Brain Advance Access originally published online on August 31, 2009
Brain 2009 132(11):3165-3174; doi:10.1093/brain/awp221
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy
1 Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK 2 Department of Pathology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, SE-413 45, Sweden 3 Department of Neurology, School of Medicine, University of Sao Paulo, 04023-900, Brazil 4 Department of Neurology, Universitá Cattolica del Sacro Cuore, Roma 00168, Italy 5 Department of Clinical Chemistry, The Sahlgrenska Academy, University of Gothenburg, Göteborg, SE-413 45, Sweden 6 Department of Neurology, Columbia University Medical Center, New York, NY 10032-3784, USA 7 The Dr. John McDonald Foundation Center for Medical Genetics, Miami Children's Hospital, Miami, FL 33155, USA 8 Department of Neurology, St Christopher's Hospital for Children, Philadelphia, PA 19134, USA 9 Medical Genetic Center, Munich 80335, Germany 10 Alfred I. duPont Hospital for Children, Division of Neurology, Wilmington, DE 19803, USA 11 Friedrich-Baur Institute, Department of Neurology, Ludwig-Mamimilians-University, Munich 80336, Germany 12 Department of Pediatrics, Itzehoe Hostpital, 25524, Germany 13 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK 14 Department of Pediatrics, The Sahlgrenska Academy, University of Gothenburg, Göteborg, SE-413 45, Sweden
Correspondence to: Rita Horvath, MD, PhD, Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. E-mail: rita.horvath{at}ncl.ac.uk
Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as ‘benign cytochrome c oxidase deficiency myopathy’ is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNAGlu mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNAGlu may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
Key Words: mitochondrial myopathy; reversible COX deficiency; homoplasmic tRNA mutation
Abbreviations: COX, cytochrome c oxidase; LHON, Leber's hereditary optic neuropathy; mt-tRNA, mitochondrial transfer RNA; RC, respiratory chain; RRF, ragged-red fibres
.
Received July 8, 2009. Revised July 21, 2009. Accepted July 23, 2009.
*These authors contributed equally to this work.