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Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.

Publication ,  Journal Article
Barba, C; Blumcke, I; Winawer, MR; Hartlieb, T; Kang, H-C; Grisotto, L; Chipaux, M; Bien, CG; Heřmanovská, B; Porter, BE; Lidov, HGW; Mader, I ...
Published in: Neurology
January 31, 2023

BACKGROUND AND OBJECTIVES: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants. METHODS: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models. RESULTS: Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses. DISCUSSION: Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.

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Published In

Neurology

DOI

EISSN

1526-632X

Publication Date

January 31, 2023

Volume

100

Issue

5

Start / End Page

e528 / e542

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Seizures
  • Retrospective Studies
  • Neurology & Neurosurgery
  • Humans
  • Epilepsy
  • Electroencephalography
  • Drug Resistant Epilepsy
  • Brain
  • 3209 Neurosciences
 

Citation

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Barba, C., Blumcke, I., Winawer, M. R., Hartlieb, T., Kang, H.-C., Grisotto, L., … SLC35A2 Study Group, . (2023). Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene. Neurology, 100(5), e528–e542. https://doi.org/10.1212/WNL.0000000000201471
Barba, Carmen, Ingmar Blumcke, Melodie R. Winawer, Till Hartlieb, Hoon-Chul Kang, Laura Grisotto, Mathilde Chipaux, et al. “Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.Neurology 100, no. 5 (January 31, 2023): e528–42. https://doi.org/10.1212/WNL.0000000000201471.
Barba C, Blumcke I, Winawer MR, Hartlieb T, Kang H-C, Grisotto L, et al. Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene. Neurology. 2023 Jan 31;100(5):e528–42.
Barba, Carmen, et al. “Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.Neurology, vol. 100, no. 5, Jan. 2023, pp. e528–42. Pubmed, doi:10.1212/WNL.0000000000201471.
Barba C, Blumcke I, Winawer MR, Hartlieb T, Kang H-C, Grisotto L, Chipaux M, Bien CG, Heřmanovská B, Porter BE, Lidov HGW, Cetica V, Woermann FG, Lopez-Rivera JA, Canoll PD, Mader I, D’Incerti L, Baldassari S, Yang E, Gaballa A, Vogel H, Straka B, Macconi L, Polster T, Grant GA, Krsková L, Shin HJ, Ko A, Crino PB, Krsek P, Lee JH, Lal D, Baulac S, Poduri A, Guerrini R, SLC35A2 Study Group. Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene. Neurology. 2023 Jan 31;100(5):e528–e542.

Published In

Neurology

DOI

EISSN

1526-632X

Publication Date

January 31, 2023

Volume

100

Issue

5

Start / End Page

e528 / e542

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Seizures
  • Retrospective Studies
  • Neurology & Neurosurgery
  • Humans
  • Epilepsy
  • Electroencephalography
  • Drug Resistant Epilepsy
  • Brain
  • 3209 Neurosciences