Clinical and genetic analysis of children with glucose transporter type 1 deficiency syndrome.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare metabolic encephalopathy with a wide variety of clinical phenotypes. In the present study, 15 patients diagnosed with GLUT1-DS were selected, all of whom had obvious clinical manifestations and complete genetic testing. Their clinical data and genetic reports were collated. All patients were provided with a ketogenic diet (KD) and an improvement in their symptoms was observed during a follow-up period of up to 1 year. The results revealed that the 15 cases had clinical symptoms, such as convulsions or dyskinesia. Although none had a cerebrospinal fluid/glucose ratio <0.4, the genetic report revealed that all had the solute carrier family 2 member 1 gene variant, and their clinical symptoms basically improved following the use of the KD. GLUT1-DS is a genetic metabolic disease that causes a series of neurological symptoms due to glucose metabolism disorders in the brain. Low glucose levels in cerebrospinal fluid and genetic testing are key diagnostic criteria, and the KD is a highly effective treatment option. By summarizing and analyzing patients with GLUT1-DS, summarizing clinical characteristics and expanding their gene profile, the findings of the present study may be of clinical significance for the early recognition and diagnosis of the disease, so as to conduct early treatment and shorten the duration of brain energy deficiency. This is of utmost importance for improving the prognosis and quality of life of affected children.

Triheptanoin Did Not Show Benefit versus Placebo for the Treatment of Paroxysmal Movement Disorders in Glut1 Deficiency Syndrome: Results of a Randomized Phase 3 Study.

BACKGROUND: Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets. OBJECTIVES: The objective was to evaluate the effectiveness and safety of triheptanoin in reducing the frequency of disabling movement disorders in patients with Glut1DS not receiving a ketogenic diet. METHODS: UX007G-CL301 was a randomized, double-blind, placebo-controlled, phase 3 crossover study. After a 6-week run-in, eligible patients were randomized 1:1 to the first sequence (triheptanoin/placebo or placebo/triheptanoin) titration plus maintenance, followed by washout and the opposite sequence titration plus maintenance. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Open-label triheptanoin was administered in the extension. The frequency of disabling paroxysmal movement disorder events per 4 weeks (recorded by diary during maintenance; primary endpoint) was assessed by Wilcoxon rank-sum test. RESULTS: Forty-three patients (children, n = 16; adults, n = 27) were randomized and treated. There was no difference between triheptanoin and placebo in the mean (interquartile range) number of disabling paroxysmal movement disorder events (14.3 [4.7-38.3] vs. 11.8; [3.2-28.7]; Hodges-Lehmann estimated median difference: 1.46; 95% confidence interval, -1.12 to 4.36; P = 0.2684). Treatment-emergent adverse events were mild/moderate in severity and included diarrhea, vomiting, upper abdominal pain, headache, and nausea. Two patients discontinued the study because of non-serious adverse events that were predominantly gastrointestinal. The study was closed early during the open-label extension because of lack of effectiveness. Seven patients continued to receive triheptanoin compassionately. CONCLUSION: There were no significant differences between the triheptanoin and placebo groups in the frequency of disabling movement disorder events during the double-blind maintenance period. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ketogenic diet therapy for glucose transporter type 1 deficiency syndrome with food allergies: a case report / 中华临床营养杂志

The development of genetic testing technology has allowed the increasing diagnosis of inherited metabolic diseases. The principle of treatment of inherited metabolic diseases is to limit the intake of the substrates of a reaction that is impaired, reduce the accumulation of harmful metabolites, and replenish insufficient metabolites. Common inherited metabolic diseases include amino acid and peptide metabolism disorders, lipid and lipoprotein metabolism disorders, fatty acid and ketone metabolism disorders, carbohydrate metabolism disorders, and other metabolic disorders. Therefore, fine modification on the ratios of nutrients is required in the clinical nutrition treatment for such diseases. The commonly used approach is diet intervention. Here we report a case of a child with glucose transporter type 1 deficiency syndrome, who received the whole course nutritional management with dietary nutrient ratio modification, and discuss the role of ketogenic diet in this disease and its implementation. We aim to explore the significance of individualized dietary therapy in improving the prognosis and quality of life in children with inherited metabolic diseases.

Ketogenic dietary therapies for epilepsy: Experience in 160 patients over 18 years.

