TY - JOUR
T1 - Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies
AU - Mereis, Michelle
AU - Wanders, Ronald J. A.
AU - Schoonen, Maryke
AU - Dercksen, Marli
AU - Smuts, Izelle
AU - van der Westhuizen, Francois H.
N1 - Funding Information:
This work is based on the research supported in part by the National Research Foundation of South Africa (Grant Number: 121311 ).
Funding Information:
This work is based on the research supported in part by the National Research Foundation of South Africa (Grant Number: 121311).
Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), or glutaric aciduria type II (GAII), is a group of clinically heterogeneous disorders caused by mutations in electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETFQO) – the two enzymes responsible for the re-oxidation of enzyme-bound flavin adenine dinucleotide (FADH2) via electron transfer to the respiratory chain at the level of coenzyme Q10. Over the past decade, an increasing body of evidence has further coupled mutations in FAD metabolism (including intercellular riboflavin transport, FAD biosynthesis and FAD transport) to MADD-like phenotypes. In this review we provide a detailed description of the overarching and specific metabolic pathways involved in MADD. We examine the eight associated genes (ETFA, ETFB, ETFDH, FLAD1, SLC25A32 and SLC52A1−3) and clinical phenotypes, and report ∼436 causative mutations following a systematic literature review. Finally, we focus attention on the value and shortcomings of current diagnostic approaches, as well as current and future therapeutic options for MADD and its phenotypic disorders.
AB - Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), or glutaric aciduria type II (GAII), is a group of clinically heterogeneous disorders caused by mutations in electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETFQO) – the two enzymes responsible for the re-oxidation of enzyme-bound flavin adenine dinucleotide (FADH2) via electron transfer to the respiratory chain at the level of coenzyme Q10. Over the past decade, an increasing body of evidence has further coupled mutations in FAD metabolism (including intercellular riboflavin transport, FAD biosynthesis and FAD transport) to MADD-like phenotypes. In this review we provide a detailed description of the overarching and specific metabolic pathways involved in MADD. We examine the eight associated genes (ETFA, ETFB, ETFDH, FLAD1, SLC25A32 and SLC52A1−3) and clinical phenotypes, and report ∼436 causative mutations following a systematic literature review. Finally, we focus attention on the value and shortcomings of current diagnostic approaches, as well as current and future therapeutic options for MADD and its phenotypic disorders.
KW - ETF
KW - ETFDH
KW - FAD
KW - Glutaric aciduria type II
KW - Multiple acyl-CoA dehydrogenase deficiency
KW - Riboflavin homeostasis
UR - https://www.scopus.com/pages/publications/85099177670
U2 - 10.1016/j.biocel.2020.105899
DO - 10.1016/j.biocel.2020.105899
M3 - Review article
C2 - 33279678
SN - 1357-2725
VL - 132
JO - international journal of biochemistry & cell biology
JF - international journal of biochemistry & cell biology
M1 - 105899
ER -