D-galactose supplementation for the treatment of mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE): a trial of precision medicine after epilepsy surgery

Abstract

Abstract Introduction: MOGHE is defined as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Approximately half of patients with histopathologically confirmed MOGHE carry a brain somatic variant in the SLC35A2 gene encoding a UDP-galactose transporter. Previous research showed D-galactose supplementation results in clinical improvement in patients with a congenital disorder of glycosylation due to germline variants in SLC35A2. We aimed to evaluate the effects of D-galactose supplementation in patients with histopathologically confirmed MOGHE, with uncontrolled seizures or cognitive impairment and epileptiform activity at the EEG after epilepsy surgery (NCT04833322). Methods: Patients were orally supplemented with D-galactose for six months in doses up to 1.5 g/kg/day, monitored for seizure frequency including 24-hour-video-EEG recording, cognition and behavioral scores, i.e., WISC, BRIEF-2, SNAP-IV, SCQ and quality of life measures, before and 6 months after treatment. Global response was defined by >50% improvement of seizure frequency and/or cognition and behavior (Clinical Global Impression of “much improved” or better). Results. Twelve patients (aged 5-28 years) were included from three different centers. Neurosurgical tissue samples were available in all patients and revealed a brain somatic variant in SLC35A2 in six patients (non-present in blood). After six months of D-galactose supplementation a 50% reduction or higher of seizure frequency was achieved in 3/6 patients, with an improvement at EEG in 2/5 patients. One patient became seizure-free. An improvement of cognitive/behavioral features encompassing impulsivity (mean SNAP-IV -3.19 [-0.84; -5.6]), social communication (mean SCQ -2.08 [-0.63;-4.90]) and executive function (BRIEF-2 inhibit -5.2 [-1.23; -9.2]) was observed. Global responder rate was 9/12 (6/6 in SLC35A2-positive). Two patients presented gastrointestinal discomfort, solved after dose spacing or dose reduction. Conclusion: Supplementation with D-galactose in patients with MOGHE is safe and well tolerated. Although the efficacy data warrant larger studies, it might build a rationale for precision medicine after epilepsy surgery.