title: POLG1 mutations associated with progressive encephalopathy in childhood.
abstract: We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.
authors.affiliation: Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: Gittan
authors.initials: G
authors.lastname: Kollberg
authors.forename: Ali-Reza
authors.initials: AR
authors.lastname: Moslemi
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.forename: Ingibjörg
authors.initials: I
authors.lastname: Bjarnadottir
authors.forename: Paul
authors.initials: P
authors.lastname: Uvebrant
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Holme
authors.forename: Atle
authors.initials: A
authors.lastname: Melberg
authors.forename: Már
authors.initials: M
authors.lastname: Tulinius
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002675:Child, Preschool; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D017809:Fatal Outcome; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human