AIM: Ketogenic dietary therapies (KDT) produce anticonvulsant and neuroprotective effects, reduce seizures and improve the cognitive state in patients with epilepsy. Our purpose was to evaluate the effects of KDT in children with refractory epilepsy (effectiveness, side effects, impact on nutritional status and growth). METHODS: A retrospective and prospective observational descriptive study was conducted in a Spanish tertiary hospital (January 2000 to December 2018). One hundred sixty pediatric patients with epilepsy were treated with KDT (82 males; mean age 5 years 9 months). Seizures, anti-epileptic drugs, anthropometric measures, side effects, and laboratory assessment were monitored baseline and at 3, 6, 12 and 24 months after the onset of KDT. RESULTS: In these time intervals, the seizure-free patients were: 13.7, 12.5, 14.4 and 10.6%, respectively, and a reduction of seizures ≥ 50% was achieved in 41.9, 37.5, 28.7 and 16.2%. Side effects were frequent, especially digestive disorders, hypercalciuria, hypoglycemia, hepatic dysfunction and dyslipidemia. Prealbumin, retinol binding protein, vitamin A and magnesium decreased significantly. Height was affected, especially in children below 2 years. CONCLUSIONS: KDT are effective for refractory epilepsy in children. However, adverse effects are frequent, and it may affect nutritional status and growth.

Terapias dietéticas cetogénicas en epilepsia: experiencia en 160 pacientes durante 18 años / Ketogenic dietary therapies for epilepsy: Experience in 160 patients over 18 years

Introducción: Las terapias dietéticas cetogénicas (TDC) tienen efecto neuroprotector y anticonvulsivante, reducen las crisis epilépticas y mejoran el estado cognitivo en pacientes epilépticos. Nuestro propósito fue evaluar los efectos de las TDC en niños con epilepsia refractaria (eficacia, efectos secundarios, impacto en el estado nutricional y crecimiento).Métodos: Se realizó un estudio observacional descriptivo retrospectivo y prospectivo en un hospital terciario español (enero de 2000-diciembre de 2018). Ciento sesenta pacientes pediátricos con epilepsia fueron tratados con TDC (82 varones; edad media 5 años 9 meses). Las convulsiones, los fármacos antiepilépticos, la antropometría, los efectos secundarios y los parámetros analíticos se controlaron al inicio del tratamiento y a los 3, 6, 12 y 24 meses.Resultados: En estos intervalos los pacientes libres de crisis fueron: 13,7%, 12,5%, 14,4% y 10,6%, respectivamente, lográndose una reducción de las convulsiones≥50% en el 41,9%, 37,5%, 28,7% y 16,2%. Los efectos secundarios fueron frecuentes, especialmente trastornos digestivos, hipercalciuria, hipoglucemia, disfunción hepática y dislipidemia. La prealbúmina, la proteína de unión al retinol, la vitamina A y el magnesio disminuyeron significativamente. La talla se vio afectada, especialmente en niños menores de 2 años.Conclusiones: Las TDC son efectivas para la epilepsia refractaria infantil. Sin embargo, los efectos adversos son frecuentes y pueden afectar al estado nutricional y al crecimiento. (AU)

Aim: Ketogenic dietary therapies (KDT) produce anticonvulsant and neuroprotective effects, reduce seizures and improve the cognitive state in patients with epilepsy. Our purpose was to evaluate the effects of KDT in children with refractory epilepsy (effectiveness, side effects, impact on nutritional status and growth).Methods: A retrospective and prospective observational descriptive study was conducted in a Spanish tertiary hospital (January 2000 to December 2018). One hundred sixty pediatric patients with epilepsy were treated with KDT (82 males; mean age 5 years 9 months). Seizures, anti-epileptic drugs, anthropometric measures, side effects, and laboratory assessment were monitored baseline and at 3, 6, 12 and 24 months after the onset of KDT.Results: In these time intervals, the seizure-free patients were: 13.7, 12.5, 14.4 and 10.6%, respectively, and a reduction of seizures≥50% was achieved in 41.9, 37.5, 28.7 and 16.2%. Side effects were frequent, especially digestive disorders, hypercalciuria, hypoglycemia, hepatic dysfunction and dyslipidemia. Prealbumin, retinol binding protein, vitamin A and magnesium decreased significantly. Height was affected, especially in children below 2 years.Conclusions: KDT are effective for refractory epilepsy in children. However, adverse effects are frequent, and it may affect nutritional status and growth.(AU)

Diagnostic and Clinical Manifestation Differences of Glucose Transporter Type 1 Deficiency Syndrome in a Family with SLC2A1 Gene Mutation.

