SLC6A1 – Myoclonic-Astatic Epilepsy

SLC6A1 encodes the γ-aminobutyric acid (GABA) transporter 1 (GAT-1), a sodium- and chloride-coupled transporter responsible for GABA reuptake from the synaptic cleft. Pathogenic heterozygous variants in SLC6A1 cause myoclonic-astatic epilepsy (MAE), also known as Doose syndrome, a generalized epilepsy syndrome with prominent myoclonic and atonic seizures and early childhood onset.

Genetic evidence supports an autosomal dominant inheritance mode, with most cases arising de novo. In a series of 34 subjects (24 unrelated probands) carrying SLC6A1 variants, 97% exhibited intellectual disability, and the mean age of seizure onset was 3.7 years with myoclonic-atonic and atonic seizures predominating ([PMID:29315614]). Segregation analysis identified six additional affected family members with co-segregating variants, confirming dominant transmission.

Case series and targeted gene panels further identified SLC6A1 pathogenic variants in 7 of 61 early childhood-onset generalized epilepsy patients ([PMID:31401500]) and in 2 of 85 MAE patients in a cohort of 101 ([PMID:32469098]). Reported variants are predominantly missense changes affecting transmembrane domains, such as c.491G>A (p.Cys164Tyr), which predictably alters substrate binding and transporter stability.

Functional studies consistently demonstrate that MAE-associated SLC6A1 variants impair GAT-1 trafficking to the plasma membrane and reduce GABA uptake. In vitro assays of seven epilepsy-linked variants showed significant loss of GABA transport activity ([PMID:30132828]), while knock-in mouse and Drosophila models recapitulate seizure phenotypes and spike-wave discharges, confirming pathogenicity.

No studies to date have refuted the SLC6A1–MAE association. The concordant genetic and functional data across multiple cohorts and model systems establish a strong gene-disease relationship with a loss-of-function mechanism.

Key take-home: Routine screening of SLC6A1 in children with myoclonic-atonic seizures facilitates precise diagnosis, informs prognosis, and may guide individualized therapies targeting GABAergic dysfunction.

References

• Epilepsia • 2018 • Defining the phenotypic spectrum of SLC6A1 mutations PMID:29315614
• Seizure • 2019 • Dissecting the phenotypic and genetic spectrum of early childhood-onset generalized epilepsies PMID:31401500
• Epilepsia • 2020 • Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures PMID:32469098
• Epilepsia • 2018 • SLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport PMID:30132828

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