Yu Kobayashi1, Jun Tohyama2, Mitsuhiro Kato3, Noriyuki Akasaka1, Shinichi Magara1, Hideshi Kawashima1, Tsukasa Ohashi1, Hideaki Shiraishi4, Mitsuko Nakashima5, Hirotomo Saitsu5, Naomichi Matsumoto5. 1. Department of Child Neurology, Nishi-Niigata Chuo National Hospital, Niigata, Japan. 2. Department of Child Neurology, Nishi-Niigata Chuo National Hospital, Niigata, Japan; Niigata University Medical and Dental Hospital, Niigata, Japan. Electronic address: jtohyama@masa.go.jp. 3. Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan; Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan. 4. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 5. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Abstract
OBJECTIVE: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders. METHODS: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes. RESULTS: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients. CONCLUSIONS: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities.
OBJECTIVE: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders. METHODS: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes. RESULTS: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients. CONCLUSIONS: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities.
Authors: Bobby G Ng; Erik A Eklund; Sergey A Shiryaev; Yin Y Dong; Mary-Alice Abbott; Carla Asteggiano; Michael J Bamshad; Eileen Barr; Jonathan A Bernstein; Shabeed Chelakkadan; John Christodoulou; Wendy K Chung; Michael A Ciliberto; Janice Cousin; Fiona Gardiner; Suman Ghosh; William D Graf; Stephanie Grunewald; Katherine Hammond; Natalie S Hauser; George E Hoganson; Kimberly M Houck; Jennefer N Kohler; Eva Morava; Austin A Larson; Pengfei Liu; Sujana Madathil; Colleen McCormack; Naomi J L Meeks; Rebecca Miller; Kristin G Monaghan; Deborah A Nickerson; Timothy Blake Palculict; Gabriela Magali Papazoglu; Beth A Pletcher; Ingrid E Scheffer; Andrea Beatriz Schenone; Rhonda E Schnur; Yue Si; Leah J Rowe; Alvaro H Serrano Russi; Rossana Sanchez Russo; Farouq Thabet; Allysa Tuite; María Mercedes Villanueva; Raymond Y Wang; Richard I Webster; Dorcas Wilson; Alice Zalan; Lynne A Wolfe; Jill A Rosenfeld; Lindsay Rhodes; Hudson H Freeze Journal: J Inherit Metab Dis Date: 2020-08-05 Impact factor: 4.982
Authors: Sonja Martin; Adam Chamberlin; Deepali N Shinde; Maja Hempel; Tim M Strom; Allison Schreiber; Jessika Johannsen; Lilian Bomme Ousager; Martin J Larsen; Lars Kjaersgaard Hansen; Ali Fatemi; Julie S Cohen; Johannes Lemke; Kristina P Sørensen; Katherine L Helbig; Davor Lessel; Rami Abou Jamra Journal: Am J Hum Genet Date: 2017-12-07 Impact factor: 11.025
Authors: Riley E Perszyk; Scott J Myers; Hongjie Yuan; Alasdair J Gibb; Hiro Furukawa; Alexander I Sobolevsky; Stephen F Traynelis Journal: J Physiol Date: 2020-06-15 Impact factor: 5.182
Authors: Stephan J Sanders; Arthur J Campbell; Jeffrey R Cottrell; Rikke S Moller; Florence F Wagner; Angie L Auldridge; Raphael A Bernier; William A Catterall; Wendy K Chung; James R Empfield; Alfred L George; Joerg F Hipp; Omar Khwaja; Evangelos Kiskinis; Dennis Lal; Dheeraj Malhotra; John J Millichap; Thomas S Otis; Steven Petrou; Geoffrey Pitt; Leah F Schust; Cora M Taylor; Jennifer Tjernagel; John E Spiro; Kevin J Bender Journal: Trends Neurosci Date: 2018-04-23 Impact factor: 13.837
Authors: Kathleen M Gorman; Esther Meyer; Detelina Grozeva; Egidio Spinelli; Amy McTague; Alba Sanchis-Juan; Keren J Carss; Emily Bryant; Adi Reich; Amy L Schneider; Ronit M Pressler; Michael A Simpson; Geoff D Debelle; Evangeline Wassmer; Jenny Morton; Diana Sieciechowicz; Eric Jan-Kamsteeg; Alex R Paciorkowski; Mary D King; J Helen Cross; Annapurna Poduri; Heather C Mefford; Ingrid E Scheffer; Tobias B Haack; Gary McCullagh; John J Millichap; Gemma L Carvill; Jill Clayton-Smith; Eamonn R Maher; F Lucy Raymond; Manju A Kurian Journal: Am J Hum Genet Date: 2019-04-11 Impact factor: 11.025