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

Publication ,  Journal Article
Winawer, MR; Griffin, NG; Samanamud, J; Baugh, EH; Rathakrishnan, D; Ramalingam, S; Zagzag, D; Schevon, CA; Dugan, P; Hegde, M; Sheth, SA ...
Published in: Ann Neurol
June 2018

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.

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Published In

Ann Neurol

DOI

EISSN

1531-8249

Publication Date

June 2018

Volume

83

Issue

6

Start / End Page

1133 / 1146

Location

United States

Related Subject Headings

  • Young Adult
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinases
  • Neurons
  • Neurology & Neurosurgery
  • Neocortex
  • Mutation
  • Monosaccharide Transport Proteins
  • Malformations of Cortical Development
  • Male
 

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Winawer, M. R., Griffin, N. G., Samanamud, J., Baugh, E. H., Rathakrishnan, D., Ramalingam, S., … Heinzen, E. L. (2018). Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol, 83(6), 1133–1146. https://doi.org/10.1002/ana.25243
Winawer, Melodie R., Nicole G. Griffin, Jorge Samanamud, Evan H. Baugh, Dinesh Rathakrishnan, Senthilmurugan Ramalingam, David Zagzag, et al. “Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.Ann Neurol 83, no. 6 (June 2018): 1133–46. https://doi.org/10.1002/ana.25243.
Winawer MR, Griffin NG, Samanamud J, Baugh EH, Rathakrishnan D, Ramalingam S, et al. Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol. 2018 Jun;83(6):1133–46.
Winawer, Melodie R., et al. “Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.Ann Neurol, vol. 83, no. 6, June 2018, pp. 1133–46. Pubmed, doi:10.1002/ana.25243.
Winawer MR, Griffin NG, Samanamud J, Baugh EH, Rathakrishnan D, Ramalingam S, Zagzag D, Schevon CA, Dugan P, Hegde M, Sheth SA, McKhann GM, Doyle WK, Grant GA, Porter BE, Mikati MA, Muh CR, Malone CD, Bergin AMR, Peters JM, McBrian DK, Pack AM, Akman CI, LaCoursiere CM, Keever KM, Madsen JR, Yang E, Lidov HGW, Shain C, Allen AS, Canoll PD, Crino PB, Poduri AH, Heinzen EL. Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol. 2018 Jun;83(6):1133–1146.
Journal cover image

Published In

Ann Neurol

DOI

EISSN

1531-8249

Publication Date

June 2018

Volume

83

Issue

6

Start / End Page

1133 / 1146

Location

United States

Related Subject Headings

  • Young Adult
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinases
  • Neurons
  • Neurology & Neurosurgery
  • Neocortex
  • Mutation
  • Monosaccharide Transport Proteins
  • Malformations of Cortical Development
  • Male