later. Excess amounts of glutaric and ethylmalonic acids were found in the urine, consistent with defective dehydrogenation of isovaleryl CoA and butyryl CoA, respectively. These organic acids plus others are excreted in the urine in excess in Jamaican vomiting sickness, caused by the ingestion of unripe akee. Unripe akee contains the toxin hypoglycin, which inhibits several acyl CoA dehydrogenases. Cultured fibroblasts in the patient of Dusheiko et al. (1979) showed reduced ability to oxidize radiolabeled butyrate and lysine.Mongini et al. (1992) reported a 25-year-old woman who complained of episodes of muscle weakness, nausea and vomiting since the age of 10 years. She had been born with bilateral cataracts and strabismus. Muscle biopsy showed free fatty acid accumulation. Low-fat diet reduced the episodes of muscle weakness.Liang et al. (2009) reported 4 Taiwanese patients from 3 unrelated families with MADD due to mutations in the ETFDH gene (231675.0003-231675.0005). There was marked phenotypic variability, even between 2 affected sibs with the same genotype. The first patient was a 27-year-old woman who had exercise intolerance since early childhood. In her teens, she developed several episodes of acute pancreatitis. At age 19, she developed dysphagia with progressive weakness of neck and proximal limb muscles, and later had a more severe episode of muscle weakness with acute respiratory failure, but no metabolic acidosis and hypoketotic hypoglycemia. Serum creatine kinase was elevated, and muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. Urinary profile was consistent with MADD. Her older sister had a milder phenotype, with 2 bouts of muscle weakness and difficulty climbing stairs and combing her hair. She never had metabolic crisis, hypoketotic hypoglycemia, or respiratory failure. Laboratory studies showed low serum carnitine, increased serum acylcarnitine levels, and elevated glutaric, ethylmalonic, 2-hydroxylglutaric, 3-methylglutaconic, and lactic acids in urine. Both patients responded well to riboflavin and carnitine treatment. The third patient developed exercise intolerance, dysphagia, poor head control, and limb weakness at age 14 years, and was wheelchair-bound by age 16. He had neck and proximal muscle weakness with wasting, lordosis, winged scapula, and absent tendon reflexes. He did not have metabolic acidosis or hypoketotic hypoglycemia. Pulmonary function tests demonstrated a severe restrictive ventilatory defect. Muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. He also responded well to riboflavin and carnitine treatment. The last patient was a 10-year-old girl who was a slow runner since childhood. She had an upper respiratory tract infection followed by progressive proximal muscle weakness. A few days after discharge from the hospital, her condition rapidly deteriorated and she developed fatal cardiopulmonary failure associated with marked metabolic acidosis, hyperammonemia, and hypoglycemia.Biochemical FeaturesBack to TopBy fusion of isovaleric acidemia (243500) cells with those of GA II, Dubiel et al. (1983) showed that these disorders are genetically distinct, since complementation was observed. In both disorders, isovaleryl-CoA dehydrogenation is blocked. The defect in GA II is in one of the proteins involved in the transfer of electrons from acyl-CoA dehydrogenases to coenzyme Q of the mitochondrial electron transport chain. Sarcosinemia and sarcosinuria are also observed in this disorder (Goodman et al., 1980;