title: Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency.
abstract: We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases.
authors.affiliation: Department of Medical Genetics, National Center for Mitochondrial diseases, Nice Teaching Hospital, Nice, France.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Fragaki
authors.forename: Samira
authors.initials: S
authors.lastname: Ait-El-Mkadem
authors.forename: Annabelle
authors.initials: A
authors.lastname: Chaussenot
authors.forename: Catherine
authors.initials: C
authors.lastname: Gire
authors.forename: Raymond
authors.initials: R
authors.lastname: Mengual
authors.forename: Laurent
authors.initials: L
authors.lastname: Bonesso
authors.forename: Marie
authors.initials: M
authors.lastname: Bénéteau
authors.forename: Jean-Ehrland
authors.initials: JE
authors.lastname: Ricci
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics; D017304:Annexin A5 / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D002648:Child; D004827:Epilepsy / Q000473:pathology*; D059472:Exome / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005915:Globosides / Q000378:metabolism; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D018895:Microsatellite Repeats / Q000235:genetics; D028361:Mitochondrial Diseases / Q000473:pathology*; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012799:Sialyltransferases / Q000172:deficiency; D013053:Spectrophotometry
chemical_list: D017304:Annexin A5; D005915:Globosides; D012799:Sialyltransferases; D019883:Alkyl and Aryl Transferases; C540142:prenyl diphosphate synthase, subunit 2, human