SLC2A1 – GLUT1 Deficiency Syndrome

SLC2A1 is definitively associated with GLUT1 deficiency syndrome, an inborn error of brain energy metabolism. Patients typically present in infancy with drug-resistant seizures, global developmental delay, acquired microcephaly, movement disorders, and a characteristic hypoglycorrhachia. The diagnosis is confirmed by a low cerebrospinal fluid to blood glucose ratio and identification of pathogenic SLC2A1 variants. Extensive genetic, segregation, and experimental data over >30 years support a definitive ClinGen classification.

Autosomal dominant haploinsufficiency is the primary inheritance mode in GLUT1 deficiency syndrome, although rare autosomal recessive presentations have been reported. Sequencing and copy-number studies across 30 families ([PMID:28407523]) demonstrate segregation of heterozygous SLC2A1 mutations with disease, with incomplete penetrance in some pedigrees. Case series in epilepsy and movement-disorder cohorts include 504 probands in idiopathic generalized epilepsy ([PMID:23280796]) and 84 in myoclonic-astatic epilepsy ([PMID:21555602]), revealing >100 distinct pathogenic variants including missense, frameshift, splice, and large deletions ([PMID:10980529]).

Functional studies establish loss of GLUT1 transport activity as the mechanism of disease. In Xenopus oocytes and mammalian cells, classic pathogenic variants (e.g., p.Gly75Trp) reduce glucose uptake by 60–80% without affecting protein expression or membrane targeting ([PMID:16171377]). The T295M variant preferentially impairs glucose efflux while sparing influx, explaining normal erythrocyte uptake yet persistent hypoglycorrhachia ([PMID:20630673]). Structural mapping on the 3.2 Å GLUT1 crystal reveals that mutations cluster at transmembrane helices critical for alternating-access transport, corroborating functional deficits ([PMID:24847886]).

Animal and in vitro models further confirm pathogenicity: heterozygous GLUT1-deficient mice show compensatory upregulation of monocarboxylate transporters and altered brain energy metabolism, recapitulating human neurologic phenotypes ([PMID:16880609]). Glycosylation and C-terminal truncation assays define structural elements essential for high-affinity glucose binding and transport, reinforcing haploinsufficiency as the disease basis ([PMID:1761560]; [PMID:1575755]).

Some variants (e.g., T295M) exhibit normal erythrocyte 3-OMG uptake, and up to 5% of clinical GLUT1 deficiency cases lack detectable SLC2A1 mutations, underscoring the need for CSF glucose measurement and functional assays even when genetic testing is negative ([PMID:21838819]; [PMID:23483445]).

Early identification of SLC2A1 mutations in patients with unexplained infantile seizures, developmental delay, and hypoglycorrhachia enables prompt initiation of ketogenic diet or alternative metabolic therapies, significantly improving seizure control and neurodevelopmental outcome. Key Take-home: Genetic confirmation of GLUT1 deficiency facilitates targeted dietary and pharmacologic management in this treatable neurodevelopmental disorder.

References

• Neurochemical Research • 1999 • Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome. PMID:10227690
• Human Mutation • 2000 • Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. PMID:10980529
• Annals of Neurology • 2005 • Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. PMID:15622525
• Biochemistry • 2005 • Bench meets bedside: a 10-year-old girl and amino acid residue glycine 75 of the facilitative glucose transporter GLUT1. PMID:16171377
• Nature • 2014 • Crystal structure of the human glucose transporter GLUT1. PMID:24847886

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