Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis.
Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis is an extremely rare condition, so far reported in a single family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. Genetic study allowed to identify a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. The mutation decreased C18-ceramide levels. In addition, downregulation of CerS1 in neuroblastoma cell line showed activation of ER stress response and induction of proapoptotic pathways. This observation demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.
Regional Epilepsy Center, Reggio Calabria, Italy; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
Edoardo
E
Ferlazzo
Department of Neurosciences, 'G. Gaslini' Institute, Genova, Italy.
Pasquale
P
Striano
Department of Clinical and Experimental Medicine, University of Messina, Italy.
Domenico
D
Italiano
Division of Child Neurology and Psychiatry, University of Messina, Italy.
Tiziana
T
Calarese
Regional Epilepsy Center, Reggio Calabria, Italy; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
Sara
S
Gasparini
Department of Neurosciences, 'G. Gaslini' Institute, Genova, Italy.
Nicola
N
Vanni
Department of Neurosciences, 'G. Gaslini' Institute, Genova, Italy.
Floriana
F
Fruscione
Hôpital Henri-Gastaut, Marseille, France.
Pierre
P
Genton
Department of Neurosciences, 'G. Gaslini' Institute, Genova, Italy.
Federico
F
Zara
D000328:Adult; D000462:Algeria; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D051049:Sphingosine N-Acyltransferase / Q000235:genetics*; D055815:Young Adult
D008565:Membrane Proteins; C493790:CERS1 protein, human; D051049:Sphingosine N-Acyltransferase
ER stress response; ceramide synthase; epilepsy; neurodegeneration; progressive myoclonus epilepsies