Guido Rubboli1,2, Pierangelo Veggiotti3, Antonella Pini4, Angela Berardinelli5, Gaetano Cantalupo6, Enrico Bertini7, Francesco Danilo Tiziano8, Adele D'Amico7, Elena Piazza5, Emanuela Abiusi8, Stefania Fiori8, Elena Pasini2, Francesca Darra6, Giuseppe Gobbi4, Roberto Michelucci2. 1. Danish Epilepsy Center, Filadelfia/University of Copenhagen, Dianalund, Denmark. 2. Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy. 3. Department of Brain and Behavioral Sciences, Child Neuropsychiatry Unit, IRCCS C. Mondino National Neurological Institute, University of Pavia, Pavia, Italy. 4. Child Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy. 5. Child Neuropsychiatry Unit, IRCCS C. Mondino National Neurological Institute, Pavia, Italy. 6. Department of Life and Reproduction Sciences, University of Verona, Verona, Italy. 7. IRCCS Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy. 8. Medical Genetics Institute, Catholic University, Rome, Italy.
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. SIGNIFICANCE: 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. Wiley Periodicals, Inc.
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. SIGNIFICANCE: 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. Wiley Periodicals, Inc.
Authors: Jakub Sikora; Shaalee Dworski; E Ellen Jones; Mustafa A Kamani; Matthew C Micsenyi; Tomo Sawada; Pauline Le Faouder; Justine Bertrand-Michel; Aude Dupuy; Christopher K Dunn; Ingrid Cong Yang Xuan; Josefina Casas; Gemma Fabrias; David R Hampson; Thierry Levade; Richard R Drake; Jeffrey A Medin; Steven U Walkley Journal: Am J Pathol Date: 2017-04 Impact factor: 4.307
Authors: Shaalee Dworski; Ping Lu; Aneal Khan; Bruno Maranda; John J Mitchell; Rossella Parini; Maja Di Rocco; Boris Hugle; Makoto Yoshimitsu; Bo Magnusson; Balahan Makay; Nur Arslan; Norberto Guelbert; Karoline Ehlert; Andrea Jarisch; Janet Gardner-Medwin; Rawane Dagher; Maria Teresa Terreri; Charles Marques Lorenco; Lilianna Barillas-Arias; Pranoot Tanpaiboon; Alexander Solyom; James S Norris; Xingxuan He; Edward H Schuchman; Thierry Levade; Jeffrey A Medin Journal: Biochim Biophys Acta Mol Basis Dis Date: 2016-12-01 Impact factor: 5.187