title: Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation.
abstract: BACKGROUND
  The SCN8A gene on chromosome 12q13 encodes the voltage gated sodium channel Na(v)1.6, which is widely expressed in neurons of the CNS and PNS. Mutations in the mouse ortholog of SCN8A result in ataxia and other movement disorders.
  
  
  METHODS
  We screened the 26 coding exons of SCN8A in 151 patients with inherited or sporadic ataxia.
  
  
  RESULTS
  A 2 bp deletion in exon 24 was identified in a 9 year old boy with mental retardation, pancerebellar atrophy, and ataxia. This mutation, Pro1719ArgfsX6, introduces a translation termination codon into the pore loop of domain 4, resulting in removal of the C-terminal cytoplasmic domain and predicted loss of channel function. Three additional heterozygotes in the family exhibit milder cognitive and behavioural deficits including attention deficit hyperactivity disorder (ADHD). No additional occurrences of this mutation were observed in 625 unrelated DNA samples (1250 chromosomes).
  
  
  CONCLUSIONS
  The phenotypes of the heterozygous individuals suggest that mutations in SCN8A may result in motor and cognitive deficits of variable expressivity, but the study was limited by lack of segregation in the small pedigree and incomplete information about family members. Identification of additional families will be required to confirm the contribution of the SCN8A mutation to the clinical features in ataxia, cognition and behaviour disorders.
authors.forename: M M
authors.initials: MM
authors.lastname: Trudeau
authors.forename: J C
authors.initials: JC
authors.lastname: Dalton
authors.forename: J W
authors.initials: JW
authors.lastname: Day
authors.forename: L P W
authors.initials: LP
authors.lastname: Ranum
authors.forename: M H
authors.initials: MH
authors.lastname: Meisler
mesh_terms: D000483:Alleles; D001284:Atrophy; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D002531:Cerebellum / Q000473:pathology*; D002648:Child; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D005820:Genetic Testing; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D040582:Inheritance Patterns; D008607:Intellectual Disability / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D017384:Sequence Deletion; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C100681:SCN8A protein, human; D015222:Sodium Channels