G.P.115 Recurrent myoglobinuria and deranged acyl-carnitines due to mutation of the COII gene of mtDNA

Abstract Mitochondrial myopathies generally present with exercise intolerance in which the typical symptoms constitute breathlessness and fatigue on exercise. Exercise-induced rhabdomyolysis and myoglobinuria occur very rarely. This case presents the story of a 43-year old man with a life-long history of exercise intolerance, associated with recurrent episodes of exercise-induced myoglobinuria. His parents sought medical assistance when he as a young boy could not keep up with his younger sister when walking. He was believed to be affected by multiple acyl-CoA dehydrogenase deficiency (MADD), because of his symptoms, and because his acyl-carnitine profiles looked typical for MADD. He was treated with riboflavin, which however, worsened his symptoms. Results: On testing, the patient had a normal neurological examination, except for mild weakness in hip flexion bilaterally. Resting plasma lactate ranged from normal to 3.8 mmol/L. A muscle biopsy showed only mild myopathic changes, no abnormal lipid accumulation, approximately 40% COX-negative fibers, and a few ragged blue fibers and multiple fibers with subsarcolemmal accumulation of mitochondria. Biochemical assessment showed a selective complex IV deficiency (20% of normal). No mutation in the three genes responsible for MADD could be found, but sequencing of the mitochondrial genome revealed a novel, frame-shifting mutation in the COII subunit gene (8156dupG). The mutation load in muscle was 56%. The mutation was not present in fibroblasts or blood from the patient. In accordance with the exercise intolerance, the patient had a peak oxygen uptake of 23 ml O2 /min/kg on cycle testing, which is about 60% of normal for the age. Mutations in COII of mtDNA have only been reported in a handful of patients, and the present case demonstrates that a phenotype of a disorder of lipid oxidation can be mimicked with this defect, with recurrent episode of myoglobinuria and acyl-carnitine profiles reminiscent of MADD.