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Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

ABSTRACT: OBJECTIVE:Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS:We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS:We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. INTERPRETATION:We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

SUBMITTER: Winawer MR

PROVIDER: S-EPMC6105543 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

Winawer Melodie R MR Griffin Nicole G NG Samanamud Jorge J Baugh Evan H EH Rathakrishnan Dinesh D Ramalingam Senthilmurugan S Zagzag David D Schevon Catherine A CA Dugan Patricia P Hegde Manu M Sheth Sameer A SA McKhann Guy M GM Doyle Werner K WK Grant Gerald A GA Porter Brenda E BE Mikati Mohamad A MA Muh Carrie R CR Malone Colin D CD Bergin Ann Marie R AMR Peters Jurriaan M JM McBrian Danielle K DK Pack Alison M AM Akman Cigdem I CI LaCoursiere Christopher M CM Keever Katherine M KM Madsen Joseph R JR Yang Edward E Lidov Hart G W HGW Shain Catherine C Allen Andrew S AS Canoll Peter D PD Crino Peter B PB Poduri Annapurna H AH Heinzen Erin L EL

Annals of neurology 20180516 6

<h4>Objective</h4>Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.<h4>Methods</h4>We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequenc ...[more]

PMID: 29679388

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Project description:ObjectiveIt remains unclear whether drug-resistant temporal lobe epilepsy (TLE) is associated with cumulative brain damage, with no expert consensus and no quantitative syntheses of the available evidence.MethodsWe conducted a systematic review and meta-analysis of MRI studies on progressive atrophy, searching PubMed and Ovid MEDLINE databases for cross-sectional and longitudinal quantitative MRI studies on drug-resistant TLE.ResultsWe screened 2,976 records and assessed eligibility of 248 full-text articles. Forty-two articles met the inclusion criteria for quantitative evaluation. We observed a predominance of cross-sectional studies, use of different clinical indices of progression, and high heterogeneity in age-control procedures. Meta-analysis of 18/1 cross-sectional/longitudinal studies on hippocampal atrophy (n = 979 patients) yielded a pooled effect size of r = -0.42 for ipsilateral atrophy related to epilepsy duration (95% confidence interval [CI] -0.51 to -0.32; p < 0.0001; I2 = 65.22%) and r = -0.35 related to seizure frequency (95% CI -0.47 to -0.22; p < 0.0001; I2 = 61.97%). Sensitivity analyses did not change the results. Narrative synthesis of 25/3 cross-sectional/longitudinal studies on whole brain atrophy (n = 1,504 patients) indicated that >80% of articles reported duration-related progression in extratemporal cortical and subcortical regions. Detailed analysis of study design features yielded low to moderate levels of evidence for progressive atrophy across studies, mainly due to dominance of cross-sectional over longitudinal investigations, use of diverse measures of seizure estimates, and absence of consistent age control procedures.ConclusionsWhile the neuroimaging literature is overall suggestive of progressive atrophy in drug-resistant TLE, published studies have employed rather weak designs to directly demonstrate it. Longitudinal multicohort studies are needed to unequivocally differentiate aging from disease progression.

Dataset Information

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

Publications

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.

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