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

• 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.

Nyckelord

Acyl-CoA Dehydrogenase

deficiency

Adolescent

Adult

Brain Diseases

Metabolic

enzymology

genetics

Carnitine

analogs & derivatives

blood

Child

Child

Preschool

Electron Transport

physiology

Electron-Transferring Flavoproteins

genetics

Fatty Acids

metabolism

Female

Humans

Iron-Sulfur Proteins

genetics

Male

Metabolism

Inborn Errors

genetics

metabolism

pathology

Mitochondria

Muscle

metabolism

Mitochondrial Myopathies

drug therapy

genetics

metabolism

pathology

Muscle

Skeletal

metabolism

pathology

Mutation

Oxidation-Reduction

Oxidoreductases Acting on CH-NH Group Donors

genetics

Riboflavin

therapeutic use

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