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Lookup NU author(s): Dr Helen Swalwell, Dr Denise Kirby, Dr Anna MitchellORCiD, Emeritus Professor Doug Turnbull, Professor Bobby McFarlandORCiD, Professor Robert Taylor
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Defects of the mitochondrial respiratory chain are associated with a diverse spectrum of clinical phenotypes, and may be caused by mutations in either the nuclear or the mitochondrial genome (mitochondrial DNA (mtDNA)). Isolated complex I deficiency is the most common enzyme defect in mitochondrial disorders, particularly in children in whom family history is often consistent with sporadic or autosomal recessive inheritance, implicating a nuclear genetic cause. In contrast, although a number of recurrent, pathogenic mtDNA mutations have been described, historically, these have been perceived as rare causes of paediatric complex I deficiency. We reviewed the clinical and genetic findings in a large cohort of 109 paediatric patients with isolated complex I deficiency from 101 families. Pathogenic mtDNA mutations were found in 29 of 101 probands (29%), 21 in MTND subunit genes and 8 in mtDNA tRNA genes. Nuclear gene defects were inferred in 38 of 101 (38%) probands based on cell hybrid studies, mtDNA sequencing or mutation analysis (nuclear gene mutations were identified in 22 probands). Leigh or Leigh-like disease was the most common clinical presentation in both mtDNA and nuclear genetic defects. The median age at onset was higher in mtDNA patients (12 months) than in patients with a nuclear gene defect (3 months). However, considerable overlap existed, with onset varying from 0 to 460 months in both groups. Our findings confirm that pathogenic mtDNA mutations are a significant cause of complex I deficiency in children. In the absence of parental consanguinity, we recommend whole mitochondrial genome sequencing as a key approach to elucidate the underlying molecular genetic abnormality. European Journal of Human Genetics (2011) 19, 769-775; doi:10.1038/ejhg.2011.18; published online 2 March 2011
Author(s): Swalwell H, Kirby DM, Blakely EL, Mitchell A, Salemi R, Sugiana C, Compton AG, Tucker EJ, Ke X, Lamont PJ, Turnbull DM, McFarland R, Taylor RW, Thorburn DR
Publication type: Article
Publication status: Published
Journal: European Journal of Human Genetics
Year: 2011
Volume: 19
Issue: 7
Pages: 769-775
Print publication date: 01/07/2011
ISSN (print): 1018-4813
ISSN (electronic): 1476-5438
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/ejhg.2011.18
DOI: 10.1038/ejhg.2011.18
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