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

Abstract

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 O 2 /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.