Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations

Objective: To assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene. Design: We used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis. Setting: University neuromuscular and neurogenetics and magnetic resonance imaging units. Patients: Eighteen patients with dominant optic atrophy were enrolled from 8 unrelated families, 7 of which carried an OPA1 mutation predicted to induce haplo-insufficiency and 1 with a missense mutation in exon 27. Fifteen patients had documented optic atrophy. Main Outcome Measures: Presence of skeletal muscle mitochondrial oxidative phosphorylation dysfunction as assessed by phosphorus 31 magnetic resonance spectroscopy, serum lactate levels, and histological and mitochondrial DNA analysis. Results: Phosphorus 31 magnetic resonance spectroscopy showed reduced phosphorylation potential in the calf muscle at rest in patients with an OPA1 mutation (-24% from normal mean; P = .003) as well as a reduced maximum rate of mitochondrial adenosine triphosphate synthesis (-36%; P