Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy

Abstract

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.

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

“…With the exception of reversible COX deficiencies due to TRM 15 and mt-tRNAglu, 16 isolated COX deficiency is a devastating disease. Currently, no satisfactory treatment is available.…”

Mitochondrial Disease in Childhood: mtDNA Encoded

“…The muscle biopsy material demonstrates absent muscle complex IV or COX activity. These patients improve spontaneously between 5 and 20 months of age with reversal to normal COX activity and are phenotypically healthy and without major symptoms [88,89]. The etiology is a homoplasmic m.14674 T>C mutation in the tRNA Glu gene [89].…”

“…Homoplasmic mutations are often manifested only in isolated tissues with incomplete penetrance [58][59][60]. Recently, a developmentallyexpressed point mutation in a tRNA gene has also been described-reversible infantile cytochrome c oxidase (COX) deficiency [61]. Specific criteria have been formulated to separate the many mtDNA mutations that are neutral polymorphisms from disease-causing mutations (Table 2) [62].…”

“…Although first described by DiMauro et al [88] in the early 1980s, the genetic defect was not elucidated until 2009 [89]. Affected infants present with hypotonia and severe muscle weakness in the first few days to weeks of life.…”

Mitochondrial DNA Repair

“…The majority of the proteins dedicated to DNA repair have to be transcribed and translated from nuclear DNA where they are encoded and imported into the mitochondrion . Many inherited diseases result from mutations in the mitochondrial genome or due to mutations in nuclear genes that encode mitochondrial components (Chan and Copeland, 2009;Horvath et al, 2009;Tuppen et al, 2010). Somatic mutations in mitochondrial DNA are increasingly linked to common diseases, including age-related degenerative disorders and cancers.…”