Reference Center for Inborn Errors of Metabolism, Robert-Debré University Hospital, Paris, France
Riboflavin (7,8-dimethyl-10-ribityl-isoalloxazine, vitamin B2) is a water soluble vitamin which is the precursor of the active coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), important cofactors for more than 80 enzymes (called flavoproteins) involved in carbohydrate, amino acid and lipid metabolism, most of them located in the mitochondrion and acting as mitochondrial oxidoreductases.
More importantly, FAD is the essential cofactor for the 2 electron transporters: Electron Transfer Flavoprotein (ETF) and Electron Tranfer Flavoprotein Ubiquinone Oxidoreductase (ETF-QO). FAD is also the essential cofactor for 11 ETF dependent dehydrogenases involved in 5 different categories of metabolic pathways. In terms of biochemistry, inborn errors of riboflavin metabolism or ETF/ETF-QO deficiencies have in common a multiple acyl-CoA dehydrogenase deficiency (MADD) profile on the acylcarnitine profile. Of note, this MADD profile is not always present in inborn errors of riboflavin metabolism and when present may be incomplete.
In clinical practice, riboflavin-responsive disorders, defined as diseases for which the clinical course is improved by pharmacological doses of riboflavin, are probably overlooked. They encompass inborn errors of riboflavin metabolism: disorders of intestinal riboflavin transporters (previously called Brown Vialetto-Van Laere [BVVL] or Fazio Londe [FL] syndromes) and disorders of intracellular riboflavin metabolism including FAD synthase and mitochondrial FAD transporter deficiencies. As a whole, defects of riboflavin metabolism present with a wide spectrum of clinical severity from early onset severe mitochondrial disease-like neurodegenerative disorder to late onset exercise intolerance. Even in the setting of a severe neuromotor presentation, riboflavin supplementation may be life saving leading to a dramatic improvement of the clinical condition especially in BVVL/FL syndromes.
Besides inborn errors of riboflavin metabolism, late onset ETF-QO deficient patients presenting with exercise intolerance were shown to exhibit substantial clinical improvement upon riboflavin supplementation. Similarly, a significant number of acyl-CoA dehydrogenase 9 (ACAD9, a mitochondrial respiratory chain Complex I assembly factor) defective patients were recently reported to exhibit clinical improvement upon riboflavin therapy.