POLG1 Mutations Associated With Progressive Encephalopathy in Childhood

• Published in: Journal of neuropathology and experimental neurology 2006-08, Vol.65 (8), p.758-768
• Main Authors: Kollberg, Gittan, Moslemi, Ali-Reza, Darin, Niklas, Nennesmo, Inger, Bjarnadottir, Ingibjörg, Uvebrant, Paul, Holme, Elisabeth, Melberg, Atle, Tulinius, Már, Oldfors, Anders
• Format: Article
• Language: English
• Subjects: Adolescent; Age of Onset; Alpers-Huttenlocher syndrome; Biological and medical sciences; biosynthesis; Brain; Brain - metabolism; Brain - pathology; Brain - physiopathology; Child; Child, Preschool; Conserved Sequence; Conserved Sequence - genetics; COX deficiency; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diffuse Cerebral Sclerosis of Schilder; Diffuse Cerebral Sclerosis of Schilder - genetics; Diffuse Cerebral Sclerosis of Schilder - metabolism; Diffuse Cerebral Sclerosis of Schilder - physiopathology; DNA; DNA Mutational Analysis; DNA Polymerase gamma; DNA, Mitochondrial - biosynthesis; DNA, Mitochondrial - genetics; DNA-Directed DNA Polymerase; DNA-Directed DNA Polymerase - genetics; Electron Transport Complex IV; Electron Transport Complex IV - genetics; Electron Transport Complex IV - metabolism; Fatal Outcome; Female; Genetic Predisposition to Disease; Genetic Predisposition to Disease - genetics; Genetic Screening; Genetic Testing; genetics; Hematologic and hematopoietic diseases; Humans; Infant; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Liver Diseases; Liver Diseases - genetics; Liver Diseases - pathology; Liver Diseases - physiopathology; Male; MEDICAL AND HEALTH SCIENCES; Medical sciences; MEDICIN; MEDICIN OCH HÄLSOVETENSKAP; MEDICINE; metabolism; Missense; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial; Mitochondrial Diseases; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - physiopathology; Mitochondrial Myopathies; Mitochondrial Myopathies - genetics; Mitochondrial Myopathies - metabolism; Mitochondrial Myopathies - physiopathology; mitochondrial myopathy; MtDNA deletions; MtDNA depletion; Muscle; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Mutation; Mutation, Missense - genetics; Neurology; pathology; Pedigree; physiopathology; polymerase gamma; Preschool; Skeletal; Syndrome
• ISSN: 0022-3069; 1554-6578; 1554-6578
• DOI: 10.1097/01.jnen.0000229987.17548.6e

ABSTRACTWe have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol γ), 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.