SLC2A1 – Myoclonic-Astatic Epilepsy

SLC2A1 encodes the facilitative glucose transporter GLUT1 at the blood–brain barrier, critical for neuronal energy supply. Heterozygous variants in SLC2A1 cause glucose transporter type 1 deficiency and a spectrum of epilepsies, including myoclonic-astatic epilepsy (MAE). Early diagnosis guides treatment with ketogenic diet, which bypasses defective glucose transport.

Genetic evidence for SLC2A1 in MAE includes a de novo insertion causing frameshift in a child with MAE achieving seizure freedom on ketogenic diet (1 proband) (PMID:31045803). In a cohort of 84 unrelated MAE probands, 4 carried pathogenic SLC2A1 variants (4 probands) (PMID:21555602). A broader study of early childhood-onset generalized epilepsies found SLC2A1 variants in 4 of 61 patients with MAE or related syndromes (PMID:31401500). These five unrelated probands harbor missense or frameshift alleles consistent with loss of function.

Segregation data are limited: most MAE cases with SLC2A1 variants are de novo, with no additional affected relatives reported.

Functional assays, including site-directed mutagenesis and Xenopus oocyte transport studies, demonstrate that disease-associated missense and truncating GLUT1 mutants markedly reduce glucose transport activity, consistent with haploinsufficiency (PMID:1761560).

Conflicting evidence arises from a screen of 120 MAE patients that identified no SLC2A1 mutations, suggesting that aberrations in this gene account for a minority of MAE cases (PMID:26537434).

Integration of genetic and experimental data supports a moderate association between SLC2A1 and MAE. Functional concordance and therapeutic response to ketogenic diet underscore clinical utility. Key take-home: testing SLC2A1 in MAE enables targeted dietary therapy and informs prognosis.

References

• Medicine • 2019 • Treatment of myoclonic-atonic epilepsy caused by SLC2A1 de novo mutation with ketogenic diet: A case report. PMID:31045803
• Archives of neurology • 2011 • Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. PMID:21555602
• Seizure • 2019 • Dissecting the phenotypic and genetic spectrum of early childhood-onset generalized epilepsies. PMID:31401500
• Epilepsia • 2015 • The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. PMID:26537434
• The Journal of biological chemistry • 1991 • The role of N-glycosylation of GLUT1 for glucose transport activity. PMID:1761560

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