SV2A – Epilepsy

Multiple independent reports describe pathogenic variants in SV2A in individuals with epilepsy, often with poor response to levetiracetam. In a consanguineous family, a homozygous p.Arg383Gln variant was found in one proband and an earlier-born brother who died at 7 months, with both parents as carriers (2 probands; 1 affected sibling) ([PMID:26002053]). A separate mother–daughter pair harbored a heterozygous SV2A variant presenting with epilepsy exacerbated by levetiracetam, highlighting autosomal dominant inheritance and intrafamilial segregation (2 probands; 1 affected relative) ([PMID:31005049]). A third family exhibited a missense change c.1978>A (p.Gly660Arg) segregating with epilepsy in multiple members (≥3 probands) ([PMID:36758444]).

The inheritance pattern is predominantly autosomal dominant, although homozygous presentation confirms a recessive mechanism in rare cases. Segregation analysis across three pedigrees shows two additional affected relatives with SV2A variants contributing to familial epilepsy. Overall, seven affected individuals across three unrelated families provide compelling genetic evidence for SV2A in epilepsy.

All reported pathogenic alleles are missense substitutions affecting conserved residues within functional domains of SV2A. The spectrum currently includes p.Arg383Gln and p.Gly660Arg, with evidence of recurrence in two autosomal dominant pedigrees and one autosomal recessive kindred. No loss-of-function or truncating variants have been described to date.

Functional studies in vivo and in vitro support a loss-of-function mechanism. A knock-in rat model carrying Sv2a(L174Q) exhibits increased seizure susceptibility, facilitated kindling, and impaired GABA release due to reduced synaptotagmin-1 levels in hippocampus ([PMID:27265781]). Cellular replacement assays show that the human R383Q mutant mislocalizes to the plasma membrane, fails to rescue synaptotagmin-1 expression and trafficking, and has reduced binding to synaptotagmin-1 ([PMID:32341095]).

Mechanistically, SV2A appears to act as a phospho-dependent chaperone for synaptotagmin-1 retrieval and modulator of calcium-evoked neurotransmitter release. Disruption of these processes by missense variants leads to impaired inhibitory transmission and seizure activity, consistent across cellular and animal models.

Together, these data fulfill ClinGen criteria for a Strong gene–disease association. Genetic evidence (seven probands, segregation in two relatives) and moderate functional evidence (knock-in rat model, neuronal assays) concordantly support SV2A as a epilepsy gene. Additional case series are emerging but do not yet exceed the current evidence cap.

Key Take-home: SV2A missense variants cause autosomal dominant epilepsy via loss of SV2A–synaptotagmin-1 interactions, predicting poor response to levetiracetam and guiding genetic testing.

References

• Pediatric neurology • 2015 • Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation. PMID:26002053
• Clinical neurology and neurosurgery • 2019 • Levetiracetam-induced a new seizure type in a girl with a novel SV2A gene mutation. PMID:31005049
• Epilepsy research • 2023 • Broadening the phenotypic spectrum of the presumably epilepsy-related SV2A gene variants. PMID:36758444
• Scientific reports • 2016 • Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission. PMID:27265781
• The Journal of neuroscience • 2020 • An Epilepsy-Associated SV2A Mutation Disrupts Synaptotagmin-1 Expression and Activity-Dependent Trafficking. PMID:32341095

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