Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy

  • Ann Neurol. 2014 Aug;76(2):206-12. doi: 10.1002/ana.24170.
Nicola Vanni  1 ,  Floriana Fruscione ,  Edoardo Ferlazzo ,  Pasquale Striano ,  Angela Robbiano ,  Monica Traverso ,  Thomas Sander ,  Antonio Falace ,  Elisabetta Gazzerro ,  Placido Bramanti ,  Jacek Bielawski ,  Anna Fassio ,  Carlo Minetti ,  Pierre Genton ,  Federico Zara
Affiliations
  • 1. Department of Neuroscience, Institute G. Gaslini, Genoa, Italy.
PMID: 24782409 DOI: 10.1002/ana.24170
Abstract

Objective: Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders.

Methods: We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides.

Results: We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways.

Interpretation: This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.