title: A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation.
abstract: BACKGROUND
  Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6).
  
  
  OBJECTIVE
  To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation.
  
  
  METHODS
  A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects.
  
  
  RESULTS
  A single heterozygous base change in exon 9, c1213G-->A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed.
  
  
  CONCLUSIONS
  This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.
authors.affiliation: Department Child Neuropsychiatry and Neurorehabilitation IRCCS, E Medea Scientific Institute, Bosisio Parini, Lecco, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Romaniello
authors.forename: Claudio
authors.initials: C
authors.lastname: Zucca
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tonelli
authors.forename: Sara
authors.initials: S
authors.lastname: Bonato
authors.forename: Cinzia
authors.initials: C
authors.lastname: Baschirotto
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zanotta
authors.forename: Roberta
authors.initials: R
authors.lastname: Epifanio
authors.forename: Andrea
authors.initials: A
authors.lastname: Righini
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Maria T
authors.initials: MT
authors.lastname: Bassi
authors.forename: Renato
authors.initials: R
authors.lastname: Borgatti
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D015220:Calcium Channels / Q000235:genetics*; D002540:Cerebral Cortex / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D004568:Electrodiagnosis; D004569:Electroencephalography; D005071:Evoked Potentials / Q000502:physiology; D005091:Exons / Q000235:genetics; D005260:Female; D020546:Fourth Ventricle / Q000473:pathology; D006801:Humans; D020325:Migraine with Aura / Q000209:etiology / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000235:genetics; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type