Epilepsy, Progressive Myoclonic 7

A number sign (#) is used with this entry because of evidence that progressive myoclonic epilepsy-7 (EPM7) is caused by heterozygous mutation in the KCNC1 gene (176258) on chromosome 11p15.

Description

Progressive myoclonic epilepsy-7 is a neurologic disorder characterized by onset of severe progressive myoclonus and infrequent tonic-clonic seizures in the first or second decades of life. Most patients become wheelchair-bound; some patients may have cognitive decline (summary by Muona et al., 2015).

For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).

Clinical Features

Muona et al. (2015) reported 13 unrelated patients with progressive myoclonic epilepsy. After normal development in early childhood, the patients presented between 6 and 14 years of age with progressive myoclonus, sometimes reported as tremor. One patient developed ataxia at an early age, but this was overshadowed by myoclonus. All patients also had infrequent tonic-clonic seizures. The movement disorder generally became disabling in adolescence, with most patients becoming wheelchair-bound. Some patients had learning disabilities or mild cognitive decline. Brain imaging was essentially normal, except for cerebellar atrophy in some patients. One of the probands had 3 affected family members, and the phenotype in this family was slightly milder compared to that in the other families. Muona et al. (2015) called this disorder 'myoclonic epilepsy with ataxia due to potassium channel mutation,' symbolized 'MEAK.'

Inheritance

Muona et al. (2015) found that progressive myoclonic epilepsy-7 occurred as a de novo event in 12 probands. One other proband was found to have an affected sib and 2 affected children who also carried the pathogenic mutation, consistent with autosomal dominant inheritance; however, peripheral blood DNA from both mutation-negative unaffected parents of the proband did not suggest mosaicism.

Molecular Genetics

In 13 unrelated patients with childhood-onset progressive myoclonic epilepsy-7, Muona et al. (2015) identified the same de novo heterozygous missense mutation in the KCNC1 gene (R320H; 176258.0001). The mutation was found in 11 (13%) of 84 patients who underwent exome sequencing and in 2 (7%) of 28 patients who underwent direct sequencing of the KCNC1 gene. In vitro functional expression studies showed that the mutation caused a loss of channel function with a dominant-negative effect. Muona et al. (2015) noted that KCNC1 is prominently expressed in inhibitory GABAergic interneurons in the central nervous system, and suggested that loss of these currents may contribute to myoclonus and seizures.