title: Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia.
abstract: BACKGROUND
  Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA).
  
  
  METHODS
  We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy.
  
  
  RESULTS
  De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases.
  
  
  CONCLUSIONS
  Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias.
authors.affiliation: Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Travaglini
authors.affiliation: Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Nardella
authors.affiliation: Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bellacchio
authors.affiliation: Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Capuano
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frusciante
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Di Capua
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cusmai
authors.affiliation: Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Barresi
authors.affiliation: Unit of Medical Genetics, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morlino
authors.affiliation: Laboratori de Fisiologia Molecular i Canalopaties, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Fernández
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Trivisano
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Valeriani
authors.affiliation: Department of Neurosciences, Unit of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Vigevano
authors.affiliation: Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: ginevra.zanni@opbg.net.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Zanni
mesh_terms: D001259:Ataxia / Q000150:complications / Q000235:genetics*; D001284:Atrophy / Q000473:pathology; D020864:Calcium Channels, N-Type / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008881:Migraine Disorders / Q000150:complications / Q000235:genetics; D020125:Mutation, Missense; D059906:Neuroimaging; D010375:Pedigree; D010641:Phenotype
chemical_list: D020864:Calcium Channels, N-Type
keywords: Alpha-1a subunit (CACNA1A); Calcium channel; Cerebellar atrophy; Congenital ataxia; P/Q type; Targeted resequencing; Voltage-dependent