Toshitaka Kawarai1, Ryosuke Miyamoto2, Eiji Nakagawa3, Reiko Koichihara3, Takashi Sakamoto4, Hideo Mure5, Ryoma Morigaki6, Hidetaka Koizumi2, Ryosuke Oki2, Celeste Montecchiani7, Carlo Caltagirone8, Antonio Orlacchio7, Ayako Hattori9, Hideaki Mashimo10, Yuishin Izumi2, Takahiro Mezaki11, Satoko Kumada10, Makoto Taniguchi12, Fusako Yokochi13, Shinji Saitoh9, Satoshi Goto14, Ryuji Kaji2. 1. Department of Clinical Neuroscience, Tokushima University, Tokushima, Japan. Electronic address: tkawarai@tokuhshima-u.ac.jp. 2. Department of Clinical Neuroscience, Tokushima University, Tokushima, Japan. 3. Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan. 4. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan. 5. Department of Neurosurgery, Tokushima University, Tokushima, Japan. 6. Department of Neurosurgery, Tokushima University, Tokushima, Japan; Department of Neurodegenerative Disorders Research, And Parkinson's Disease and Dystonia Research Center, Tokushima University, Tokushima, Japan. 7. Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy; Dipartimento di Scienze Chirurgiche e Biomediche, Università di Perugia, Perugia, Italy. 8. Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy. 9. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 10. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu City, Tokyo, Japan. 11. Department of Neurology, Sakakibara Hakuho Hospital, 5630 Sakakibara-cho, Tsu City, Mie, Japan. 12. Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Fuchu City, Tokyo, Japan. 13. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Fuchu City, Tokyo, Japan. 14. Department of Neurodegenerative Disorders Research, And Parkinson's Disease and Dystonia Research Center, Tokushima University, Tokushima, Japan.
Abstract
BACKGROUND: Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. METHODS: We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. RESULTS: Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. CONCLUSIONS: We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease.
BACKGROUND: Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. METHODS: We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. RESULTS: Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. CONCLUSIONS: We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease.
Authors: Maria Abel; Robert Pfister; Iman Hussein; Fahd Alsalloum; Christina Onyinzo; Simon Kappl; Michael Zech; Walter Demmel; Martin Staudt; Manfred Kudernatsch; Steffen Berweck Journal: Front Neurol Date: 2021-05-14 Impact factor: 4.003
Authors: Laura Cif; Diane Demailly; Jean-Pierre Lin; Katy E Barwick; Mario Sa; Lucia Abela; Sony Malhotra; Wui K Chong; Dora Steel; Alba Sanchis-Juan; Adeline Ngoh; Natalie Trump; Esther Meyer; Xavier Vasques; Julia Rankin; Meredith W Allain; Carolyn D Applegate; Sanaz Attaripour Isfahani; Julien Baleine; Bettina Balint; Jennifer A Bassetti; Emma L Baple; Kailash P Bhatia; Catherine Blanchet; Lydie Burglen; Gilles Cambonie; Emilie Chan Seng; Sandra Chantot Bastaraud; Fabienne Cyprien; Christine Coubes; Vincent d'Hardemare; Asif Doja; Nathalie Dorison; Diane Doummar; Marisela E Dy-Hollins; Ellyn Farrelly; David R Fitzpatrick; Conor Fearon; Elizabeth L Fieg; Brent L Fogel; Eva B Forman; Rachel G Fox; William A Gahl; Serena Galosi; Victoria Gonzalez; Tracey D Graves; Allison Gregory; Mark Hallett; Harutomo Hasegawa; Susan J Hayflick; Ada Hamosh; Marie Hully; Sandra Jansen; Suh Young Jeong; Joel B Krier; Sidney Krystal; Kishore R Kumar; Chloé Laurencin; Hane Lee; Gaetan Lesca; Laurence Lion François; Timothy Lynch; Neil Mahant; Julian A Martinez-Agosto; Christophe Milesi; Kelly A Mills; Michel Mondain; Hugo Morales-Briceno; John R Ostergaard; Swasti Pal; Juan C Pallais; Frédérique Pavillard; Pierre-Francois Perrigault; Andrea K Petersen; Gustavo Polo; Gaetan Poulen; Tuula Rinne; Thomas Roujeau; Caleb Rogers; Agathe Roubertie; Michelle Sahagian; Elise Schaefer; Laila Selim; Richard Selway; Nutan Sharma; Rebecca Signer; Ariane G Soldatos; David A Stevenson; Fiona Stewart; Michel Tchan; Ishwar C Verma; Bert B A de Vries; Jenny L Wilson; Derek A Wong; Raghda Zaitoun; Dolly Zhen; Anna Znaczko; Russell C Dale; Claudio M de Gusmão; Jennifer Friedman; Victor S C Fung; Mary D King; Shekeeb S Mohammad; Luis Rohena; Jeff L Waugh; Camilo Toro; F Lucy Raymond; Maya Topf; Philippe Coubes; Kathleen M Gorman; Manju A Kurian Journal: Brain Date: 2020-12-05 Impact factor: 13.501