ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

Abstract

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.

Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat

“…Most mutations causing riboflavin-responsive MADD have been located in ETFDH (Olsen et al 2007;Law et al 2009;Trakadis et al 2012). The present cat, which responded to riboflavin treatment, also carried a mutation in ETFDH (Fig.…”

“…4), but not in ETFa or ETFb. The mutations inherited in human patients with riboflavin-responsive MADD all cause a single amino acid substitution (Olsen et al 2007;Law et al 2009;Trakadis et al 2012). The present cat expressed ETFDH mRNA at the same level as control cats (Fig.…”

“…However, MADD can also develop in later life. Treatment with riboflavin and L-carnitine is effective only for patients with mild symptoms (Gordon 2006;Olsen et al 2007;Henriques et al 2009;Law et al 2009;Ishii et al 2010;Lund et al 2010).…”

Anticancer Activities of Resveratrol in Colorectal Cancer

“…There are some indications in the literature which support this hypothesis. In an in vitro experiment, using fibroblasts from patients with an inborn enzyme deficiency of mitochondrial fatty acid beta-oxidation, it has been shown that cisresveratrol, trans-picied and dihydroresveratrol improved fatty acid oxidation [47], potentially through stimulating mitochondrial biogenesis or via competition for cellular extrusion of riboflavin, which is the precursor for mitochondrial FAD, the coenzyme of acyl-CoA dehydrogenases critical for fatty acid β-oxidation [48]. However, the effects of major resveratrol metabolites -resveratrol-3-O-glucuronide, resveratrol-4-O-glucuronide and resveratrol-3-O-sulfate -on fatty acid oxidation was modest to non-existent [47].…”

How Can We Treat Mitochondrial Encephalomyopathies? Approaches to Therapy

“…65 Patients with ETFDH deficiency, also reported in riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency (MADD), 66 usually show a remarkable clinical improvement on riboflavin therapy (100 mg/day). The fact that a low CoQ10 might be responsible, at least in part, for the clinical symptoms has dramatically changed the therapy of the myopathic form of CoQ10 deficiency and of MADD disease, both of which are allelic disorders.…”