Hirokazu Kurahashi1, Yoshiteru Azuma2,3, Akio Masuda4, Tatsuya Okuno4, Eri Nakahara5, Takuji Imamura6, Makiko Saitoh7, Masashi Mizuguchi7, Toshiaki Shimizu5, Kinji Ohno4, Akihisa Okumura1,5. 1. Department of Pediatrics, Aichi Medical University, Nagakute, Aichi, Japan. 2. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. 3. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom. 4. Division of Neurogenetics, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. 5. Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan. 6. Department of Pediatrics, PL General Hospital, Tondabayashi, Osaka, Japan. 7. Department of Developmental Medical Sciences, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Abstract
OBJECTIVE: Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors. METHODS: We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations. Whole-exome sequencing was performed in family members. RESULTS: Eight rare nonsynonymous single-nucleotide variants shared by all patients were identified. By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family. Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant. INTERPRETATION: MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization. We propose the term "MYRF-related mild encephalopathy with reversible myelin vacuolization." Our findings provide a new perspective on the pathogenesis of myelin vacuolization. Ann Neurol 2018;83:98-106.
OBJECTIVE: Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors. METHODS: We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations. Whole-exome sequencing was performed in family members. RESULTS: Eight rare nonsynonymous single-nucleotide variants shared by all patients were identified. By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family. Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant. INTERPRETATION: MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization. We propose the term "MYRF-related mild encephalopathy with reversible myelin vacuolization." Our findings provide a new perspective on the pathogenesis of myelin vacuolization. Ann Neurol 2018;83:98-106.
Authors: Linda Z Rossetti; Kevin Glinton; Bo Yuan; Pengfei Liu; Nishitha Pillai; Elizabeth Mizerik; Pilar Magoulas; Jill A Rosenfeld; Lefkothea Karaviti; Vernon R Sutton; Seema R Lalani; Daryl A Scott Journal: Am J Med Genet A Date: 2019-05-08 Impact factor: 2.802
Authors: Hongjian Qi; Lan Yu; Xueya Zhou; Julia Wynn; Haoquan Zhao; Yicheng Guo; Na Zhu; Alexander Kitaygorodsky; Rebecca Hernan; Gudrun Aspelund; Foong-Yen Lim; Timothy Crombleholme; Robert Cusick; Kenneth Azarow; Melissa E Danko; Dai Chung; Brad W Warner; George B Mychaliska; Douglas Potoka; Amy J Wagner; Mahmoud ElFiky; Jay M Wilson; Debbie Nickerson; Michael Bamshad; Frances A High; Mauro Longoni; Patricia K Donahoe; Wendy K Chung; Yufeng Shen Journal: PLoS Genet Date: 2018-12-10 Impact factor: 5.917
Authors: Sarah J Garnai; Michelle L Brinkmeier; Ben Emery; Tomas S Aleman; Louise C Pyle; Biliana Veleva-Rotse; Robert A Sisk; Frank W Rozsa; Ayse Bilge Ozel; Jun Z Li; Sayoko E Moroi; Steven M Archer; Cheng-Mao Lin; Sarah Sheskey; Laurel Wiinikka-Buesser; James Eadie; Jill E Urquhart; Graeme C M Black; Mohammad I Othman; Michael Boehnke; Scot A Sullivan; Gregory L Skuta; Hemant S Pawar; Alexander E Katz; Laryssa A Huryn; Robert B Hufnagel; Sally A Camper; Julia E Richards; Lev Prasov Journal: PLoS Genet Date: 2019-05-02 Impact factor: 5.917
Authors: Joshua Hagedorn; Armin Avdic; Michael J Schnieders; Benjamin R Roos; Young H Kwon; Arlene V Drack; Erin A Boese; John H Fingert Journal: BMC Ophthalmol Date: 2020-10-01 Impact factor: 2.209