, double-blind, placebo-controlled crossover study of Triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.ResultsIn an intention-to-treat analysis, Triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between Triheptanoin and placebo periods. Triheptanoin was well tolerated.ConclusionsTriheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.Trial registrationThe study has been registered with clinicaltrials.gov (NCT002408354) the 03/24/2015.
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Triheptanoin dramatically reduces paroxysmal motor disorder in patients with glut1 deficiency
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Fanny Mochel, Elodie Hainque, Samantha Caillet, Domitille Gras, Isaac M. Adanyeguh, Romain Valabregue, Bénédicte Héron, Agathe Roubertie, Elsa Kaphan, Daisy RinaldiAbstract:Objective On the basis of our previous work with Triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional 31 P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with Triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when Triheptanoin was withdrawn. Conclusions Treatment with Triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. Trial registration number NCT02014883.
Daisy Rinaldi - One of the best experts on this subject based on the ideXlab platform.
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A double-blind, placebo-controlled trial of Triheptanoin in adult polyglucosan body disease and open-label, long-term outcome
Journal of Inherited Metabolic Disease, 2018Co-Authors: Raphael Schiffmann, Mary E. Wallace, Daisy Rinaldi, Isabelle Ledoux, Marie-pierre Luton, Scott Coleman, H. Orhan Akman, Karine Martin, Jean-yves Hogrel, Derek BlankenshipAbstract:Background Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of Triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. Methods and results This was a two-site, randomized crossover trial of 23 patients (age 35–73 years; 63% men) who received Triheptanoin or vegetable oil as placebo. The trial took place over 1 year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389 ± 164 m (range 95–672; n = 19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on Triheptanoin versus placebo was 6 m; 95% confidence interval (CI) −11 to 22; p = 0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4 years. Conclusions We cannot conclude that Triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity. ClinicalTrials.gov Identifier: NCT00947960.
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A double-blind, placebo-controlled trial of Triheptanoin in adult polyglucosan body disease and open-label, long-term outcome.
Journal of Inherited Metabolic Disease, 2017Co-Authors: Raphael Schiffmann, Mary E. Wallace, Daisy Rinaldi, Isabelle Ledoux, Marie-pierre Luton, Scott Coleman, H. Orhan Akman, Karine Martin, Jean-yves Hogrel, Derek M. BlankenshipAbstract:Background Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of Triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit.
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Triheptanoin dramatically reduces paroxysmal motor disorder in patients with glut1 deficiency
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Fanny Mochel, Elodie Hainque, Samantha Caillet, Domitille Gras, Isaac M. Adanyeguh, Romain Valabregue, Bénédicte Héron, Agathe Roubertie, Elsa Kaphan, Daisy RinaldiAbstract:Objective On the basis of our previous work with Triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional 31 P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with Triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when Triheptanoin was withdrawn. Conclusions Treatment with Triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. Trial registration number NCT02014883.
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Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Fanny Mochel, Elodie Hainque, Samantha Caillet, Isaac Adanyeguh, Domitille Gras, Romain Valabregue, Bénédicte Héron, Agathe Roubertie, Elsa Kaphan, Daisy RinaldiAbstract:Objective On the basis of our previous work with Triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional 31P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with Triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when Triheptanoin was withdrawn. Conclusions Treatment with Triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.
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Triheptanoin improves brain energy metabolism in patients with Huntington disease.
Neurology, 2015Co-Authors: Isaac M. Adanyeguh, Daisy Rinaldi, Samantha Caillet, Pierre-gilles Henry, Romain Valabregue, Alexandra Durr, Fanny MochelAbstract:Objective: Based on our previous work in Huntington disease (HD) showing improved energy metabolism in muscle by providing substrates to the Krebs cycle, we wished to obtain a proof-of-concept of the therapeutic benefit of Triheptanoin using a functional biomarker of brain energy metabolism validated in HD. Methods: We performed an open-label study using 31 P brain magnetic resonance spectroscopy (MRS) to measure the levels of phosphocreatine (PCr) and inorganic phosphate (Pi) before (rest), during (activation), and after (recovery) a visual stimulus. We performed 31 P brain MRS in 10 patients at an early stage of HD and 13 controls. Patients with HD were then treated for 1 month with Triheptanoin after which they returned for follow-up including 31 P brain MRS scan. Results: At baseline, we confirmed an increase in Pi/PCr ratio during brain activation in controls—reflecting increased adenosine triphosphate synthesis—followed by a return to baseline levels during recovery ( p = 0.013). In patients with HD, we validated the existence of an abnormal brain energy profile as previously reported. After 1 month, this profile remained abnormal in patients with HD who did not receive treatment. Conversely, the MRS profile was improved in patients with HD treated with Triheptanoin for 1 month with the restoration of an increased Pi/PCr ratio during visual stimulation ( p = 0.005). Conclusion: This study suggests that Triheptanoin is able to correct the bioenergetic profile in the brain of patients with HD at an early stage of the disease. Classification of evidence: This study provides Class III evidence that, for patients with HD, treatment with Triheptanoin for 1 month restores an increased MRS Pi/PCr ratio during visual stimulation.