Glucose transporter type 1 deficiency syndrome is a rare genetic disease that manifests neurological symptoms such as mental impairment or movement disorders, mostly seen in pediatric patients. Here, we highlight the main symptoms, diagnostic difficulties, and genetic correlations of this disease based on different clinical presentations between the members of a family carrying the same mutation. In this report, we studied siblings-a 5-year-old girl and a 6-year-old boy-who were admitted to a pediatric ward with various neurological symptoms. Different diagnostic procedures such as lumbar puncture, electroencephalography, and MRI of the brain were performed on these patients. Whole genome sequencing identified mutations in the SLC2A1 and GLUT1-DS genes, following which a ketogenic diet was implemented. This diet modification resulted in a good clinical response. Our case report reveals patients with the same genetic mutations having distinctive clinical manifestations.

[Ketogenic dietary therapies for epilepsy: Experience in 160 patients over 18 years]. / Terapias dietéticas cetogénicas en epilepsia: experiencia en 160 pacientes durante 18 años.

AIM: Ketogenic dietary therapies (KDT) produce anticonvulsant and neuroprotective effects, reduce seizures and improve the cognitive state in patients with epilepsy. Our purpose was to evaluate the effects of KDT in children with refractory epilepsy (effectiveness, side effects, impact on nutritional status and growth). METHODS: A retrospective and prospective observational descriptive study was conducted in a Spanish tertiary hospital (January 2000 to December 2018). One hundred sixty pediatric patients with epilepsy were treated with KDT (82 males; mean age 5 years 9 months). Seizures, anti-epileptic drugs, anthropometric measures, side effects, and laboratory assessment were monitored baseline and at 3, 6, 12 and 24 months after the onset of KDT. RESULTS: In these time intervals, the seizure-free patients were: 13.7, 12.5, 14.4 and 10.6%, respectively, and a reduction of seizures≥50% was achieved in 41.9, 37.5, 28.7 and 16.2%. Side effects were frequent, especially digestive disorders, hypercalciuria, hypoglycemia, hepatic dysfunction and dyslipidemia. Prealbumin, retinol binding protein, vitamin A and magnesium decreased significantly. Height was affected, especially in children below 2 years. CONCLUSIONS: KDT are effective for refractory epilepsy in children. However, adverse effects are frequent, and it may affect nutritional status and growth.

NGS-Based Diagnosis of Treatable Neurogenetic Disorders in Adults: Opportunities and Challenges.

The identification of neurological disorders by next-generation sequencing (NGS)-based gene panels has helped clinicians understand the underlying physiopathology, resulting in personalized treatment for some rare diseases. While the phenotype of distinct neurogenetic disorders is generally well-known in childhood, in adulthood, the phenotype can be unspecific and make the standard diagnostic approach more complex. Here we present three unrelated adults with various neurological manifestations who were successfully diagnosed using NGS, allowing for the initiation of potentially life-changing treatments. A 63-year-old woman with progressive cognitive decline, pyramidal signs, and bilateral cataract was treated by chenodeoxycholic acid following the diagnosis of cerebrotendinous xanthomatosis due to a homozygous variant in CYP27A1. A 32-year-old man with adult-onset spastic paraplegia, in whom a variant in ABCD1 confirmed an X-linked adrenoleukodystrophy, was treated with corticoids for adrenal insufficiency. The third patient, a 28-year-old woman with early-onset developmental delay, epilepsy, and movement disorders was treated with a ketogenic diet following the identification of a variant in SLC2A1, confirming a glucose transporter type 1 deficiency syndrome. This case study illustrates the challenges in the timely diagnosis of medically actionable neurogenetic conditions, but also the considerable potential for improving patient health through modern sequencing technologies.

Use of Remote Monitoring by E-mail for Long-Term Management of the Classic Ketogenic Diet.

The classic ketogenic diet (cKD) requires constant nutritional monitoring over time both to ensure its effectiveness and to reduce the likelihood of short- and long-term adverse effects. We retrospectively described the use of remote monitoring by e-mail during the first year of follow-up on cKD in 34 children (47% males; age range: 2-17 years) diagnosed with drug-resistant epilepsy (DRE; n = 14) or glucose transporter type 1 deficiency syndrome (GLUT1-DS; n = 20). All the e-mails were evaluated analyzing their frequency and content at 3, 6 and 12 months. Three families never sent e-mails. A median of 36.0 (IQR 23.0-64.0) e-mails per family were sent during the 12 follow-up months by the 31 patients. GLUT1-DS patients sent a greater number of e-mails than the DRE group (median 39.0 (IQR 25.5-56.5) vs. median 26.0 (IQR 19.0-65.0)). At the end of the follow-up period, a greater number of e-mails had been exchanged between the nutritional team and the families belonging to the group that increased its linear growth (median 83.5; IQR 48.0-102.0), compared to the other ones. Constant remote monitoring by e-mail could be a feasible and effective way for a better cKD management.

