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

• Published in: Brain (London, England : 1878) Vol. 130; no. 8; pp. 2045 - 2054
• Main Authors: Olsen, Rikke K. J., Olpin, Simon E., Andresen, Brage S., Miedzybrodzka, Zofia H., Pourfarzam, Morteza, Merinero, Begoña, Frerman, Frank E., Beresford, Michael W., Dean, John C. S., Cornelius, Nanna, Andersen, Oluf, Oldfors, Anders, Holme, Elisabeth, Gregersen, Niels, Turnbull, Douglass M., Morris, Andrew A. M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2007; Oxford Publishing Limited (England)
• Subjects: Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenase - deficiency; Adolescent; Adult; analogs & derivatives; Biological and medical sciences; blood; Brain Diseases; Brain Diseases, Metabolic - enzymology; Brain Diseases, Metabolic - genetics; Carnitine; Carnitine - analogs & derivatives; Carnitine - blood; Child; Child, Preschool; deficiency; Diseases of striated muscles. Neuromuscular diseases; drug therapy; electron transfer flavoprotein ubiquinone oxidoreductase; Electron Transport; Electron Transport - physiology; Electron-Transferring Flavoproteins; Electron-Transferring Flavoproteins - genetics; enzymology; Fatty Acids; Fatty Acids - metabolism; Female; genetics; Humans; Inborn Errors; Iron-Sulfur Proteins; Iron-Sulfur Proteins - genetics; Male; MEDICAL AND HEALTH SCIENCES; Medical sciences; MEDICIN OCH HÄLSOVETENSKAP; Metabolic; metabolism; Metabolism, Inborn Errors - genetics; Metabolism, Inborn Errors - metabolism; Metabolism, Inborn Errors - pathology; Mitochondria; Mitochondria, Muscle - metabolism; Mitochondrial Myopathies; Mitochondrial Myopathies - drug therapy; Mitochondrial Myopathies - genetics; Mitochondrial Myopathies - metabolism; Mitochondrial Myopathies - pathology; mitochondrial myopathy; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Muscle; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Mutation; mutations; Neurology; Oxidation-Reduction; Oxidoreductases Acting on CH-NH Group Donors; Oxidoreductases Acting on CH-NH Group Donors - genetics; pathology; physiology; Preschool; Riboflavin; Riboflavin - therapeutic use; riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency; Skeletal; therapeutic use; riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency; mitochondrial myopathy; mutations; electron transfer flavoprotein ubiquinone oxidoreductase; Nervous system diseases; Enzyme; Deficiency; Riboflavin; Electron transfer; Metabolic diseases; B-Vitamins; Enzymopathy; Congenital disease; Striated muscle disease; Mitochondria; Ubiquinone; Mitochondrial myopathy; Mutation; Oxidoreductases
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awm135

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.