Novel mutations in myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy M.T. Medina, MD T. Suzuki, PhD M.E. Alonso, MD R.M. Duro ´ n, MD I.E. Martı ´nez-Jua ´rez, MD J.N. Bailey, PhD D. Bai, MD Y. Inoue, MD I. Yoshimura, MD S. Kaneko, MD M.C. Montoya, MD A. Ochoa, MSc A. Jara Prado, PhD M. Tanaka, MD J. Machado-Salas, MD, PhD S. Fujimoto, MD M. Ito, MD S. Hamano, MD K. Sugita, MD Y. Ueda, MD M. Osawa, PhD H. Oguni, PhD F. Rubio-Donnadieu, MD K. Yamakawa, PhD A.V. Delgado-Escueta, MD ABSTRACT Background: Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, the GENESS Consortium demonstrated four missense mutations in Myoclonin1/EFHC1 of chro- mosome 6p12.1 segregating in 20% of Hispanic families with JME. Objective: To examine what percentage of consecutive JME clinic cases have mutations in Myo- clonin1/EFHC1. Methods: We screened 44 consecutive patients from Mexico and Honduras and 67 patients from Japan using heteroduplex analysis and direct sequencing. Results: We found five novel mutations in transcripts A and B of Myoclonin1/EFHC1. Two novel heterozygous missense mutations (c.755CA and c.1523CG) in transcript A oc- curred in both a singleton from Mexico and another singleton from Japan. A deletion/frame- shift (C.789del.AV264fsx280) in transcript B was present in a mother and daughter from Mexico. A nonsense mutation (c.829CT) in transcript B segregated in four clinically and seven epileptiform-EEG affected members of a large Honduran family. The same nonsense mutation (c.829CT) occurred as a de novo mutation in a sporadic case. Finally, we found a three-base deletion (-364^–362del.GAT) in the promoter region in a family from Japan. Conclusion: Nine percent of consecutive juvenile myoclonic epilepsy cases from Mexico and Hon- duras clinics and 3% of clinic patients from Japan carry mutations in Myoclonin1/EFCH1. These results represent the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group. Neurology ® 2008;70:1–1 GLOSSARY CAE = childhood absence epilepsy; FS = febrile seizures in infancy/childhood; GM = grand mal tonic clonic seizure; JME = Juvenile myoclonic epilepsy; PSW = 3– 6 Hz polyspike and slow wave complexes; SW = single spike and slow wave complex. Juvenile myoclonic epilepsy (JME) is the most common cause of primary grand mal seizures. 1,2 It is responsible for 6 to 12% up to 30% of all epilepsies in hospitals/clinics 3 and for 3% according to a door-to-door population study. 4 The JME phenotype is char- acterized by adolescent onset and lifelong grand mal (clonic-tonic-clonic), myoclonic, and absence seizures and EEG diffuse 3.5– 6 Hz polyspike waves. 2,5,6 Three mutation-harboring genes have been identified for JME. One is the gamma- aminobutyric acid receptor alpha-1 (GABRA1) gene on chromosome 5q34-q35, found to From the Neurology Training Program (M.T.M., R.M.D., M.C.M.), National Autonomous University of Honduras, Tegucigalpa; Epilepsy Genetics/Genomics Laboratories (M.T.M., R.M.D., I.E.M.-J., J.N.B., D.B., M.T., J.M.-S., A.V.D.-E.), Epilepsy Center of Excellence, Neurology & Research Services, VA Greater Los Angeles Healthcare System–West Los Angeles Medical Center and David Geffen School of Medicine at UCLA; RIKEN Brain Science Institute (T.S., K.Y.), Saitama, Japan; National Institute of Neurology and Neurosurgery “Manuel Velasco Sua ´rez” (M.E.A., I.E.M.-J., A.O., A.J.P., F.R.-D.), Mexico; Semel Institute for Neuroscience (J.N.B.), David Geffen School of Medicine at UCLA; National Epilepsy Center (Y.I.), Shizuoka Inst. of Epilepsy Neurological Disorders, Japan; Department of Neuropsychiatry (I.Y., S.K.), School of Medicine, Hirosaki University, Aomori, Japan; Nagoya City University School of Medicine (S.F.), Japan; Department of Pediatrics (M.I.), Shiga Medical Center for Children, Moriyama, Japan; Children’s Medical Center (S.H.), Saitama, Japan; Oral Health Science Center (K.S.), Department of Paediatrics, Ichikawa General Hospital, Tokyo Dental College, Shiga, Japan; Department of Psychiatry (Y.U.), Miyazaki Medical College, University of Miyazaki, Kiyotake, Japan; and Department of Pediatrics (M.O., H.O.), Tokyo Woman’s Medical University, Japan. AVDE and this project are supported in part by NIH RO1-NS42376, Veterans Administration Merit Review Grant, and the Neurology and Research Services of Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA. The Horowitz Foundation and the Neurology Training Program at the National Autonomous University of Honduras, Instituto de Neurociencias at Tegucigalpa, and the National Institute of Neurology and Neurosurgery “Manuel Velasco Sua ´rez,” Mexico, also supported this project with funds and logistical aspects. For this work, K.Y. and T.S. were supported in part by a grant from RIKEN Brain Science Institute of Japan. Disclosure: The authors report no disclosures. Supplemental data at www.neurology.org Address correspondence and reprint requests to Dr. Antonio V. Delgado-Escueta, Epilepsy Genetics/Genomics Laboratories, Epilepsy Center of Excellence, Neurology & Research Services, VA Greater Los Angeles Healthcare System–West Los Angeles Medical Center and David Geffen School of Medicine at UCLA, Bldg 500, Room 3405 (127B), VA GLAHS, 11301 Wilshire Blvd., Los Angeles, CA 90073 escueta@ucla.edu balt4/znl-neurol/znl-neurol/znl12208/znl5509-08a shropsha S12 4/14/08 10:54 Art: WNL189296 Input-nlm Copyright © 2008 by AAN Enterprises, Inc. 1 Fn1 <article article-typeresearch-article> • <article-id pub-id-typedoi>10.1212/01.wnl.0000313149.73035.99</article-id>