Glucose transporter type 1 deficiency syndrome (GLUT1DS)

Glut1DS is a disorder of brain energy metabolism affecting the central nervous system. Onset is typically in infancy or early childhood, most frequently between one and six months of age, with milder phenotypes occasionally presenting in later childhood, adolescence, or adulthood. The cardinal features in infancy and early childhood are paroxysmal eye-head movement abnormalities, pharmacoresistant seizures of varying types, deceleration of head growth with acquired microcephaly, and developmental delay; complex movement disorders and intellectual disability ranging from mild to severe emerge subsequently. When the diagnosis is first established in later childhood or adulthood, the predominant findings are complex paroxysmal movement disorders, spasticity, ataxia,
dystonia, speech difficulty, and intellectual disability. Inter- and intra-individual variability is pronounced: clinical severity spans a severe infantile-onset phenotype to a milder later-onset phenotype with intermittent epilepsy, exercise-induced dyskinesias, and ataxia, and correlates with the
extent of residual Glut1 transporter function.

The estimated prevalence is 1/24,000 in Scotland. Earlier population-based estimates from Australia (1/90,000) and Scandinavia (1/83,000) are considerably lower, reflecting cohort and ascertainment differences.

Glut1DS is caused by heterozygous germline pathogenic variants in SLC2A1 (1p34.2), which encodes the glucose transporter type 1 (Glut1) protein. Glut1 exclusively facilitates glucose transport across the endothelial cells forming the blood-brain barrier and across the astrocyte plasma membrane. Loss-of-function variants reduce Glut1 transporter activity to approximately 50% in classic Glut1DS, limiting cerebral glucose supply and producing the neurologic phenotype.

Glut1DS is inherited in an autosomal dominant manner. Approximately 90% of affected individuals have a de novo pathogenic variant; the remainder have inherited the variant from an affected parent, who may have a markedly milder phenotype. The recurrence risk for offspring of an affected individual is 50%. Autosomal recessive inheritance has rarely been reported. Prenatal molecular
testing is technically possible once the familial pathogenic variant has been identified.

Hypoglycorrhachia – a reduced cerebrospinal fluid (CSF) glucose concentration with a concurrently normal blood glucose – is the single most important laboratory observation. The classic severe phenotype shows CSF glucose <40 mg/dL, a CSF-to-blood glucose ratio <0.4 (range 0.19 to 0.59), and a low or low-normal CSF lactate; milder phenotypes show CSF glucose of 41 to 52 mg/dL. The blood sample is obtained after a four-hour fast and immediately before lumbar puncture. Cerebral fluorodeoxyglucose positron emission tomography (FDG-PET) shows a distinctive pattern of diffuse cortical hypometabolism with regional hypometabolism of the cerebellum and thalamus and relatively preserved basal-ganglia metabolism, persisting from infancy into adulthood. The erythrocyte glucose uptake assay is a functional surrogate, showing on average 50% uptake in classic Glut1DS.

Main differential diagnoses include:

• Genetic (congenital) hyperinsulinism: hypoglycorrhachia with concomitantly low blood glucose (blood glucose is normal in Glut1DS); ABCC8, KCNJ11
• Developmental and epileptic encephalopathies: pharmacoresistant epilepsy with developmental delay overlapping Glut1DS, but without hypoglycorrhachia and without the carbohydrate-responsive or preprandial seizure pattern characteristic of Glut1DS; e.g. STXBP1, SCN1A, and others
• Levodopa-responsive (DOPA-responsive) dystonia: paroxysmal or diurnal movement disorder responsive to levodopa rather than to carbohydrate intake or ketogenic diet, with normal CSF glucose; GCH1, TH, SPR

• Confirming the suspected clinical diagnosis at the molecular level and providing a definitive aetiological explanation for the observed clinical features.
• Enabling specific and individualised surveillance and clinical management tailored to the molecular diagnosis; early initiation of ketogenic diet therapies, ideally in infancy, results in better seizure control and improved long-term neurologic outcome, with management decisions made by the treating physicians in consultation with the affected individual.
• Allowing predictive testing of at-risk family members once the familial pathogenic variant has been identified, supporting informed reproductive decision-making and timely clinical evaluation of relatives.

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• Klepper J, Akman C, Armeno M, Auvin S, Cervenka M, Cross HJ, et al. Glut1 deficiency syndrome (Glut1DS): state of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open. 2020;5(3):354-365. PMID: .