title: ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study.
abstract: ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A>G (r.124a>g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital 'Spedali Civili', Brescia, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Filosto
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aureli
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Castellotti
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital 'Spedali Civili', Brescia, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Rinaldi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Domitilla
authors.initials: D
authors.lastname: Schiumarini
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Valsecchi
authors.affiliation: Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Lualdi
authors.affiliation: Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mazzotti
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Pensato
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital 'Spedali Civili', Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rota
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Gellera
authors.affiliation: Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital 'Spedali Civili', Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D011247:Pregnancy; D035781:Siblings
chemical_list: C526693:ASAH1 protein, human; D055573:Acid Ceramidase