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

Abstract

Background and Objectives:TheSLC35A2gene, located at chromosome Xp11.23, encodes for a uridine diphosphate (UDP)-galactose transporter. We describe clinical, genetic, neuroimaging, EEG and histopathological findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somaticSLC35A2gene 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 somaticSLC35A2variants: 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 (MOGHE) in 44/47 patients and was inconclusive in three. The 47 patients harbored 42 distinct mosaicSLC35A2variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, four (9.5%) in-frame deletions/duplications, and one (2.4%) splicing variant. Variant allele frequencies (VAF) 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 somaticSLC35A2gene variants are associated with two main clinical phenotypes, EE and DR-FE, and a histopathological 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.

Frontal lobe epilepsy and mild malformation with oligodendroglial hyperplasia: Further observations on electroclinical and imaging phenotypes, and surgical perspectives

“…With this single‐center small case series we present further evidence supporting previous data in MOGHE literature, as regards the presence of a Frontal Lobe Seizure in older patients and an early‐age onset Epileptic Encephalopathy Phenotype. Our results are strikingly similar to those of a recently published large multicenter study, including 47 cases, 7 especially as regards the Epileptic Encephalopathy phenotype, not explicitly described in previous reports, which matches our independent observations in a smaller sample. We also confirm their observations as regards an older‐age Frontal Lobe phenotype and further elaborate on some semiological peculiarities, observed in our sample, as well as data from previous studies suggesting a high proportion of cases with widespread areas of epileptogenicity on surface EEG studies, well beyond the limits of the imaging abnormality 4 …”

“…Mild Malformation with Oligodendroglial Hyperplasia (MOGHE) has been recently described, as a distinct clinicopathologic entity in adult and pediatric epilepsy patients, most of them with Frontal Lobe Epilepsy [1][2][3][4][5][6][7][8] as well as with "Temporal plus" 9 occipitotemporal, 10,11 and Epileptic Encephalopathy 7 electroclinical phenotypes. Although MRI features in some cases suggest FCD IIa type, 3 on histopathologic grounds MOGHE is an entity distinct from FCD, its cardinal features consist of normal cortical architecture, increased oligodendrocyte numbers and proliferative activity in the deep cortical layers and superficial white matter, heterotopic neurons in the white matter, as well as cortical-white matter blurring and hypomyelinated white matter areas.…”

Seizure Control Outcomes following Resection of Cortical Dysplasia in Patients with DEPDC5 Variants: A Systematic Review and Individual Patient Data Analysis

“…In these two studies, all, if not most, patients achieved improvement in seizure frequency or seizure freedom. 24,25 As stated previously, genes involved with the mTOR pathway have been consistently reported to have success from surgical intervention. However, there has been some hesitation on whether to proceed with surgery due to varying reports of success.…”

SLC35A2 –Related Epilepsy

“…2,3 But our understanding of the role that SLC35A2 has in epilepsy is evolving. In this issue of Neurology® , Barba et al 10 published a retrospective, multicenter, clinicopathological, and genetic analysis of 47 patients who underwent surgery for drug-resistant epilepsy secondary to brain somatic SLC35A2 variants. Patients underwent detailed clinical, neurophysiologic, and cognitive testing followed by resective surgery.…”

“…9 Further research will be necessary to elucidate the link among the expected dysmyelination, development of the MOGHE-specific cellular abnormalities, and consequent broad neuronal network dysfunction resulting in epilepsy and cognitive impairment. In the meantime, the collaborative study of Barba et al 10 serves as a methodical primer for a multifaceted deep analysis of a genetic focal epilepsy. Our patients deserve no less!…”