title: Infantile nystagmus and late onset ataxia associated with a CACNA1A mutation in the intracellular loop between s4 and s5 of domain 3.
abstract: OBJECTIVE
  Mutations in the 1A-subunit of the brain P/Q-type calcium channel gene CACNA1A are responsible for spinocerebellar ataxia type 6 (SCA6), familial haemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). Considerable clinical and genetic overlap exists between these 3 allelic disorders. Clinical findings are varied and may include nystagmus.
  
  
  OBJECTIVE
  To study the clinical phenotype and identify a causative mutation in a family who presented when the youngest member was diagnosed with apparent isolated congenital nystagmus (age 3 months).
  
  
  METHODS
  8 patients from one family underwent detailed clinical phenotyping comprising; ophthalmic and neurological examination, nystagmology, electrodiagnostic tests and brain imaging. The CACNA1A gene was screened for mutations by direct sequencing in one patient. Co-segregation of the disease and an identified sequence variation was shown using direct sequencing.
  
  
  RESULTS
  Phenotyping revealed isolated atypical nystagmus in 4 family members and nystagmus in addition to late onset ataxia in 1 family member. Direct sequencing of the CACNA1A gene identified a novel missense mutation; (c.4110T>G p.Phe1370Leu (NM_000068.3)).
  
  
  CONCLUSIONS
  We have shown that a mutation in the intracellular domain between s4 and s5 of repeat 3 can cause atypical nystagmus/cerebellar phenotypes, including isolated nystagmus in an infant. We also illustrate the necessity for detailed examination of relatives in cases of apparent isolated congenital nystagmus.
authors.affiliation: Southampton Eye Unit, Southampton General Hospital, Southampton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Self
authors.forename: C
authors.initials: C
authors.lastname: Mercer
authors.forename: E M J
authors.initials: EM
authors.lastname: Boon
authors.forename: M
authors.initials: M
authors.lastname: Murugavel
authors.forename: F
authors.initials: F
authors.lastname: Shawkat
authors.forename: S
authors.initials: S
authors.lastname: Hammans
authors.forename: P
authors.initials: P
authors.lastname: Hodgkins
authors.forename: H
authors.initials: H
authors.lastname: Griffiths
authors.forename: A
authors.initials: A
authors.lastname: Lotery
mesh_terms: D000328:Adult; D017668:Age of Onset; D001259:Ataxia / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics*; D002531:Cerebellum / Q000473:pathology; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020417:Nystagmus, Congenital / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D017422:Sequence Analysis, DNA; D055815:Young Adult; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type