Mitochondrial fatty acid oxidation defects--remaining challenges.
Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3-4 'new' disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the 'old' defects: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, riboflavin responsive multiple acyl-CoA dehydrogenation (RR-MAD) deficiency, and short-chain acyl-CoA dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only approximately 50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q(10). With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically.
Gregersen
Niels
N
Research Unit for Molecular Medicine, Institute of Clinical Medicine, The Faculty of Health Sciences, Aarhus University, Aarhus N, Denmark. nig@ki.au.dk
Andresen
Brage S
BS
Pedersen
Christina B
CB
Olsen
Rikke K J
RK
Corydon
Thomas J
TJ
Bross
Peter
P
D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics; D044926:Butyryl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D017510:Protein Folding
D005227:Fatty Acids; D044926:Butyryl-CoA Dehydrogenase; D042964:Acyl-CoA Dehydrogenase