Charles R. Roe - One of the best experts on this subject based on the ideXlab platform.
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Anaplerotic treatment of long-chain fat oxidation disorders with Triheptanoin: Review of 15 years Experience
Molecular genetics and metabolism, 2015Co-Authors: Charles R. Roe, Henri BrunengraberAbstract:Abstract Background The treatment of long-chain mitochondrial β-oxidation disorders (LC-FOD) with a low fat-high carbohydrate diet, a diet rich in medium-even-chain triglycerides (MCT), or a combination of both has been associated with high morbidity and mortality for decades. The pathological tableau appears to be caused by energy deficiency resulting from reduced availability of citric acid cycle (CAC) intermediates required for optimal oxidation of acetyl-CoA. This hypothesis was investigated by diet therapy with carnitine and anaplerotic Triheptanoin (TH). Methods Fifty-two documented LC-FOD patients were studied in this investigation (age range: birth to 51 years). Safety monitoring included serial quantitative measurements of routine blood chemistries, blood levels of carnitine and acylcarnitines, and urinary organic acids. Results The average frequency of serious clinical complications were reduced from ~ 60% with conventional diet therapy to 10% with TH and carnitine treatment and mortality decreased from ~ 65% with conventional diet therapy to 3.8%. Carnitine supplementation was uncomplicated. Conclusion The energy deficiency in LC-FOD patients was corrected safely and more effectively with the Triheptanoin diet and carnitine supplement than with conventional diet therapy. Safe intervention in neonates and infants will permit earlier intervention following pre-natal diagnosis or diagnosis by expanded newborn screening.
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Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice
PloS one, 2014Co-Authors: Min Jung Park, Susan Aja, Alicia L. Degano, Judith Penati, Justin Zhuo, Charles R. Roe, Gabriele V. RonnettAbstract:Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with Triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with Triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on Triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.
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Principal component analysis shows unique metabolomic profile of mice eating Triheptanoin diet.
2014Co-Authors: Min Jung Park, Susan Aja, Alicia L. Degano, Judith Penati, Justin Zhuo, Charles R. Roe, Gabriele V. RonnettAbstract:(A) Principal component analysis (PCA) score plot of liver samples from Mecp2 KO and WT mice on Triheptanoin diet and control diets. (B) PCA score plot of skeletal muscle samples from Mecp2 KO and WT mice on Triheptanoin diet and control diets.
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Anaplerosis of hepatic TCA cycle intermediates with Triheptanoin diet.
2014Co-Authors: Min Jung Park, Susan Aja, Alicia L. Degano, Judith Penati, Justin Zhuo, Charles R. Roe, Gabriele V. RonnettAbstract:Heptanoate (C7) from Triheptanoin diet (Trihep) enters the portal circulation, and is largely metabolized by liver to betaketopentanoate (BKP), then to acetyl-CoA and propionyl-CoA. Some BKP, in equilibrium with betahydroxypentanoate (BHP), is exported to the systemic circulation. Propionyl-CoA is metabolized further to provide succinyl-CoA to the TCA cycle. This is expected to increase TCA cycle flux, replenishing oxaloacetate (OAA) so that acetyl groups from acetyl-CoA fuel can enter the TCA cycle. Bar graphs of Figure 6 show metabolomics data from liver of WT (black bars) and Mecp2 KO mice (hatched bars), on either chow, a high-soybean oil control diet (SBO), or anaplerotic Triheptanoin diet. Triheptanoin diet resulted in significantly elevated levels of free CoA. Combined with increased TCA cycle flux, this permitted increased hepatic citrate in mice on Triheptanoin diet. Data in bar graphs were normalized to the median of the WT+chow control group, median scaled to 1, but are presented as averages with standard errors. Symbols denote group differences by ANOVA contrast comparisons of log-transformed data (p≤0.05): asterisk, differs from matching chow control, dagger, differs from matching WT control; double dagger, differs from matching SBO control.
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Anaplerotic Triheptanoin diet permits efficient glycolysis in skeletal muscle.
2014Co-Authors: Min Jung Park, Susan Aja, Alicia L. Degano, Judith Penati, Justin Zhuo, Charles R. Roe, Gabriele V. RonnettAbstract:Mice fed the high-soybean oil control diet (SBO) mice had elevated muscle levels of late-glycolytic intermediates (fructose-1,6-bisphosphate, 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and pyruvate), whereas Triheptanoin-fed mice (Trihep) did not. This pattern was the same as seen for acetyl-CoA in muscle (Figure 6), suggesting a back-up of glycolysis due to inefficient entry of acetate carbons in the SBO-fed mice. The early-glycolytic metabolites (glucose and G-6-P) were decreased in Triheptanoin-fed mice, suggesting enhanced glucose uptake and metabolism in Triheptanoin-fed mice. Data in bar graphs were normalized to the median of the WT+chow control group, median scaled to 1, but are presented as averages with standard errors. Symbols denote group differences by ANOVA contrast comparisons of log-transformed data (p≤0.05): asterisk, differs from matching chow control, dagger, differs from matching WT control; double dagger, differs from matching SBO control.
