Authors

J. N. Bailey, Veterans Affairs Greater Los Angeles Healthcare System
L. de Nijs, University of Liege
D. Bai, Veterans Affairs Greater Los Angeles Healthcare System
T. Suzuki, RIKEN Brain Science Institute, Saitama
H. Miyamoto, RIKEN Brain Science Institute, Saitama
M. Tanaka, Veterans Affairs Greater Los Angeles Healthcare System
C. Patterson, Veterans Affairs Greater Los Angeles Healthcare System
Y.-C. Lin, Veterans Affairs Greater Los Angeles Healthcare System
M. T. Medina, National Autonomous University of Honduras
M. E. Alonso, National Institute of Neurology and Neurosurgery Manuel Velasco Suarez
J. M. Serratosa, Veterans Affairs Greater Los Angeles Healthcare System
R. M. Durón, Veterans Affairs Greater Los Angeles Healthcare System
Viet-Hong Nguyen, Chapman UniversityFollow
J. E. Wight, Veterans Affairs Greater Los Angeles Healthcare System
I. E. Martínez‑Juárez, National Institute of Neurology and Neurosurgery Manuel Velasco Suarez
A. Ochoa, National Institute of Neurology and Neurosurgery Manuel Velasco Suarez
A. Jara-Prado, National Institute of Neurology and Neurosurgery Manuel Velasco Suarez
L. Guilhoto, Universidade Federal de São Paulo
Y. Molina, National Autonomous University of Honduras
E. M. Yacubian, Universidade Federal de São Paulo
M. López‑Ruiz, General Hospital of Mexico
Y. Inoue, Shizuoka Institute of Epilepsy and Neurological Disorders
S. Kaneko, Hirosaki University
S. Hirose, Fukuoka University
M. Osawa, Tokyo Women’s Medical University
H. Oguni, Tokyo Women’s Medical University
S. Fujimoto, Nagoya City University
T. M. Grisar, University of Liege
J. M. Stern, University of California, Los Angeles
K. Yamakawa, RIKEN Brain Science Institute, Saitama
B. Lakaye, University of Liege
A. V. Delgado-Escueta, Veterans Affairs Greater Los Angeles Healthcare System

Document Type

Article

Publication Date

3-15-2018

Abstract

BACKGROUND

In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis.

METHODS

Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase (ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case–control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick.

RESULTS

A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic–clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia.

CONCLUSIONS

Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.)

Comments

This article was originally published in New England Journal of Medicine, volume 378, in 2018. DOI: 10.1056/NEJMoa1700175

Copyright

Massachusetts Medical Society

Available for download on Saturday, September 15, 2018

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