title: Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy.
abstract: Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: D A
authors.initials: DA
authors.lastname: Dyment
authors.forename: E
authors.initials: E
authors.lastname: Sell
authors.forename: M R
authors.initials: MR
authors.lastname: Vanstone
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Garandeau
authors.forename: V
authors.initials: V
authors.lastname: Garcia
authors.forename: S
authors.initials: S
authors.lastname: Carpentier
authors.forename: E
authors.initials: E
authors.lastname: Le Trionnaire
authors.forename: F
authors.initials: F
authors.lastname: Sabourdy
authors.forename: C L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: J A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: H J
authors.initials: HJ
authors.lastname: McMillan
authors.forename: J
authors.initials: J
authors.lastname: Majewski
authors.forename: D E
authors.initials: DE
authors.lastname: Bulman
authors.forename: T
authors.initials: T
authors.lastname: Levade
authors.forename: K M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D002648:Child; D004576:Electromyography; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation
chemical_list: C526693:ASAH1 protein, human; D055573:Acid Ceramidase
keywords: acid ceramidase deficiency; ceramide; progressive myoclonic epilepsy; spinal muscular atrophy; whole exome sequencing