title: A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease.
abstract: Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors.
authors.affiliation: UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery and the MRC Centre for Neuromuscular Diseases, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Rajakulendran
authors.affiliation: UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom and Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London SE5 8AF, United Kingdom.
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.affiliation: Department of Clinical Neurosciences, UCL Institute of Neurology, London NW3 2PF, United Kingdom.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.affiliation: Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: Harry
authors.initials: H
authors.lastname: Costello
authors.affiliation: Department of Neurogenetics, UCL Institute of Neurology and National Hospital for Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: Department of Neurogenetics, UCL Institute of Neurology and National Hospital for Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Cathy E
authors.initials: CE
authors.lastname: Woodward
authors.affiliation: Division of Neuropathology, UCL Institute of Neurology and National Hospital for Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Zane
authors.initials: Z
authors.lastname: Jaunmuktane
authors.affiliation: Division of Neuropathology, UCL Institute of Neurology and National Hospital for Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health and Department of Histopathology, Great Ormond Street Hospital for Children Foundation Trust, London WC1N 1EH, United Kingdom.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.affiliation: Division of Neuropathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Harding
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford OX3 7LE, United Kingdom.
authors.forename: Carl
authors.initials: C
authors.lastname: Fratter
authors.affiliation: UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery and the MRC Centre for Neuromuscular Diseases, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, United Kingdom.|Metabolic Unit, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics / Q000473:pathology; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human