Abstract
Focal malformations of cortical development (MCD) are linked to somatic brain mutations occurring during neurodevelopment. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a newly recognized clinico-pathological entity associated with pediatric drug-resistant focal epilepsy, and amenable to neurosurgical treatment. MOGHE is histopathologically characterized by clusters of increased oligodendroglial cell densities, patchy zones of hypomyelination, and heterotopic neurons in the white matter. The molecular etiology of MOGHE remained unknown so far. We hypothesized a contribution of mosaic brain variants and performed deep targeted gene sequencing on 20 surgical MOGHE brain samples from a single-center cohort of pediatric patients. We identified somatic pathogenic SLC35A2 variants in 9/20 (45%) patients with mosaic rates ranging from 7 to 52%. SLC35A2 encodes a UDP-galactose transporter, previously implicated in other malformations of cortical development (MCD) and a rare type of congenital disorder of glycosylation. To further clarify the histological features of SLC35A2-brain tissues, we then collected 17 samples with pathogenic SLC35A2 variants from a multicenter cohort of MCD cases. Histopathological reassessment including anti-Olig2 staining confirmed a MOGHE diagnosis in all cases. Analysis by droplet digital PCR of pools of microdissected cells from one MOGHE tissue revealed a variant enrichment in clustered oligodendroglial cells and heterotopic neurons. Through an international consortium, we assembled an unprecedented series of 26 SLC35A2-MOGHE cases providing evidence that mosaic SLC35A2 variants, likely occurred in a neuroglial progenitor cell during brain development, are a genetic marker for MOGHE.
Highlights
Malformations of cortical development (MCD) represent an important cause of pediatric epilepsy resistant to antiseizure medication [13, 37]
The neuropathological diagnosis of MOGHE was in accordance with previously reported MOGHE criteria [35], consisting in the presence of: (1) clusters of increased Olig2-immunoreactive cell density as compared to neighboring regions, close to the grey-white matter junction and deep white matter (Fig. 1a, b); (2) increased densities of heterotopic neurons in the deep white matter according to Mühlebner et al [28] (Fig. 1c); (3) patchy areas of hypomyelination in the white matter identified by Patient ID Sex Age at seizure onset/Age surgery
In this study we report the so far largest cohort of patients with MOGHE, a newly recognized clinico-pathological entity belonging to the spectrum of epileptogenic mild malformations of cortical development
Summary
Malformations of cortical development (MCD) represent an important cause of pediatric epilepsy resistant to antiseizure medication [13, 37]. Focal MCD comprise distinct histopathological entities, including Focal Cortical Dysplasia (FCD) type 1, 2 and 3 [4], mild MCD (mMCD), and a newly recognized clinicopathological entity termed mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). Mosaic variants in the SLC35A2 gene, encoding the major Golgi‐ localized UDP‐galactose transporter required for protein and sphingolipid glycosylation, have been identified in various forms of non-lesional focal epilepsies, as well as FCD type 1 and mMCD [2, 25, 38, 39, 41]. Loss of SLC35A2 protein function abolishes transport of UDP-galactose from the cytosol into the Golgi apparatus, resulting in the synthesis of truncated glycans lacking galactose residues [30, 38]; yet, how this relates to the clinical phenotype is still unknown
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