Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy

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-tRNA(Glu) 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 tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.

Deutsche Forschungsgemeinschaft (DFG)[HO 2505/2-1]

Academy of Medical Sciences

RVI/NGH and Newcastle upon Tyne Hospitals NHS Charity[RES0211/7262]

Wellcome Trust[074454/Z/04/Z]

BBSRC[BB/F011520/1]

United Mitochondrial Diseases Foundation

Medical Research Council (UK)

UK Parkinson`s Disease Society

UK NIHR

German ministry of education and research (BMBF, Bonn, Germany)[S1]

German ministry of education and research (BMBF, Bonn, Germany)[01GM0601]

NIH[HD32062]

Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF)

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