SLC35A2 somatic variants in drug resistant epilepsy: FCD and MOGHE

Abstract

De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug resistant epilepsy (DRE) associated with malformations of cortical development, in particular, focal cortical dysplasias (FCD). Somatic variants in at least 16 genes have been linked to FCD type II, all encoding components of the mechanistic target of rapamycin (mTOR) pathway. FCD type II is characterized histopathologically by cytomegalic dysmorphic neurons and balloon cells. In contrast, the molecular pathogenesis of FCD I subtypes is less well understood, and histological features are characterized by alterations in columnar or laminar organization without cytomegalic dysmorphic neurons or balloon cells. In 2018, we reported somatic mutations in Solute Carrier Family 35 member A2 (SLC35A2) linked to DRE underlying FCD type I and subsequently to a new histopathological phenotype: excess oligodendrocytes and heterotopic neurons in subcortical white matter known as MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia). These discoveries opened the door to studies linking somatic mutations to FCD. In this review, we discuss the biology of SLC35A2 somatic mutations in epilepsy in FCD and MOGHE, and insights into SLC35A2 epilepsy pathogenesis, describing progress to date and critical areas for investigation.

Keywords: Cortical malformations; Epilepsy; Focal cortical dysplasia; Glycosylation; Somatic.

Fig. 1.

Predicted protein structure of UGT-1. In light and dark blue, are the predicted transmembrane domains.

Fig. 2.

SLC35A2 mRNA and protein expression (Protein Atlas).

Fig. 3.

SLC35A2 mRNA and Protein Expression in the brain (Protein Atlas).

Fig. 4.

Schematic depiction of SLC35A2 and UGT-1 biology. (A), UGT-1 is located within the Golgi membrane, tethered via multiple transmembrane domains. UGT-1 adds galasctose residues (GAL) to synthesized proteins. (B) Following galactosylation, proteins exit the Golgi into the cytoplasm to enter the membrane, lysosomes, or other cellular destinations. (C) Somatic mutations in SLC35A2 occurring in a single neuroglial progenitor cell (red) among progenitors with normal genotype (green) yields a population of daughter progeny cells (D) expressing the SLC35A2 variant (D, neurons in red). Neurons (green) derived from progenitors with normal genotypes do not express SLC35A2 mutations. The focal nature of the SLC35A2 somatic mutation yields a focal MCD either FCD I or MOGHE.