title: 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.
authors.affiliation: The Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, Aarhus, Denmark. rikke.olsen@ki.au.dk
authors.forename: Rikke K J
authors.initials: RK
authors.lastname: Olsen
authors.forename: Simon E
authors.initials: SE
authors.lastname: Olpin
authors.forename: Brage S
authors.initials: BS
authors.lastname: Andresen
authors.forename: Zofia H
authors.initials: ZH
authors.lastname: Miedzybrodzka
authors.forename: Morteza
authors.initials: M
authors.lastname: Pourfarzam
authors.forename: Begoña
authors.initials: B
authors.lastname: Merinero
authors.forename: Frank E
authors.initials: FE
authors.lastname: Frerman
authors.forename: Michael W
authors.initials: MW
authors.lastname: Beresford
authors.forename: John C S
authors.initials: JC
authors.lastname: Dean
authors.forename: Nanna
authors.initials: N
authors.lastname: Cornelius
authors.forename: Oluf
authors.initials: O
authors.lastname: Andersen
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Holme
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Andrew A M
authors.initials: AA
authors.lastname: Morris
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency*; D000293:Adolescent; D000328:Adult; D001928:Brain Diseases, Metabolic / Q000201:enzymology / Q000235:genetics; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004579:Electron Transport / Q000502:physiology; D044927:Electron-Transferring Flavoproteins / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008931:Mitochondria, Muscle / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010084:Oxidation-Reduction; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D012256:Riboflavin / Q000627:therapeutic use*
chemical_list: D044927:Electron-Transferring Flavoproteins; D005227:Fatty Acids; D007506:Iron-Sulfur Proteins; C116917:acylcarnitine; D042964:Acyl-CoA Dehydrogenase; D000587:Oxidoreductases Acting on CH-NH Group Donors; C023120:electron-transferring-flavoprotein dehydrogenase; D002331:Carnitine; D012256:Riboflavin