Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

Eur J Hum Genet. 2013 May;21(5):528-34. doi: 10.1038/ejhg.2012.202. Epub 2012 Sep 19.


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.

Publication types

  • Case Reports

MeSH terms

  • Alkyl and Aryl Transferases / genetics
  • Annexin A5 / metabolism
  • Base Sequence
  • Brain / pathology*
  • Cells, Cultured
  • Child
  • Epilepsy / pathology*
  • Exome / genetics
  • Fibroblasts / metabolism
  • Globosides / metabolism
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mass Spectrometry
  • Membrane Potential, Mitochondrial / physiology
  • Microsatellite Repeats / genetics
  • Mitochondrial Diseases / pathology*
  • Molecular Sequence Data
  • Pedigree
  • Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Sialyltransferases / deficiency
  • Spectrophotometry


  • Annexin A5
  • Globosides
  • Sialyltransferases
  • Alkyl and Aryl Transferases
  • prenyl diphosphate synthase, subunit 2, human

Supplementary concepts

  • Amish Infantile Epilepsy Syndrome