Journal Article

<i>ETFDH</i> mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

Rikke K. J. Olsen, Simon E. Olpin, Brage S. Andresen, Zofia H. Miedzybrodzka, Morteza Pourfarzam, Begoña Merinero, Frank E. Frerman, Michael W. Beresford, John C. S. Dean, Nanna Cornelius, Oluf Andersen, Anders Oldfors, Elisabeth Holme, Niels Gregersen, Douglass M. Turnbull and Andrew A. M. Morris

in Brain

Published on behalf of The Guarantors of Brain

Volume 130, issue 8, pages 2045-2054
Published in print August 2007 | ISSN: 0006-8950
Published online June 2007 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awm135
ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

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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.

Keywords: riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency; electron transfer flavoprotein ubiquinone oxidoreductase; mutations; mitochondrial myopathy

Journal Article.  6285 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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