A number sign (#) is used with this entry because of evidence that cognitive impairment with or without cerebellar ataxia (CIAT) is caused by heterozygous mutation in the SCN8A gene (600702) on chromosome 12q13.

Trudeau et al. (2006) reported a family of Swedish and Norwegian origin with highly variable neurologic deficits. The proband was a 9-year-old boy with markedly delayed psychomotor development, attention deficit disorder, and cerebellar ataxia. Features included ataxic wide-based gait, dysmetria in the upper limbs, and dysarthria, with normal strength, tone, and reflexes. He also had esophoria, amblyopia, and gaze-evoked nystagmus. Brain MRI showed moderate pancerebellar atrophy, accentuated in the vermal and parasagittal regions, as well as optic nerve hypoplasia. There were no cerebral abnormalities. His mother and maternal aunt had a history of emotional instability and mild cognitive impairment, and a first cousin had attention deficit-hyperactivity disorder (ADHD; 143465). A brother of the proband was noted to have impaired cognition and another cousin was noted to have ADHD, but they were not studied at the molecular level. In addition, none of the family members besides the proband was available for formal clinical evaluation or brain imaging studies. The proband was ascertained during a study of 151 patients with ataxia who were screened specifically for mutations in the SCN8A gene.

Wagnon et al. (2017) reported 2 unrelated children, a 7-year-old girl and a 10-year-old boy, with global developmental delay and impaired intellectual development (IQ of 73 and 56, respectively). The girl had delayed language, hypotonia that resolved with time, and ADHD; she was able to attend a special school. The boy had severe speech delay, temper tantrums, and a history of unsteady gait. Neither patient had seizures, and brain imaging performed in 1 patient was normal.

The transmission pattern of CIAT in the family reported by Trudeau et al. (2006) was consistent with autosomal dominant inheritance with variable expressivity.

Trudeau et al. (2006) screened the 26 coding exons of SCN8A in 151 patients with inherited or sporadic ataxia and no mutations in known ataxia-related genes. The SCN8A gene was chosen for study because it is widely expressed in neurons of the central and peripheral nervous systems, and because mutations in the mouse ortholog result in ataxia and other movement disorders. A heterozygous 2-bp deletion in exon 24 (600702.0001) was identified in 1 patient, a 9-year-old boy with mental retardation, pancerebellar atrophy, and ataxia. Three additional family members who were heterozygous for the mutation exhibited milder cognitive behavioral deficits including ADHD. However, Trudeau et al. (2006) noted that it was unclear whether the relatives of the proband had a milder version of the neurologic abnormalities seen in the proband due to haploinsufficiency for SCN8A, or if the proband's symptoms were caused by an unrelated developmental disorder.

In 2 unrelated children with CIAT, Wagnon et al. (2017) identified de novo heterozygous missense mutations in the SCN8A gene (G964R, 600702.0013 and E1218K, 600702.0014). The mutations, which were found by exome sequencing, occurred at highly conserved residues in transmembrane domains. Neither mutation was present in the ExAC database. The mutation occurred de novo in 1 patient; it was not found in the unaffected mother of the other patient, but DNA from the father was not available. In vitro functional expression studies in transfected cells showed that both mutations caused a complete loss of channel activity. Wagnon et al. (2017) suggested that loss of neuronal activity due to the mutation may alter the dynamics of synaptic plasticity during maturation and lead to aberrant cerebral circuitry and impaired intellectual development.