P1719fsX1724 is the first reported mutation in human SCN8A
. Several lines of evidence indicate that the loss of the C‐terminal domain in the SCN8A
mutant allele results in loss of function. This domain of the voltage gated sodium channels has been highly conserved during evolution and is thought to play a role in channel inactivation. An interaction site for the sodium channel β1 subunit has been localised within the C‐terminal domain.27
Biophysical studies of similarly located mutations in the channels SCN1A
have been carried out in transfected mammalian cells; the results demonstrate that truncation of the C‐terminal domain greatly reduces or eliminates channel activity.28,29
Many additional mutations in SCN1A
that result in severe myoclonic epilepsy of infancy are deletions of the C‐terminal domain.4
The reduced level of Nav
1.6 in heterozygous individuals is expected to reduce neuronal excitability, resulting in altered firing patterns. Electrophysiological studies of neurons from heterozygous null mice would be of great value for understanding the consequences of reduced Nav
1.6 in different types of neurons. Preliminary studies have detected impaired learning and increased anxiety in mice heterozygous for an SCN8A
null mutation (B McKinney, M Meisler, and G Murphy, unpublished observations).
The tissue specific expression of SCN8A
in the nervous system, the predicted loss of channel activity by the mutant allele, and the low population frequency of the mutant allele, are all consistent with a causal role for this mutation in the neurological deficits of the proband. It is not unexpected that a reduction in the amount of the Nav
1.6 sodium channel, due to heterozygosity for a loss of function allele, would have clinical consequences. Haploinsufficiency for the closely related channel SCN1A
1.1) results in a severe seizure disorder,4
demonstrating that levels of expression in a null heterozygote can be insufficient for normal function. The threshold for uncompromised motor function in the mouse is between 10% and 50% of normal levels of Nav
The severity of cognitive defects in family members who are heterozygous for the SCN8A
mutation varies from mental retardation in the proband to ADHD in his first cousin. If 50% is close to the threshold for normal SCN8A
function, then variation in genetic background or environment may be expected to influence cognitive outcome. SCN8A
expression is particularly high in the cerebellum, and targeted inactivation of SCN8A
in Purkinje cells is sufficient to produce ataxia.30
On the other hand, cerebellar malformation has not been observed in Scn8a
null or heterozygous mice. The ataxic features of the proband are consistent with the moderate pancerebellar atrophy revealed by MRI, but the lack of MRIs for the other heterozygotes in the family preclude firm conclusions regarding the role of the SCN8A
mutation in the cerebellar atrophy.
The CpT dinucleotide deletion in the SCN8A mutation P1719fsX1724 occurs in the context of a C6 nucleotide sequence. Deletion of one or two nucleotides from C4 to C6 repeats are responsible for the common deafness allele of connexin 26 and RAI1 mutations in patients with Smith‐Magenis syndrome. However, no other mutations in this C6 run were observed among 625 unrelated individuals, indicating that this is not a highly unstable site.
Follow up studies will be required to assess the prevalence of SCN8A
mutations and their significance in disorders of cognition and behaviour. In future screening, it will be worthwhile to include the recently described 5′ non‐coding exons and promoter region of the gene,31
which were not included in the present study. Families with both motor and cognitive features should be investigated in future studies.