Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation
- 1Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618, USA
- 2Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA
- 3Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA
- 4Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA
- Correspondence to: Dr Miriam H Meisler 4909 Buhl Box 0618, University of Michigan Medical School, Ann Arbor, MI 48109-0618, USA;
- Received 8 June 2005
- Accepted 1 October 2005
- Revised 27 September 2005
- Published Online First 19 October 2005
Background: The SCN8A gene on chromosome 12q13 encodes the voltage gated sodium channel Nav1.6, 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.
Published Online First 19 October 2005
This work was supported by NIH grants NS34509 (MHM) and NS040389 (LPWR), The Wilson Family Medical Foundation (MHM), and the National Ataxia Foundation (LPWR)
Competing interests: none declared
Ethics approval: blood samples were obtained with Internal Review Board approved consent from subjects at the University of Minnesota
The patient details described in this report are published with consent