Epilepsy, Juvenile Myoclonic, Susceptibility To, 10

A number sign (#) is used with this entry because of evidence that susceptibility to juvenile myoclonic epilepsy-10 (EJM10) is conferred by heterozygous mutation in the ICK gene (612325) on chromosome 6p12.

Description

Juvenile myoclonic epilepsy-10 is an autosomal dominant seizure disorder with variable manifestations, even within families. Affected individuals have febrile, myoclonic, tonic-clonic, or absence seizures, although several seizure types can occur in the same individual. The age of onset also shows great variability: some patients present in the first years of life, whereas other have onset of seizures in teenage years. EEG typically shows 3.5 to 5 Hz polyspike wave discharges. There is evidence of incomplete penetrance (summary by Bailey et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of juvenile myoclonic epilepsy, see 254770.

Clinical Features

Bailey et al. (2018) reported a large multigenerational family from Belize (family A) in which 8 individuals had a seizure disorder that was most consistent with juvenile myoclonic epilepsy. The phenotype was variable within the family: most patients had onset of myoclonic tonic-clonic seizures (MTC) in late childhood or the teenage years, although several of these patients also experienced febrile seizures earlier in the first 2 years of life. Three patients had spanioleptic absence seizures, with or without MTC seizures, and 4 had myoclonic seizures upon awakening. Four additional family members were clinically asymptomatic, but had polyspike waves on EEG. From a cohort of 310 families with EJM, 23 additional probands with variants in the ICK gene were identified. Three of the 23 families (families D, E, and R) carried a pathogenic ICK mutation according to ACMG criteria and had a similar phenotype. Seizure types included MTC, pyknoleptic absence seizures, and tonic-clonic seizures, most of which occurred in the first 2 decades of life. The other probands carried variants that could not definitively be classified as pathogenic. Among them, the variant segregated with the disorder in 9 families and did not segregate with the disorder in 3 families; 5 patients were singleton probands. There was striking variation with respect to epilepsy phenotypes both within and among families. Of 34 affected nonproband family members, 5 (15%) had juvenile myoclonic epilepsy, 10 (29%) had myoclonic-tonic-clonic seizures, 4 (12%) had pyknoleptic petit mal seizures alone or with myoclonic-tonic-clonic seizures, 4 (12%) had febrile seizures alone or with absence or myoclonic seizures, and 11 (32%) were clinically asymptomatic but had polyspikes or focal spikes on EEG. Most families had asymptomatic mutation carriers. None of the patients had photosensitivity. The results suggested that ICK is pleiotropic with different phenotypic consequences.

Inheritance

The transmission pattern of EJM10 in the families reported by Bailey et al. (2018) was consistent with autosomal dominant inheritance with incomplete penetrance.

Molecular Genetics

In affected members of a family from Belize (family A) with EJM10, Bailey et al. (2018) identified a heterozygous missense mutation in the ICK gene (K305T, 612325.0002). The mutation was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing. Sequencing of the ICK gene in 310 probands with juvenile myoclonic epilepsy identified heterozygous variants in another 23 probands. Of the 24 probands, 9 came from families with other affected members, and the implicated ICK variant segregated with the disorder in the family. Five additional probands had no family history, and in 3 additional families, the variant did not segregate with the disorder. Of the 24 variants, 8 were absent and 12 were extremely rare in the ethnically matched population groups in the gnomAD database. The patients were of mixed European and American Indian ancestry (17 probands), European ancestry (4 probands,) and Japanese ancestry (3 probands). Overall, 21 rare variants were found in 22 patients (7%); however, only 4 variants were classified as pathogenic according to ACMG guidelines (K305T; K220E, 612325.0003; A615T, 612325.0004, and R632X, 612325.0005). Other variants were considered to be benign polymorphisms or only met some of the criteria for being pathogenic. There was evidence of incomplete penetrance, as several unaffected individuals carried mutations. Electroporation of the K305T, K220E, A615T, and R632X variants into neural progenitor cells in the mouse neocortex resulted in impaired radial migration of neurons during development, decreased numbers of mitotic cells and decreased cell-cycle exit index, indicating impairment of the cell cycle, and increased apoptosis compared to controls. A615T had a slightly different effect, with less impaired radial migration and less apoptosis compared to the other variants. Bailey et al. (2018) postulated haploinsufficiency as a pathogenic mechanism.

Animal Model

Bailey et al. (2018) found that heterozygous Ick+/- mice developed tonic-clonic seizures associated with diffuse polyspike waves on EEG compared to wildtype.