Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene
Abstract
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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© 2022 American Academy of Neurology.
Publication History
Received: May 3, 2022
Accepted: September 9, 2022
Published online: October 28, 2022
Published in print: January 31, 2023
Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.
Study Funding
R. Guerrini and C. Barba were supported by the Tuscany Region Call for Health 2018 (grant DECODE-EE) and the Optical Brain Mapping project by Fondazione Cassa di Risparmio di Firenze. P. Krsek, L. Krsková, B. Straka, M. Koblížek, J. Zámečník, and B. Heřmanovská were supported by the Ministry of Health of the Czech Republic (grant no. NV19-04-00369). B. Heřmanovská was also supported by the Charles University Fac Med 2 (project GA UK No 212029). Sara Baldassari was supported by the European Research Council (No. 682345) and ANR-18-RHUS-0005. This work was supported by the NIH–National Institute of Neurological Disorders and Stroke (NINDS) (R01NS094596 [EH, PCr], R01NS115017 [EH, PCr], R01NS089552 [MW, PCr], R01NS114122 [MW, PCr, EH], and R21NS101303 [MW, PC]).
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