METABOLIC MYOPATHIES I: P.274Heterozygous mutation in ISCU associated with recurrent rhabdomyolysis

Abstract

Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron-sulfur (Fe-S) clusters. We report here the case of 17 years-old girl native from French Caribbean Islands who presented with acute diffuse muscle pain, facial edema, and mild proximal muscle weakness (3/5). Medical history revealed exercise intolerance and three episods of rhabdomyolysis (maximum CK levels at 74,000; 20,000 and 3,000 UI/L) without renal failure during the last two years. Blood testing showed markedly increased CK levels (195,560 UI/L, normal<200) and lactic acidosis. Muscle biopsy showed myofiber anisodiametry, and scaterred basophilic fibers. Immunohistochemical study showed numerous NCAM-positive regenerating fibers, most often grouped in areas. MHC-1 immunostaining disclosed a few randomly distributed positive fibers. C5b-9 immunostaining showed 'rabbit poop' sarcolemmal complément deposits. Perls (prussian blue) stain showed some fibers with mild punctuate accumulation of iron (Fe3+). Genetic analysis (NGS) disclosed compound heterozygous mutation c418+382G>C in ISCU. Present case indicates that ISCU mutations can be considered as a possible cause of recurrent rhabdomyolysis. In the context of rhabdomyolysis, histopathological techniques should include Perls stain to detect suggestive myofiber iron accumulations.