Gregersen et al., 1980).Ikeda et al. (1985) concluded that defective synthesis of ETFA was the fundamental defect in 3 cell lines from patients with severe MADD.Moon and Rhead (1987) detected 2 complementation groups in cell lines from patients with severe multiple acyl-CoA dehydrogenation disorder. This was consistent with the different defects in glutaric aciduria IIA and glutaric aciduria IIB. The metabolic block in the cell lines from the latter disorder was 3 times more severe than the former, as assayed by oxidation of radiolabelled palmitate. No intragenic complementation was observed within either group. Complementation was started after polyethylene glycol fusion.Onkenhout et al. (2001) determined the fatty acid composition of liver, skeletal muscle, and heart obtained postmortem from patients with deficiency of 1 of 3 types of acyl-CoA dehydrogenase: medium-chain (MCAD; 607008), multiple (MADD), and very long-chain (VLCADD; 201475). Increased amounts of multiple unsaturated fatty acids were found exclusively in the triglyceride fraction. They could not be detected in the free fatty acid or phospholipid fractions. Onkenhout et al. (2001) concluded that intermediates of unsaturated fatty acid oxidation that accumulate as a consequence of MCADD, MADD, and VLCADD are transported to the endoplasmic reticulum for esterification into neutral glycerolipids. The pattern of accumulation is characteristic for each disease, which makes fatty acid analysis of total lipid of postmortem tissues a useful tool in the detection of mitochondrial fatty acid oxidation defects in patients who have died unexpectedly.Riboflavin-responsive multiple acylcoenzyme A dehydrogenase deficiency is characterized by, among other features, a decrease in fatty acid beta-oxidation capacity. Muscle uncoupling protein-3 (UCP3; 602044) is upregulated under conditions that either increase the levels of circulating free fatty acid and/or decrease fatty acid beta-oxidation. Using a relatively large cohort of 7 MADD patients, Russell et al. (2003) studied the metabolic disturbances of this disease and determined if they might increase UCP3 expression. Biochemical and molecular tests demonstrated decreases in fatty acid beta-oxidation and in the activities of respiratory chain complexes I (see 157655) and II (see 600857). These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. The authors postulated that upregulation of UCP3 in MADD is due to the accumulation of muscle fatty acid/acylCoA. The authors considered MADD an optimal model to study the hypothesis that UCP3 is involved in the outward translocation of an excess of fatty acid from the mitochondria and to show that, in humans, the effects of fatty acid on UCP3 expression are direct and independent of fatty acid beta-oxidation.InheritanceBack to TopMantagos et al. (1979) proved autosomal recessive inheritance of MADD by demonstration of partial enzyme deficiency in each parent of a female patient.DiagnosisBack to TopCosta et al. (1996) noted that a number of subclinical deficiencies caused by malabsorption could be misdiagnosed as inherited mitochondrial fatty acid oxidation defects. They suggested that in the presence of organic acid profiles reminiscent of a defect in the beta-oxidation pathway or a profile reminiscent of glutaric aciduria type II, a possible digestive disorder should be ruled out.<Suhead> Prenatal