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Mitochondrial tRNALeu(UUR) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study

Ballhausen, Diana ; Guerry, Frédéric ; Hahn, Dagmar ; Schaller, André ; Nuoffer, Jean-Marc ; Bonafé, Luisa ; Jeannet, Pierre-Yves ; Jacquemont, Sebastien

In: Journal of Inherited Metabolic Disease, 2010, vol. 33, p. 219-226

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    Titel
    • Mitochondrial tRNALeu(UUR) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study
    Autor
    • Ballhausen, Diana. Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, CI 02-35, Av. P. Decker 2, 1011, Lausanne, Switzerland
    • Guerry, Frédéric. Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
    • Hahn, Dagmar. University Institute of Clinical Chemistry, Inselspital Bern, Switzerland
    • Schaller, André. Department of Pediatrics, Division of Human Genetics, Inselspital Bern, Switzerland
    • Nuoffer, Jean-Marc. University Institute of Clinical Chemistry, Inselspital Bern, Switzerland
    • Bonafé, Luisa. Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, CI 02-35, Av. P. Decker 2, 1011, Lausanne, Switzerland
    • Jeannet, Pierre-Yves. Neuropediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
    • Jacquemont, Sebastien. Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Journal of Inherited Metabolic Disease, 2010, vol. 33, p. 219-226. Springer Netherlands
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:310391
    Summary
    Mitochondrial tRNALeu(UUR) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNALeu(UUR) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected families