title: The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort.
abstract: Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Niccolo E
authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Léa
authors.initials: L
authors.lastname: R'bibo
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK, Department of Physiology and Institute of Neurosciences Federico-Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, Granada 18071, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Bandres-Ciga
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy, Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
authors.forename: Miryam
authors.initials: M
authors.lastname: Carecchio
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.affiliation: Neuropediatrics Unit, IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
authors.affiliation: Molecular Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Amit
authors.initials: A
authors.lastname: Batla
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck 23538, Germany and.
authors.forename: Anne
authors.initials: A
authors.lastname: Weissbach
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck 23538, Germany and.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), Tübingen 72076, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), Tübingen 72076, Germany.
authors.forename: Ebba
authors.initials: E
authors.lastname: Lohmann
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK, n.wood@ucl.ac.uk.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D020864:Calcium Channels, N-Type / Q000235:genetics*; D003062:Codon; D015331:Cohort Studies; D020821:Dystonic Disorders / Q000453:epidemiology* / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D059472:Exome; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation
chemical_list: C500545:CACNA1B protein, human; D020864:Calcium Channels, N-Type; D003062:Codon