Brain Advance Access originally published online on June 20, 2007
Brain 2007 130(8):2045-2054; doi:10.1093/brain/awm135
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ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency
1The Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, Aarhus, Denmark, 2Department of Clinical Chemistry, Sheffield Children's Hospital, Sheffield, UK, 3Institute of Human Genetics and The Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, Aarhus, Denmark, 4Department of Medicine & Therapeutics, University of Aberdeen, Aberdeen, UK, 5Department of Child Health, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK, 6Centro de Diagnóstico de Enfermedades Moleculares, Centro Biología Molecular ‘Severo Ochoa’, Universidad Autónoma, Madrid, Spain, 7Department of Pediatrics, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado, USA, 8Royal Liverpool Children's NHS Trust, Alder Hey Hospital, 9Department of Medical Genetics, Medical School, University of Aberdeen, Aberdeen, UK, 10Department of Neurology, 11Department of Pathology, 12Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden, 13Department of Neurology, Medical School, University of Newcastle Upon Tyne, Newcastle Upon Tyne and 14Willink Unit, Royal Manchester Children's Hospital, Manchester, UK
Correspondence to: Rikke K.J. Olsen, PhD, The Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, Aarhus, Denmark, E-mail: rikke.olsen{at}ki.au.dk and Andrew A.M. Morris, PhD, Willink Unit, Royal Manchester Children's Hospital, Manchester, UK, E-mail: andrew.morris{at}cmmc.nhs.uk
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.
Key Words: riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency; electron transfer flavoprotein ubiquinone oxidoreductase; mutations; mitochondrial myopathy
Abbreviations: AMP, adenosine 5'-monophosphate; ETF, electron transfer flavoprotein; ETF:QO, ETF: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide; MADD, multiple acyl-CoA dehydrogenation deficiency; PTC, premature termination codon
Received June 12, 2006. Revised May 14, 2007. Accepted May 18, 2007.