Journal Article

Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene

Rita Horvath, Gavin Hudson, Gianfrancesco Ferrari, Nancy Fütterer, Sofia Ahola, Eleonora Lamantea, Holger Prokisch, Hanns Lochmüller, Robert McFarland, V. Ramesh, Thomas Klopstock, Peter Freisinger, Fabrizio Salvi, Johannes A. Mayr, Rene Santer, Marketa Tesarova, Jiri Zeman, Bjarne Udd, Robert W. Taylor, Douglass Turnbull, Michael Hanna, Doreen Fialho, Anu Suomalainen, Massimo Zeviani and Patrick F. Chinnery

in Brain

Published on behalf of The Guarantors of Brain

Volume 129, issue 7, pages 1674-1684
ISSN: 0006-8950
Published online May 2006 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awl088
Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene

Show Summary Details

Preview

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase γ (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.

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

Journal Article.  5221 words.  Illustrated.

Subjects: Neurology ; Neuroscience

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.