title: Cerebellar ataxia, hemiplegic migraine, and related phenotypes due to a CACNA1A missense mutation: 12-year follow-up of a large Portuguese family.
abstract: OBJECTIVE
  To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar ataxia, hemiplegic migraine, and related syndromes caused by missense mutation c.1748 (p.R583Q) in the CACNA1A gene.
  
  
  METHODS
  Observational 12-year follow-up study.
  
  
  METHODS
  Community and hospital care.
  
  
  METHODS
  Sixteen patients in a 4-generation family were identified in 1998 in a population-based survey. The follow-up revealed 28 patients (25 of whom were observed) and 32 unaffected relatives with an a priori risk of 50%.
  
  
  RESULTS
  Four major phenotypes (migraine with multiple auras, transient focal neurological deficits without headache, coma triggered by minor head trauma, and slowly progressive cerebellar ataxia) were present in various combinations. The initial manifestation was ataxia in 16 patients and a transient episode in 12 patients. Eighteen patients did not have migraine, and 11 showed only ataxia. The c.1748 (p.R583Q) mutation in CACNA1A was confirmed in all 23 of the patients who were tested but was not found in any of the 27 adult relatives. The CACNA1A CAG repeat expansion was excluded.
  
  
  CONCLUSIONS
  A unique missense mutation in the CACNA1A gene, which exhibits a very high penetrance and expressivity, may present a phenotypic spectrum that is broader than current descriptions. Single-gene disorders can behave as complex traits, which reinforces the importance of genetic modifiers in the tightly regulated function of P/Q-type calcium channels. The clinical spectrum of missense mutation CACNA1A -related disorders is much broader than strictly familial hemiplegic migraine.
authors: Serviço de Neurologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal. josebarros.neuro@hgsa.min-saude.pt
authors: José
authors: J
authors: Barros
authors: Joana
authors: J
authors: Damásio
authors: Assunção
authors: A
authors: Tuna
authors: Ivânia
authors: I
authors: Alves
authors: Isabel
authors: I
authors: Silveira
authors: José
authors: J
authors: Pereira-Monteiro
authors: Jorge
authors: J
authors: Sequeiros
authors: Isabel
authors: I
authors: Alonso
authors: Alda
authors: A
authors: Sousa
authors: Paula
authors: P
authors: Coutinho
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015220:Calcium Channels / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020325:Migraine with Aura / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011174:Portugal; D055815:Young Adult; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type