Brain Advance Access first published online on April 18, 2006
This version published online on May 19, 2006
Brain, doi:10.1093/brain/awl088
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1 Metabolic Diseases Centre, Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, Academic Hospital Schwabing, Munich, Germany
* To whom correspondence should be addressed. Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase
Received February 20, 2006
Revised March 14, 2006
Accepted March 15, 2006
Article
Phenotypic spectrum associated with mutations of the mitochondrial polymerase
Rita Horvath 1,
Gavin Hudson 2,
Gianfrancesco Ferrari 3,
Nancy Fütterer 4,
Sofia Ahola 5,
Eleonora Lamantea 3,
Holger Prokisch 6,
Hanns Lochmüller 7,
Robert McFarland 8,
V. Ramesh 9,
Thomas Klopstock 10,
Peter Freisinger 4,
Fabrizio Salvi 11,
Johannes A. Mayr 12,
Rene Santer 13,
Marketa Tesarova 14,
Jiri Zeman 14,
Bjarne Udd 15,
Robert W. Taylor 2,
Douglass Turnbull 2,
Anu Suomalainen 3,
Massimo Zeviani 3,
Michael Hanna 16,
Doreen Fialho 16,
and
Patrick F. Chinnery 17 *
gene
2 Mitochondrial Research Group, University of Newcastle upon Tyne, UK
3 Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute, Milan, Italy
4 Metabolic Diseases Centre, Munich-Schwabing, Children's Hospital and Institute of Medical Genetics, Technical University, Munich, Germany
5 Department of Medical Genetics, Programme of Neurosciences, University of Helsinki, Finland
6 Institute of Human Genetics, GSF Research Centre for Environment and Health, Neuherberg, Germany
7 Friedrich Baur Institute, Ludwig Maximilians University, Munich, Germany
8 Mitochondrial Research Group, University of Newcastle upon Tyne, UK; Department of Paediatric Neurology, Newcastle General Hospital, Newcastle upon Tyne, UK
9 Department of Paediatric Neurology, Newcastle General Hospital, Newcastle upon Tyne, UK
10 Department of Neurology, Ludwig Maximilians University, Munich, Germany
11 Department of Neurosciences, Unit of Neurology, ‘Bellaria’ Hospital, Bologna, Italy
12 Clinic of Pediatrics, Paracelsus Medical University, Salzburg, Austria
13 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
14 Department of Pediatrics and Centre for Applied Genomics, Faculty of Medicine, Charles University, Prague, Czech Republic
15 Department of Neurology, Vaasa Central Hospital, Vaasa, Finland
16 Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK
17 Mitochondrial Research Group, University of Newcastle upon Tyne, UK; Institute for Human Genetics, University of Newcastle upon Tyne, UK
Patrick F. Chinnery, E-mail: P.F.Chinnery{at}ncl.ac.uk
Abstract 
(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. 1399GA (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.
This version contains a correction to the original version published on April 18, 2006. "A767N" has been corrected to "A767D" throughout the paper.
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