Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation

• Published in: Journal of medical genetics 2006-06, Vol.43 (6), p.527-530
• Main Authors: Trudeau, M M, Dalton, J C, Day, J W, Ranum, L P W, Meisler, M H
• Format: Article
• Language: English
• Subjects: ADHD; Alleles; ataxia; Atrophy; attention deficit hyperactivity disorder; Base Sequence; Biological and medical sciences; Cardiology. Vascular system; Cerebellar Ataxia - complications; Cerebellar Ataxia - diagnosis; Cerebellar Ataxia - genetics; Cerebellum - pathology; Child; Codon, Nonsense; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; DNA Mutational Analysis; Frameshift Mutation; General aspects. Genetic counseling; Genes; Genetic Testing; haploinsufficiency; Haplotypes; Heterozygote; Humans; Inheritance Patterns; Intellectual Disability - complications; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Letter to JMG; Male; Medical genetics; Medical sciences; Mutation; NAV1.6 Voltage-Gated Sodium Channel; Nerve Tissue Proteins - genetics; Nervous system (semeiology, syndromes); Neurology; Pedigree; retardation; Rodents; Sequence Deletion; Sodium; sodium channel; Sodium Channels - genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2005.035667

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.