Synaptic Vesicle Glycoprotein 2 A (SV2A) is a membrane protein of synaptic vesicles and the binding site of antiepileptic drug levetiracetam. Biallelic Arg383Gln is reported in a family with intractable epilepsy earlier. Here, we report on the second family with early onset drug resistant epilepsy. We identified homozygous Arg289Ter variant by exome sequencing that segregated with the phenotype in the family. The affected children in these two families are normal at birth and developed recurrent seizures beginning in the second month of life and developed secondary failure of growth and development. Knock out mice models earlier had replicated the human phenotype observed in these two families. These findings support that biallelic loss of function variants in SV2A result in early onset intractable epilepsy in humans.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Data available on request from the authors
Rossi R, Arjmand S, Bærentzen SL, Gjedde A, Landau AM. Synaptic vesicle glycoprotein 2A: features and functions. Front Neurosci. 2022;16:864514.
Nowack A, Yao J, Custer KL, Bajjalieh SM. SV2 regulates neurotransmitter release via multiple mechanisms. Am J Physiol Cell Physiol. 2010;299:C960–7.
Crowder KM, Gunther JM, Jones TA, Hale BD, Zhang HZ, Peterson MR, et al. Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc Natl Acad Sci USA. 1999;96:15268–73.
Serajee FJ, Huq AM. Homozygous mutation in synaptic vesicle glycoprotein 2A gene results in intractable epilepsy, involuntary movements, microcephaly, and developmental and growth retardation. Pediatr Neurol. 2015;52:642–6.e1.
Wang D, Zhou Q, Ren L, Lin Y, Gao L, Du J, et al. Levetiracetam-induced a new seizure type in a girl with a novel SV2A gene mutation. Clin Neurol Neurosurg. 2019;181:64–6.
Calame DG, Herman I, Riviello JJ. A de novo heterozygous rare variant in SV2A causes epilepsy and levetiracetam-induced drug-resistant status epilepticus. Epilepsy Behav Rep. 2021;15:100425.
Badura-Stronka M, Kuszel Ł, Wencel-Warot A, Cudnoch K, Wołyńska K, Rutkowska K, et al. Broadening the phenotypic spectrum of the presumably epilepsy-related SV2A gene variants. Epilepsy Res. 2023;190:107101.
Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA. 2004;101:9861–6.
Harper CB, Small C, Davenport EC, Low DW, Smillie KJ, Martínez-Mármol R, et al. An epilepsy-associated SV2A mutation disrupts synaptotagmin-1 expression and activity-dependent trafficking. J Neurosci. 2020;40:4586–95.
The authors declare no competing interests.
The tests were performed on a clinical basis and consent was obtained from parents for publication of photographs.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Al-Maawali, A., Al-Murshedi, F., Al-Futaisi, A. et al. Biallelic variants in the synaptic vesicle glycoprotein 2 A are associated with epileptic encephalopathy. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01493-8