ETF dehydrogenase advances in molecular genetics and impact on treatment

Crit Rev Biochem Mol Biol. 2021 Aug;56(4):360-372. doi: 10.1080/10409238.2021.1908952. Epub 2021 Apr 7.


Electron transfer flavoprotein dehydrogenase, also called ETF-ubiquinone oxidoreductase (ETF-QO), is a protein localized in the inner membrane of mitochondria, playing a central role in the electron-transfer system. Indeed, ETF-QO mediates electron transport from flavoprotein dehydrogenases to the ubiquinone pool. ETF-QO mutations are often associated with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD, OMIM#231680), a multisystem genetic disease characterized by various clinical manifestations with different degrees of severity. In this review, we outline the clinical features correlated with ETF-QO deficiency and the benefits obtained from different treatments, such as riboflavin, L-carnitine and/or coenzyme Q10 supplementation, and a diet poor in fat and protein. Moreover, we provide a detailed summary of molecular and bioinformatic investigations, describing the mutations identified in ETFDH gene and highlighting their predicted impact on enzymatic structure and activity. In addition, we report biochemical and functional analysis, performed in HEK293 cells and patient fibroblasts and muscle cells, to show the relationship between the nature of ETFDH mutations, the variable impairment of enzyme function, and the different degrees of RR-MADD severity. Finally, we describe in detail 5 RR-MADD patients carrying different ETFDH mutations and presenting variable degrees of clinical symptom severity.

Keywords: ETF-QO; lipid storage myopathy; multiple acyl-CoA dehydrogenase deficiency; phenotype–genotype correlation; riboflavin treatment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Video-Audio Media

MeSH terms

  • Animals
  • Carnitine / genetics
  • Carnitine / metabolism
  • Electron-Transferring Flavoproteins* / genetics
  • Electron-Transferring Flavoproteins* / metabolism
  • Humans
  • Iron-Sulfur Proteins* / genetics
  • Iron-Sulfur Proteins* / metabolism
  • Mitochondria* / enzymology
  • Mitochondria* / genetics
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency* / enzymology
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency* / genetics
  • Mutation*
  • Oxidoreductases Acting on CH-NH Group Donors* / genetics
  • Oxidoreductases Acting on CH-NH Group Donors* / metabolism
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / genetics
  • Ubiquinone / metabolism


  • Electron-Transferring Flavoproteins
  • Iron-Sulfur Proteins
  • Ubiquinone
  • Oxidoreductases Acting on CH-NH Group Donors
  • electron-transferring-flavoprotein dehydrogenase
  • coenzyme Q10
  • Carnitine