Novel mitochondrial transfer RNA^Phe gene mutation associated with late-onset neuromuscular disease

Background: An extensive range of molecular defects have been identified in the human mitochondrial genome (mitochondrial DNA); many are associated with well-characterized, progressive neurological syndromes, but a minority of patients have uncharacteristic phenotypes in which symptoms may be relatively mild. Objective: To describe a novel transfer RNA^Phe mutation of mitochondrial DNA in a late-onset case with a mild phenotype of mitochondrial disease. Design: Case report. Patient: A 66-year-old woman presented with a 4-year history of walking difficulties due to exercise intolerance and paresthesia in the feet. Clinical examination results were normal. Her deceased mother had similar walking difficulties, but her sister and 2 children were unaffected. Results: The demonstration of a marked histochemical defect in cytochrome c oxidase activity on muscle biopsy prompted molecular investigation of mitochondrial DNA, revealing a novel maternally inherited mutation in the variable loop of the mitochondrial transfer RNA^Phe gene. This 622G>A transition was heteroplasmic and segregated with cytochrome c oxidase deficiency in single fibers. Conclusion: This case serves to illustrate that primary defects of the mitochondrial genome should be considered even in older patients with late-onset, mild neuromuscular symptoms.