P.17.10 New ETFDH mutations in a group of Italian patients with Riboflavin-Responsive Multiple Acyl-CoA Dehydrogenase Deficiency (RR-MADD)

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a rare autosomal recessive disorder of the electron transfer flavoproteins. Three clinical forms have been described: two with neonatal onset (I and II), and a late-onset form (type III). Type III patients manifest with proximal myopathy, sometimes with hepatomegaly and encephalopathy. Mutations in ETFDH has been often associated with a Riboflavin response in those patients. We report, herein, clinical, biochemical and molecular genetic features in five Italian RR-MADD patients. Clinically, all patients variably presented with acute recurrent episodes of myalgias, exercise intolerance, rhabdomyolysis and proximal muscle weakness. Serum CK was elevated (from 1000 to 8000 UI/L) as well as lactacidemia. Medium- and long-chain acyl carnitines were increased in all subjects. Muscle biopsy showed a vacuolar myopathy with lipid storage. Total and free muscle carnitines were reduced whereas muscle CoQ10 levels were normal. Oral Riboflavin treatment (400 mg/die) resulted in a dramatic improvement of clinical conditions of all patients. Mutational analysis of ETFDH identified seven novel mutations: 5 missense mutations, a 2-base-pair deletion in the coding region and one splice-site mutation. Our data confirm that blood acylcarnitine profile are sensitive and predictive markers for MADD diagnosis whereas muscle CoQ10 levels may be normal. We identified seven novel ETFDH mutations, all located in conserved domains. These new changes were distinct from the others described in previous reported cases but, also our group of patients, dramatically responded to Riboflavin administration.