Febrile Seizures, Familial, 11

A number sign (#) is used with this entry because of evidence that familial febrile seizures-11 (FEB11) is caused by homozygous mutation in the CPA6 gene (609562) on chromosome 8q13.

Description

Familial febrile seizures-11 is an autosomal recessive seizure disorder characterized by early childhood onset of simple or complex seizures associated with fever. These seizures usually remit later in childhood with no neurologic sequelae (summary by Salzmann et al., 2012).

For a general description and a discussion of genetic heterogeneity of familial febrile seizures, see FEB1 (121210).

Clinical Features

Salzmann et al. (2012) reported 4 sibs, born of consanguineous Moroccan parents, with highly variable manifestations of a seizure disorder. Three patients had febrile seizures only, and 1 had febrile seizures and later developed temporal lobe epilepsy. The first patient was a 30-year-old woman who had a single febrile seizure at age 3 years, with no recurrence and normal psychomotor development. The second patient, aged 26 years, had 2 simple and 1 complex partial febrile seizure between 9 and 10 months of age. At age 17, she developed recurrent complex partial seizures with right temporal spikes on EEG associated with right hippocampal atrophy on brain imaging. Psychomotor development was normal, and she was said to be in remission at age 26. The third patient was a 17-year-old girl who had a single complex febrile seizure and 2 simple febrile seizures at age 3 years, which were successfully treated with no recurrence; psychomotor development was normal. The fourth patient was a 9-year-old boy who had neonatal convulsions with intracerebral hemorrhage. This was followed by simple and complex febrile seizures during infancy as well as recurrence at age 7 when treatment was stopped. He had mild mental delay.

Mapping

By homozygosity mapping of a consanguineous Moroccan family with febrile seizures, Salzmann et al. (2012) found linkage to a 9.6-Mb region on chromosome 8q12.1-q13.2. The region overlapped the FEB1 locus (121210) identified by Wallace et al. (1996) in an Australian family. Although screening of the CPA6 gene in a family reported by Wallace et al. (1996) did not reveal any pathogenic mutations, Salzmann et al. (2012) could not exclude the possibility of a mutation in the promoter or noncoding region, or a copy number variant of the CPA6 gene in that family.

Molecular Genetics

By homozygosity mapping followed by candidate gene analysis of a consanguineous Moroccan family in which 4 sibs had febrile seizures, 1 of whom also had temporal lobe epilepsy, Salzmann et al. (2012) identified a homozygous mutation in the CPA6 gene (A270V; 609562.0001). In vitro functional expression studies in cellular assays showed that the mutant protein had decreased activity compared to wildtype due to impaired secretion into the extracellular matrix. Those homozygous for the A270V mutation would have about 40% residual enzyme activity, consistent with a loss of function.