グルコーストランスポーター１欠損症

Glucose transporter type 1 deficiency syndrome (Glut1DS) is a neurodevelopmental disorder caused by impaired cerebral glucose transport and clinically characterized by absence-type seizures, neurodevelopmental delays, movement disorders, and cognitive deficits. The consequences of chronic cerebral glucose deficiency for glial metabolism and myelin homeostasis remain poorly understood. In this study, we combined metabolic profiling, diffusion MRI, transcriptomic and lipidomic analyses to delineate the metabolic, molecular, and microstructural alterations induced by Glut1 haploinsufficiency in a Glut1+/- mouse model. Glut1+/- mice exhibited a global decrease in glucose, glycogen, and lactate levels across multiple brain regions, consistent with impaired glucose uptake and astrocytic energy metabolism. In addition to widespread metabolic deficits, diffusion MRI revealed selective microstructural abnormalities confined to the dorsolateral striatum, a critical hub for locomotor control. These changes were characterized by increased mean diffusivity and reduced mean kurtosis, indicative of reduced tissue microstructural complexity. Striatal transcriptomic profiling revealed a reactive astrocytic signature along with coordinated downregulation of genes involved in oligodendrocyte function, myelination, and galactolipid biosynthesis. Lipidomic analysis further identified selective reductions in myelin-enriched lipid classes, including hexosylceramides and ethanolamine plasmalogens, consistent with alterations in lipid pathways relevant to myelin organization and stability. Importantly, chronic L-lactate supplementation initiated during early postnatal development partially rescued motor deficits in young adult Glut1+/- mice. Collectively, these findings support a model in which chronic glucose transport deficiency is associated with alterations in glial metabolic homeostasis and myelin-related pathways, while highlighting lactate supplementation as a potential therapeutic strategy in Glut1DS.

Background/Objectives: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare neurometabolic disorder caused by pathogenic variants in the SLC2A1 and a treatable cause of epilepsy and movement disorders. We aimed to describe clinical variability, diagnostic pathways and treatment outcomes in a paediatric case series, with a focus on ketogenic diet management. Methods: We retrospectively reviewed five paediatric patients with genetically confirmed glucose transporter type 1 deficiency syndrome followed at a tertiary center. Clinical presentation, biochemical findings, genetic results, treatment, dietary adherence and outcomes were analyzed. Results: Patients presented with development delay (4/5), movement disorders (4/5) and seizures (2/5), with symptom onset between 4 and 14 months. Diagnosis occurred between 22 and 54 months. Pathogenic SLC2A1 variants were identified in all patients, de novo in three cases. Hypoglycorrhachia was documented in two patients. All patients were treated with a classical ketogenic diet (ratio 1:1 to 3:1). Clinical improvement was observed in four patients, including better seizure control and motor function, although ketone levels were frequently suboptimal. Treatment duration ranged from two to 17 years. Long-term adherence and dietary implementation represented major challenges. Conclusions: Glucose transporter type 1 deficiency syndrome shows marked clinical heterogeneity, which may delay diagnosis. The ketogenic diet is effective in improving seizure control and neurological outcomes, although long-term adherence remains a major challenge. This case series highlights practical difficulties in diagnosis and dietary management in real-world clinical settings.

Glucose transporter deficiency syndrome type 1 (Glut1-DS) is a rare neurometabolic disorder caused by pathogenic variants in SLC2A1, characterized by epilepsy, neurodevelopmental delay, movement disorders, dysarthria, intellectual disability, and postnatal microcephaly. We aimed to characterize the natural history of a Brazilian cohort of patients with Glut1-DS. Brazilian patients of all ages were included if they presented with clinical features consistent with Glut1-DS and carried a pathogenic or likely pathogenic SLC2A1 variant. Forty patients were included (21 males; median age 9.1 years [IQR: 6.0-12.9]; median age at diagnosis 5.0 years [IQR: 3.0-9.9]), of whom 32 had the classical phenotype. The most frequent manifestations at inclusion were seizures (37/40), speech delay (34/40), and movement disorders (29/35). Thirty-four patients (85%) were receiving ketogenic dietary therapy (27 classical ketogenic diet and 7 modified Atkins diet). Cerebrospinal fluid analysis was performed in 10 patients (27.5%), all of whom had hypoglycorrhachia. Genetic testing identified 31 distinct SLC2A1 variants, including 15 novel variants. Intrafamilial phenotypic variability was observed in one of four families with recurrent disease, and reduced penetrance was identified in one affected parent. Missense variants were generally associated with milder phenotypes than truncating variants. These findings expand the phenotypic and genotypic spectrum of Glut1-DS, highlight the high proportion of previously unreported SLC2A1 variants in the Brazilian population, and reinforce the importance of comprehensive genetic evaluation and counseling for affected families.

Glucose transporter type 1 deficiency syndrome is a metabolic encephalopathy caused by impaired glucose transport across the blood-brain barrier, and ketogenic diet therapy is the first-line treatment. The patient was a 21-year-old woman. In childhood, she developed postexercise hemiparesis and decreased activity during the fasting period. Cerebrospinal fluid testing revealed low glucose levels. Subsequent genetic testing identified a pathogenic SLC2A1 variant, leading to the diagnosis. Her symptoms improved with ketogenic diet therapy. After discontinuation at 18 years of age, she remained stable. However, fasting-related fatigue recurred at the age of 20 years. At 21 years of age, she developed brief (~20 ‍s) episodes of impaired awareness with decreased muscle tone. The EEG showed 3-4 Hz generalized spike-and-wave complex. Ketogenic diet therapy was reintroduced with a ketogenic ratio of 1.5:1, leading to reduced EEG abnormalities and symptomatic improvement. Although symptoms usually lessen in adulthood, the reintroduction of ketogenic diet therapy should be considered when symptoms relapse after adolescence.

Background/Objectives: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare neurometabolic disorder with an expanding clinical spectrum, including mild and non-classical presentations. We report a boy with severe transient neonatal hyperkalemia, bilateral congenital cataracts, and later subtle neurological and neurocognitive symptoms, in whom genomic testing supported the diagnosis of mild GLUT1DS. Methods: This single-patient case report describes clinical follow-up from birth to nine years of age, including neurological, metabolic, neuropsychological, imaging, and genetic investigations. Whole-exome sequencing using next-generation sequencing technology was performed. Results: The patient required intensive care immediately after birth because of severe transient hyperkalemia of unclear etiology. Bilateral congenital cataracts were surgically corrected during infancy. Later, he developed two brief seizure episodes, reduced exercise tolerance, episodic fatigue, attentional difficulties, motor restlessness, and mild graphomotor impairment. Neuropsychological assessment showed overall average intellectual functioning, below-average verbal abilities, low-average non-verbal abilities, and attention-deficit/hyperactivity disorder. Repeated metabolic investigations, electroencephalography, and brain magnetic resonance imaging were unrevealing. Whole-exome sequencing identified an apparently de novo heterozygous SLC2A1 variant, NM_006516.4.1333_1335del, p.(Phe445del), supporting the diagnosis of mild GLUT1DS. Because of the mild phenotype and preserved everyday functioning, ketogenic diet therapy was not initiated. Conclusions: This case highlights the diagnostic challenges of mild GLUT1DS and the value of genomic testing in children with unexplained neurological or neurocognitive symptoms despite normal routine investigations. Although neonatal hyperkalemia and GLUT1DS coexisted in this patient, current evidence is insufficient to establish a causal relationship.