title: Spinal muscular atrophy associated with progressive myoclonic epilepsy: A rare condition caused by mutations in ASAH1.
abstract: OBJECTIVE
  To present the clinical features and the results of laboratory investigations in three patients with spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME), a rare condition caused by mutations in the N-acylsphingosine amidohydrosilase 1 (ASAH1) gene.
  
  
  METHODS
  The patients were submitted to clinical evaluation, neurophysiologic investigations (that included wakefulness and sleep electroencephalography [EEG], video-polygraphic recording with jerk-locked back-averaging, multimodal evoked potentials, and electromyography), brain magnetic resonance imaging (MRI), biochemical screening, muscle and skin biopsies, and molecular genetic analysis.
  
  
  RESULTS
  The main clinical features were onset in childhood with proximal muscular weakness, generalized epilepsy with absences and myoclonic seizures, cognitive impairment of variable degree; the course was progressive with muscle wasting and uncontrolled epileptic seizures. In one patient, earlier onset before the age of 2 years was associated with a more complex clinical picture, with abnormal eye movements, progressive cognitive impairment, and a more rapid and severe course. EEG/polygraphic data were consistent with PME, demonstrating generalized spike-and-wave discharges, evidence of positive and negative myoclonia, and prominent photosensitivity. In one patient, transcranial magnetic stimulation showed a hyperexcitable motor cortex, whereas somatosensory evoked potentials were unaffected. Possible involvement of the central acoustic and visual pathways was suggested by abnormal auditory and visual evoked potentials. Muscle biopsies showed typical signs of neurogenic damage. Molecular genetic analysis showed mutations of the ASAH1 gene.
  
  
  CONCLUSIONS
  Our data indicate that SMA-PME associated with ASAH1 mutations is a genetically distinct condition with specific clinical and neurophysiologic features. Further studies are warranted to explore the role of the ASAH1 gene in muscle and brain function.
authors.affiliation: Danish Epilepsy Center, Filadelfia/University of Copenhagen, Dianalund, Denmark.|Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Rubboli
authors.affiliation: Department of Brain and Behavioral Sciences, Child Neuropsychiatry Unit, IRCCS C. Mondino National Neurological Institute, University of Pavia, Pavia, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Veggiotti
authors.affiliation: Child Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pini
authors.affiliation: Child Neuropsychiatry Unit, IRCCS C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Berardinelli
authors.affiliation: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Cantalupo
authors.affiliation: IRCCS Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Medical Genetics Institute, Catholic University, Rome, Italy.
authors.forename: Francesco Danilo
authors.initials: FD
authors.lastname: Tiziano
authors.affiliation: IRCCS Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.affiliation: Child Neuropsychiatry Unit, IRCCS C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piazza
authors.affiliation: Medical Genetics Institute, Catholic University, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Abiusi
authors.affiliation: Medical Genetics Institute, Catholic University, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiori
authors.affiliation: Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pasini
authors.affiliation: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Darra
authors.affiliation: Child Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gobbi
authors.affiliation: Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Michelucci
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D005071:Evoked Potentials / Q000235:genetics; D005260:Female; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000150:complications* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020191:Myoclonic Epilepsies, Progressive / Q000150:complications* / Q000235:genetics*; D059906:Neuroimaging; D065908:Transcranial Direct Current Stimulation
chemical_list: C526693:ASAH1 protein, human; D055573:Acid Ceramidase
keywords: ASAH1 mutations; Myoclonus; Polygraphy; Progressive myoclonus epilepsy; Spinal muscular atrophy