Diagnosis Yamaguchi et al. (1990, 1991) described type II glutaric aciduria due to deficiency of ETFB. The patient had a neonatal onset of intermittent illness without congenital anomalies. The diagnosis was made at the age of 10 months. Subsequently, the parents of the patient of Yamaguchi et al. (1991) had another pregnancy and Yamaguchi et al. (1991) performed prenatal diagnosis by immunochemical procedures on cultured amniocytes and by organic acid analysis of amniotic fluid, using a stable isotope dilution method. They also described the monitoring of the clinical course and metabolite excretion in early infancy when the patient had no symptoms. Glutarate concentration was increased in the cell-free supernatant of the amniotic fluid.Clinical ManagementBack to TopGregersen et al. (1982) reported successful treatment of a 5 year old with riboflavin.Riboflavin-responsive glutaric aciduria type II was reported by Uziel et al. (1995) in a boy who developed gradually progressive spastic ataxia and a leukodystrophy without ever having experienced episodic metabolic crises.Molecular GeneticsBack to TopGlutaric aciduria IIAIndo et al. (1991), Rhead et al. (1992), and Freneaux et al. (1992) identified mutations in the ETFA gene in patients with GA IIA (e.g., 608053.0001).Glutaric aciduria IIBColombo et al. (1994) identified mutations in the ETFB gene in patients with GA IIB (e.g., 130410.0001).Glutaric aciduria IICBeard et al. (1993) identified 5 mutations in the ETFDH gene (e.g., 231675.0001) in 4 patients with GA IIC. All 5 mutations were rare and caused total lack of enzyme activity and antigen.In 4 Taiwanese patients from 3 unrelated families with relatively late-onset MADD, Liang et al. (2009) identified homozygous or compound heterozygous mutations in the ETFDH gene (231675.0003-231675.0005). The A84T mutation (231675.0003) was present in all 4 patients.Genotype/Phenotype CorrelationsBack to TopThe heterogeneous clinical features of patients with MADD fall into 3 classes (Frerman and Goodman, 2001): a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress.To examine whether the different clinical forms of MADD can be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, Olsen et al. (2003) investigated the molecular genetic basis for disease development in 9 patients representing the phenotypic spectrum of MADD. They identified and characterized 7 novel and 3 previously reported disease-causing mutations. Studies of these 9 patients yielded results consistent with 3 clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of the disease. Homozygosity for 2 null mutations caused fetal development of congenital anomalies,