MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADDAlternative titles; symbolsGLUTARIC ACIDURIA II GA II ETHYLMALONIC-ADIPICACIDURIA; EMAOther entities represented by this entryGLUTARIC ACIDURIA IIA, INCLUDED ETFA DEFICIENCY, INCLUDED GLUTARIC ACIDURIA IIB, INCLUDED ETFB DEFICIENCY, INCLUDED GLUTARIC ACIDURIA IIC, INCLUDED ETFDH DEFICIENCY, INCLUDEDGene map locus: 15q23-q25, 4q32-qter, etc.Clinical SynopsisTextBack to TopA number sign (#) is used with this entry because MADD, also known as glutaric aciduria II, can be caused by mutations in at least 3 different genes: ETFA (608053), ETFB (130410), and ETFDH (231675). The disorders resulting from defects in these 3 genes are referred to as glutaric aciduria IIA, IIB, and IIC, respectively, although there appears to be no difference in the clinical phenotypes.DescriptionBack to TopGlutaric aciduria II (GA II) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be nondistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003). Clearly, there is much heterogeneity in the group of multiple acyl-CoA dehydrogenation disorders (Amendt and Rhead, 1986).Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009).Clinical FeaturesBack to TopNeonatal Onset In the son of healthy parents from the same small town in Turkey, Przyrembel et al. (1976) described fatal neonatal acidosis and hypoglycemia with a strong 'sweaty feet' odor. Large amounts of glutaric acid were found in the blood and urine. The defect was tentatively located to the metabolism of a range of acyl-CoA compounds. A possibly identically affected child died earlier.Lehnert et al. (1982), Bohm et al. (1982), and others described malformations with multiple acyl-CoA dehydrogenation deficiency: congenital polycystic kidneys, characteristic facies, etc.Typical clinical features of the disorder are respiratory distress, muscular hypotonia, sweaty feet odor, hepatomegaly, and death often in the neonatal period. Of the 12 previously reported cases reviewed by Niederwieser et al. (1983), 7 died in the first 5 days of life and only 2 patients survived to ages 5 and 19 years. Niederwieser et al. (1983) reported the case of the son of consanguineous Jewish parents who died at age 7 months. In a note added in proof, they described the prenatal diagnosis of an affected female of the same parentage, indicating autosomal recessive inheritance.Harkin et al. (1986) described apparently characteristic and perhaps pathognomonic, cytoplasmic, homogeneous, and moderately electron-dense membrane-limited bodies in the central nervous system and renal tissues of a female patient who died at age 5 days. The kidneys were enlarged with numerous cortical