Satoru Ikemoto1, Shin-Ichiro Hamano2, Kenjiro Kikuchi3, Reiko Koichihara4, Yuko Hirata3, Ryuki Matsuura3, Takuya Hiraide5, Mitsuko Nakashima5, Ken Inoue6, Kenji Kurosawa7, Hirotomo Saitsu5. 1. Division of Neurology, Saitama Children's Medical Center, Saitama-City, Saitama 330-8777, Japan; Department of Pediatrics, Jikei University School of Medicine, Minato-ku, Tokyo 105-8471, Japan. Electronic address: ike-satoru@hotmail.co.jp. 2. Division of Neurology, Saitama Children's Medical Center, Saitama-City, Saitama 330-8777, Japan; Department for Child Health and Human Development, Saitama Children's Medical Center, Saitama-City, Saitama 330-8777, Japan. 3. Division of Neurology, Saitama Children's Medical Center, Saitama-City, Saitama 330-8777, Japan; Department of Pediatrics, Jikei University School of Medicine, Minato-ku, Tokyo 105-8471, Japan. 4. Department for Child Health and Human Development, Saitama Children's Medical Center, Saitama-City, Saitama 330-8777, Japan. 5. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. 6. Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan. 7. Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
Abstract
INTRODUCTION: Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation. CASE STUDY: A 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD). METHODS: Proteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed. RESULTS: After excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products. DISCUSSION: This is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.
INTRODUCTION:Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation. CASE STUDY: A 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD). METHODS:Proteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed. RESULTS: After excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products. DISCUSSION: This is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.
Authors: Roberta Solazzi; Marco Moscatelli; Davide Rossi Sebastiano; Laura Canafoglia; Laura Pezzoli; Maria Iascone; Tiziana Granata Journal: Neurol Genet Date: 2022-08-29
Authors: Georg Werner; Markus Damme; Martin Schludi; Johannes Gnörich; Karin Wind; Katrin Fellerer; Benedikt Wefers; Wolfgang Wurst; Dieter Edbauer; Matthias Brendel; Christian Haass; Anja Capell Journal: EMBO Rep Date: 2020-09-14 Impact factor: 8.807