Short-chain acyl–CoA dehydrogenase deficiency

Objective: To determine an underlying genetic defect within the differential diagnosis of congenital multicore myopathy. Background: A 13.5-year-old girl presented with congenital-onset facial and neck weakness, slowly progressive severe limb girdle and axial myopathy, respiratory weakness, cardiomyopathy, progressive joint contractures, lumbar lordosis, progressive external ophthalmoplegia with ptosis, and cataracts. Muscle biopsy at 3 years revealed type I fiber predominance and hypotrophy, multicores with a focal decrease in mitochondria and oxidative enzymes, and internal nuclei. Methods and Results: Serum carnitine was decreased (total, 18.2 μmol/L; free, 11.7 μmol/L). Urine organic acids intermittently revealed very large amounts of ethylmalonic and methylsuccinic acids intermittently, with elevated butyrylglycine, 2-methylbutyrylglycine, and tiglylglycine. Fibroblast acylcarnitine profiles revealed marked butyrylcarnitine elevation. Electron-transferring flavoprotein-linked reduction enzymatic assay of fibroblasts with butyryl–coenzyme A (CoA) as substrate, after immunoinactivation of medium-chain acyl–CoA dehydrogenase activity, revealed a complete absence of short-chain acyl–CoA dehydrogenase (SCAD) activity. No SCAD protein was detectable with Western blot analysis. Conclusions: This patient expands the clinical phenotype of SCAD deficiency and emphasizes the need for its consideration in the differential diagnosis of progressive external ophthalmoplegia and congenital multicore myopathy.