title: Myocerebrohepatopathy spectrum disorder due to POLG mutations: A clinicopathological report.
abstract: We report on the clinical, neuropathological, and genetic findings of a Japanese case with myocerebrohepatopathy spectrum (MCHS) disorder due to polymerase gamma (POLG) mutations. A girl manifested poor sucking and failure to thrive since 4 months of age and had frequent vomiting and developmental regression at 5 months of age. She showed significant hypotonia and hepatomegaly. Laboratory tests showed hepatocellular dysfunction and elevated protein and lactate levels in the cerebrospinal fluid. Her liver function and neurologic condition exacerbated, and she died at 8 months of age. At autopsy, fatty degeneration and fibrosis were observed in the liver. Neuropathological examination revealed white matter-predominant spongy changes with Alzheimer type II glia and loss of myelin. Enzyme activities of the respiratory chain complex I, III, and IV relative to citrate synthase in the muscle were normal in the biopsied muscle tissue, but they were reduced in the liver to 0%, 10%, and 14% of normal values, respectively. In the liver, the copy number of mitochondrial DNA compared to nuclear DNA was reduced to 3.3% of normal values as evaluated by quantitative polymerase chain reaction. Genetic analysis revealed compound heterozygous mutations for POLG (I1185T/A957V). This case represents the differential involvement of multiple organs and phenotype-specific distribution of brain lesions in mitochondrial DNA depletion disorders.
authors.affiliation: Division of Child Neurology, Faculty of Medicine, Tottori University, Yonago, Japan; Department of Family Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Hesham
authors.initials: H
authors.lastname: Montassir
authors.affiliation: Division of Child Neurology, Faculty of Medicine, Tottori University, Yonago, Japan. Electronic address: maegaki@med.tottori-u.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Maegaki
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.affiliation: Department of Pediatrics, School of Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohda
authors.affiliation: Department of Pediatrics, School of Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Iwasa
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yatsuka
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan; Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Division of Child Neurology, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Sugiura
authors.affiliation: Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nagata
authors.affiliation: Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Toyoshima
authors.affiliation: Division of Child Neurology, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Division of Child Neurology, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
mesh_terms: D001921:Brain / Q000473:pathology*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006501:Hepatic Encephalopathy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D017093:Liver Failure / Q000235:genetics / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology; D009154:Mutation
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
keywords: Alpers syndrome; Mitochondrial DNA depletion; Myocerebrohepatopathy spectrum disorder; POLG