An extremely rare genetic variant that affects the maturation, migration, and death of neurons appears 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, and her colleagues reported in the March 15 issue of the New England Journal of Medicine.
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“We report striking variation with respect to epilepsy phenotypes both within and among families,” the team wrote. “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 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.”
Despite the misnomer of intestinal-cell kinase, ICK “is ubiquitous and is expressed in all tissues,” senior study author Antonio Delgado-Escueta, MD, professor of neurology at UCLA, noted in an interview. He said the brain dysplasia, or microdysgenesis, that occurs in patients with juvenile myoclonic epilepsy (JME) “is very subtle, 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. 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-binging protein, has been implicated in JME. Dr. Bailey and her colleagues examined whether several genes in close proximity to EFHC1 also influenced that risk.
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 from the databank analyzed information from 334 families with genetic generalized epilepsies. Among these, 310 patients had adolescent-onset myoclonic seizures and polyspike waves, or had a diagnosis of JME.
The team first performed an exome-wide analysis of four affected members of a large family with genetic JME. 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 JME.
A linkage analysis confirmed two candidate genes on chromosome 6p12.1. Further analyses pinpointed a single variant: K305T on the ICK gene. This was present in each of the 12 affected members and 3 unaffected members of the initial family examined. Of those affected, three had JME, 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.
“These results genetically implicated K305T as an autosomal dominant, possibly disease-causing trait,” the authors noted.
ICK variants were also present in 24 of the 310 database patients who had JME (8%). Of these, nine belonged to families with other affected members. The team tested 24 ICK variants for pathogenicity and determined that 13 exerted significant JME risk, with odds ratios exceeding 5.0.
When the team looked for these 24 variants in the Genome Aggregation Database (gnomAD), the found that 12 were present but extremely rare, and 8 were absent. They also found an additional ICK variant in a Mexican patient who was in gnomAD. Interestingly, that variant was a benign polymorphism in Africans.
Dr. Bailey and her colleagues thus concluded that 21 ICK variants accounted for 7% of the JME among the 310 cases examined.
The team also conducted a series of in vitro and in vivo mouse experiments. They determined that ICK variants impaired the migration of neuronal progenitor cells and lowered their mitotic index. ICK transgenic mice under light sedation displayed muscle movements similar to human myoclonic seizures that occur upon awakening. These mice also displayed diffuse polyspike brain waves on EEG recordings.
“The data we obtained through the use of electroporated slices of mouse brain support the conclusion that those pathogenic variants in ICK cause 7% of cases of juvenile myoclonic epilepsy by disrupting mitosis, neuroblast migration, and apoptosis,” they concluded.
The study was funded by a number of private and public grants from within the United States and other countries. Several authors are coholders of patents on EFHC1-based diagnostic and therapeutics that have been licensed to Athena Diagnostics. Several authors also reported receiving honoraria from various pharmaceutical companies.
SOURCE: Bailey J et al. N Engl J Med. 2018;378:1018-28