title: Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study.
abstract: Mitochondrial tRNA(Leu(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 18 months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8 years, 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 tRNA(Leu(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.
authors.affiliation: Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, CI 02-35, Av P Decker 2, 1011 Lausanne, Switzerland. diana.ballhausen@chuv.ch
authors.forename: Diana
authors.initials: D
authors.lastname: Ballhausen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Guerry
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hahn
authors.forename: André
authors.initials: A
authors.lastname: Schaller
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nuoffer
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Jeannet
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
mesh_terms: D017668:Age of Onset; D001706:Biopsy; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004734:Energy Metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D017240:Mitochondrial Myopathies / Q000150:complications / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D018908:Muscle Weakness / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D010085:Oxidative Phosphorylation; D010375:Pedigree; D010641:Phenotype; D052097:Quadriceps Muscle / Q000201:enzymology / Q000503:physiopathology; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012343:RNA, Transfer / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D000077278:RNA, Mitochondrial; D012313:RNA; D012343:RNA, Transfer
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