Glucose transporter type 1 deficiency syndrome associated with autoantibodies to glutamate receptors.

BACKGROUND: The clinical spectrum of glucose transporter type 1 deficiency syndrome (GLUT1DS) has broadened, with increasing recognition of a milder phenotype. Antibodies targeting the subunits of glutamate receptors (GluRs), including GluN1, GluN2B, and GluD2, have been detected in various neurological disorders. Anti-GluD2 antibodies in particular may be associated with cerebellar symptoms. CASE REPORT: A 3-year-5-month-old boy with normal development exhibited myoclonus refractory to antiepileptic drugs from one year ago. He developed tremor and ataxia. Cerebrospinal fluid (CSF) revealed fasting-state glucose 50 mg/dl (CSF/blood glucose ratio of 0.50). Single photon emission computed tomography with 123I-iodoamphetamine revealed hypoperfusion in the cerebellum. At age 4 years and 5 months, treatment with intravenous methylprednisolone (IVMP) relieved his symptoms and improved the cerebellar hypoperfusion. However, his symptoms reappeared at age 5 years and 1 month. Treatment with IVMP was repeated, resulting in transient disappearance of symptoms. At age 6 years and 9 months, he was diagnosed with GLUT1DS by genetic analysis, and treatment with modified Atkins diet was started with efficacy. Levels of anti-GluN1, -GluN2B, and -GluD2 antibodies in the serum and CSF were measured 4 times. All antibodies in the CSF were elevated over 2 standard deviations above controls, and the levels fluctuated along with the severity of his symptoms. The level of anti-GluD2 antibodies in CSF declined to the normal range only after starting the modified Atkins diet. CONCLUSION: Treatment with IVMP transiently improved this patient's symptoms. Levels of anti-GluR antibodies may be associated with symptom severity.

Impact of the Ketogenic Diet on Linear Growth in Children: A Single-Center Retrospective Analysis of 34 Cases.

Data on the impact of the ketogenic diet (KD) on children's growth remain controversial. Here, we retrospectively investigated the occurrence of linear growth retardation in 34 children (47% males; age range: 2-17 years) diagnosed with drug-resistant epilepsy (DRE; n = 14) or glucose transporter type 1 deficiency syndrome (GLUT1-DS; n = 20) who had been treated with the KD for 12 months. The general characteristics of children with and without growth retardation were also compared. All participants received a full-calorie, traditional KD supplemented with vitamins, minerals, and citrate. Most children (80%; 11/14 in the DRE subgroup and 16/20 in the GLUT1-DS subgroup) treated with the KD did not show growth retardation at 12 months. Although participants with and without delay of growth did not differ in terms of baseline clinical characteristics, dietary prescriptions, or supplementation patterns, marked ketosis at 12 months tended to occur more frequently in the latter group. Altogether, our results indicate that growth retardation may occur in a minority of children treated with the KD. However, further research is required to identify children at risk and to clarify how increased ketones levels may affect endocrine pathways regulating growth during KD administration.

Glut1 deficiency is a rare but treatable cause of childhood absence epilepsy with atypical features.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare genetic disorder caused by pathogenic variants in SLC2A1, resulting in impaired glucose uptake through the blood-brain barrier. Our objective is to analyze the frequency of GLUT1-DS in patients with absences with atypical features. Sequencing analysis and detection of copy number variation of the SLC2A1 gene was carried out in patients with atypical absences including: early-onset absence, intellectual disability, additional seizure types, refractory epilepsy, associated movement disorders, as well as those who have first-degree relatives with absence epilepsy or atypical EEG ictal discharges. Of the 43 patients analyzed, pathogenic variations were found in 2 (4.6%). Six atypical characteristics were found in these 2 patients. The greater the number of atypical characteristics presenting in patients with absence seizures, the more likely they have a SLC2A1 mutation. Although GLUT1-DS is an infrequent cause of absence epilepsy, recognizing this disorder is important, since initiation of a ketogenic diet can reduce the frequency of seizures, the severity of the movement disorder, and also improve the quality of life of the patients and their families.

Long-Term Effect of GPi-DBS in a Patient With Generalized Dystonia Due to GLUT1 Deficiency Syndrome.

Treatment outcomes from pallidal deep brain stimulation are highly heterogeneous reflecting the phenotypic and etiologic spectrum of dystonia. Treatment stratification to neurostimulation therapy primarily relies on the phenotypic motor presentation; however, etiology including genetic factors are increasingly recognized as modifiers of treatment outcomes. Here, we describe a 53 year-old female patient with a progressive generalized dystonia since age 25. The patient underwent deep brain stimulation of the globus pallidus internus (GPi-DBS) at age 44. Since the clinical phenotype included mobile choreo-dystonic features, we expected favorable therapeutic outcome from GPi-DBS. Although mobile dystonia components were slightly improved in the long-term outcome from GPi-DBS the overall therapeutic response 9 years from implantation was limited when comparing "stimulation off" and "stimulation on" despite of proper electrode localization and sufficient stimulation programming. In order to further understand the reason for this limited motor symptom response, we aimed to clarify the etiology of generalized dystonia in this patient. Genetic testing identified a novel heterozygous pathogenic SLC2A1 mutation as cause of glucose transporter type 1 deficiency syndrome (GLUT1-DS). This case report presents the first outcome of GPi-DBS in a patient with GLUT1-DS, and suggests that genotype relations may increasingly complement phenotype-based therapy stratification of GPi-DBS in dystonia.

Glucose Transporter Type 1 Deficiency Syndrome: Developmental Delay and Early-Onset Ataxia in a Novel Mutation of the SLC2A1 Gene.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) was first described by De Vivo in 1991, and the classic clinical manifestations include infantile epilepsy, developmental delay, and acquired microcephaly. A neurological complex disorder including elements of hypotonia, spasticity, ataxia, and dystonia can frequently be present. GLUT1-DS is an inborn error of metabolism caused by impaired glucose transport through blood-brain barrier in the majority of patients because of mutation of solute carrier family 2 (facilitated glucose transporter) member 1 gene (SLC2A1), encoding the transporter protein. We report a 6-year-old girl with GLUT1-DS, which is caused by a novel heterozygous variant c.109dupC of the SLC2A1 gene. The dominating clinical features were ataxia, epilepsy started at 4 years, acquired microcephaly, and mild intellectual disability. Treatment with ketogenic diet showed clinical improvement with the reduction of ataxia and seizure control in a 10-month follow-up period.

Glut1 deficiency syndrome: Absence epilepsy and La Soupe du Jour.

For some time, paediatric neurologists have recognised glucose transporter type 1 (GluT1) deficiency syndrome as a cause of intractable infantile seizures, microcephaly, developmental delay and hypoglycorrhachia in the presence of a normal plasma glucose. It is caused by mutations in the SLC2A1 gene, coding for GluT1, leading to a reduction in the available glucose transporter sites; it responds to the ketogenic diet. Recently, a wider spectrum of seizure syndromes have been associated with functional impairment of glucose transport caused by SLC2A1 mutations. These syndromes include 12% of early-onset absence epilepsy and 1% of genetic generalised epilepsies, where they represent a risk allele contributing to polygenic inheritance. We describe a young man with early-onset absence seizures and paroxysmal exercise-induced dyskinesia. While this syndrome is uncommon, it is recognisable and its diagnosis allows consideration of treatment with the ketogenic diet. We discuss the role of genetic testing in early-onset absence seizures and genetic generalised epilepsy.

A three-year-old boy with glucose transporter type 1 deficiency syndrome presenting with episodic ataxia.

INTRODUCTION: Glucose transporter type 1 deficiency syndrome is a metabolic encephalopathy that results from impaired glucose transport into the brain as the result of a mutation of the SLC2A1 gene. It has been recognized recently that these patients can present with a much broader clinical spectrum than previously thought. We describe a 3-year-old boy presenting with episodic ataxia. CASE REPORT: Our patient exhibited periodic abnormal eye movements, including opsoclonus, since he was 4 months of age. At 2 years of age, he experienced acute cerebellar ataxia after a vaccination. Since then, he has had periodic attacks of ataxic gait, repeated vomiting, and abnormal eye movement. He was diagnosed as having episodic ataxia type 2 because the administration of acetazolamide seemed effective. By 3 years and 10 months of age, he exhibited mild mental retardation and mild trunk ataxia. The attacks were more likely to occur when he was hungry. Molecular analysis revealed that the SLC2A1 gene had a de novo mutation of heterozygous seven nucleotide insertion within exon 7, resulting in a frameshift. He has recently begun a modified Atkins diet; the frequency of attacks has been reduced, and his psychomotor and language skills have begun to develop. DISCUSSION: Glucose transporter type 1 deficiency syndrome should be considered in the differential diagnosis in children with episodic ataxia, even if acetazolamide is effective.