Thomas Bonduelle1, Till Hartlieb2,3, Sara Baldassari1, Nam Suk Sim4, Se Hoon Kim5, Hoon-Chul Kang6, Katja Kobow7, Roland Coras7, Mathilde Chipaux8, Georg Dorfmüller8, Homa Adle-Biassette9, Eleonora Aronica10,11, Jeong Ho Lee4,12, Ingmar Blumcke7, Stéphanie Baulac13. 1. Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Sorbonne Université, Hôpital Pitié-Salpêtrière - 47, bd de l'hôpital, 75013, Paris, France. 2. Center for Pediatric Neurology, Neurorehabilitation and Epileptology, Schoen Klinik, Vogtareuth, Germany. 3. Paracelsus Medical University, Salzburg, Austria. 4. Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea. 5. Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. 6. Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea. 7. Department of Neuropathology, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany. 8. Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, 75019, Paris, France. 9. Université de Paris, service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, UMR 1141, INSERM, Paris, France. 10. Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 11. Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands. 12. SoVarGen, Inc., Daejeon, 34051, Republic of Korea. 13. Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Sorbonne Université, Hôpital Pitié-Salpêtrière - 47, bd de l'hôpital, 75013, Paris, France. stephanie.baulac@icm-institute.org.
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.
Focal malformations of cortical developn>ment (n>an class="Disease">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.
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