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.
© 2014 American Neurological Association.