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Brain Advance Access originally published online on April 18, 2006
Brain 2006 129(7):1674-1684; doi:10.1093/brain/awl088
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Phenotypic spectrum associated with mutations of the mitochondrial polymerase {gamma} gene

Rita Horvath1, Gavin Hudson7, Gianfrancesco Ferrari11, Nancy Fütterer2, Sofia Ahola13, Eleonora Lamantea11, Holger Prokisch5, Hanns Lochmüller3, Robert McFarland7,9, V. Ramesh9, Thomas Klopstock4, Peter Freisinger2, Fabrizio Salvi12, Johannes A. Mayr15, Rene Santer6, Marketa Tesarova16, Jiri Zeman16, Bjarne Udd14, Robert W. Taylor7, Douglass Turnbull7, Michael Hanna10, Doreen Fialho10, Anu Suomalainen13, Massimo Zeviani11 and Patrick F. Chinnery7,8

1 Metabolic Diseases Centre, Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, Academic Hospital Schwabing Munich, Germany 2 Metabolic Diseases Centre, Munich-Schwabing, Children's Hospital and Institute of Medical Genetics, Technical University Munich, Germany 3 Friedrich Baur Institute, Ludwig Maximilians University Munich, Germany 4 Department of Neurology, Ludwig Maximilians University Munich, Germany 5 Institute of Human Genetics, GSF Research Centre for Environment and Health Neuherberg, Germany 6 Department of Pediatrics, University Medical Center Hamburg-Eppendorf Hamburg, Germany 7 Mitochondrial Research Group, University of Newcastle upon Tyne UK 8 Institute for Human Genetics, University of Newcastle upon Tyne UK 9 Department of Paediatric Neurology, Newcastle General Hospital Newcastle upon Tyne, UK 10 Department of Molecular Neuroscience, Institute of Neurology, University College London Queen Square, London, UK 11 Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute Milan, Italy 12 Department of Neurosciences, Unit of Neurology, ‘Bellaria’ Hospital Bologna, Italy 13 Department of Medical Genetics, Programme of Neurosciences, University of Helsinki Finland 14 Department of Neurology, Vaasa Central Hospital Vaasa, Finland 15 Clinic of Pediatrics, Paracelsus Medical University Salzburg, Austria 16 Department of Pediatrics and Centre for Applied Genomics, Faculty of Medicine, Charles University Prague, Czech Republic

Correspondence to: Patrick F. Chinnery, M4014, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK E-mail: P.F.Chinnery{at}ncl.ac.uk

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase {gamma} (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.

Key Words: mitochondrial encephalopathy; mitochondrial DNA; polymerase gamma; mtDNA; chronic progressive external ophthalmoplegia; Alpers syndrome

Abbreviations: mtDNA, mitochondrial DNA; PCR, polymerase chain reaction; PEO, progressive external ophthalmoplegia; pol {gamma}, polymerase {gamma}; SLE, stroke-like episodes

Received February 20, 2006. Revised March 14, 2006. Accepted March 15, 2006.


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