Rare genetic variants that affect the maturation, migration, and death of neurons appear to be responsible for about 7% of cases of juvenile myoclonic epilepsy.
Variants of the intestinal-cell kinase gene (ICK) occurred in 12 members of a family affected by the disorder and were confirmed in 22 of 310 additional patients, Julia N. Bailey, PhD, of the University of California, Los Angeles (UCLA), and her colleagues reported in the March 15 issue of the New England Journal of Medicine.
But among these 34 patients, the variants manifested as different epileptic phenotypes, suggesting genetic pleiotropism, the investigators said.
“We report striking variation with respect to epilepsy phenotypes both within and among families,” the researchers said. “Of 34 affected nonproband family members, five (15%) had juvenile myoclonic epilepsy, 10 (29%) had myoclonic-tonic-clonic seizures, four (12%) had pyknoleptic petit mal seizures alone or with myoclonic-tonic-clonic seizures, four (12%) had febrile seizures alone or with absence seizures or myoclonias, and 11 (32%) were clinically asymptomatic but had polyspikes or focal spikes on EEG. These results strongly suggest that ICK is pleiotropic ... and that epistatic loci with different genes are present in affected family members and interact with ICK and contribute to pleiotropism and clinical heterogeneity.”
ICK “is expressed in all tissues,” said senior study author Antonio Delgado-Escueta, MD, Professor of Neurology at UCLA. The subtle brain dysplasia, or microdysgenesis, that occurs in patients with juvenile myoclonic epilepsy is “diagnosed mainly microscopically, and has neuronal cells that migrated from periventricular zones to the wrong places in wrong layers of the cortical gray matter and even the white matter of the brain,” he said. “The cells can also be abnormally large and bunch up as a thicker gray matter. On voxel-based brain MRI ... focal thickenings of these abnormally migrated cells can also be partly explained by decreased pruning of cells and circuits (apoptosis).”
The gene encoding for ICK is located close to EFHC1 on chromosome 6p12. EFHC1, which encodes for a calcium-binding protein, has been implicated in juvenile myoclonic epilepsy. Dr. Bailey and her colleagues examined whether several genes in close proximity to EFHC1 also influenced that risk.
An Epilepsy Database
The investigators drew data from the GENESS (Genetic Epilepsies Studies) consortium, which has study sites in the United States, Mexico, Honduras, Brazil, and Japan. The current study analyzed information from 334 families with genetic generalized epilepsies. Among these families, 310 patients had adolescent-onset myoclonic seizures and polyspike waves or had a diagnosis of juvenile myoclonic epilepsy.
The investigators first performed an exome-wide analysis of four affected members of a large family with genetic juvenile myoclonic epilepsy. They observed the same variants in all four patients, then ran the screen in all 37 family members. Next, they screened these candidate genes in all 334 of the GENESS families and calculated risk scores for juvenile myoclonic epilepsy.
A linkage analysis confirmed two candidate genes on chromosome 6p12.2. Further analyses pinpointed a single variant: K305T on the ICK gene. This trait was present in each of the 12 affected members and three unaffected members of the initial family examined. Of those affected, three had juvenile myoclonic epilepsy, two had myoclonic-tonic-clonic convulsions only, two had febrile convulsions plus childhood absence seizures or neonatal myoclonus, one had febrile convulsions only, and four had polyspikes on EEG and were clinically asymptomatic.