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Denver Genetic Laboratories
 

Research Interests at Denver Genetic Laboratories—Glutaric Acidemia Type 2 (GA2, MADD)


 

Glutaric Acidemia Type 2 (GA2, MADD), was first described in 1976 (Przyrembel et al., 1976). Electrons from the acyl-Coenzyme A dehydrogenases involved in mitochondrial fatty acid and amino acid oxidation are transferred from their FAD coenzymes into the respiratory chain via electron transfer flavoprotein (ETF) and electron transfer flavoprotein ubiquinone oxidoreductase (ETF:QO). In the inner mitochondrial membrane, electrons first move into the flavin of ETF, and then through the flavin and iron-sulfur cluster of ETF:QO to coenzyme Q. Glutaric Acidemia Type 2 is caused by defects in ETF and ETF:QO.

Genetics

ETF and ETF:QO deficiency are both inherited as autosomal recessive traits, and the genes encoding ETF:QO and the a- and b- subunits of ETF have been mapped to chromosome 4 (4q32>ter), 15 (15q23-25) and 19 (19q13.3), respectively. Disease-causing mutations have been identified in all three genes, but only in the a -ETF gene is there a common mutant allele, i.e. T266M (Freneaux et al., 1992). Severe forms of the disease have been diagnosed in utero by demonstrating increased amounts of glutaric acid in amniotic fluid (Mitchell et al., 1983; Jacobs et al., 1884), and in some cases renal cysts have been seen in the fetus on ultrasound examination (kjaergaard et al, 1998).

Clinical Course

Glutaric acidemia type 2 was first described in a baby who died at three days of age with severe hypoglycemia, metabolic acidosis and the small of sweaty feet. Many additional patients have been described since. Patients with complete defects of ETF or ETF:QO often die during the first weeks of life, usually of conduction defects or arrhythmias (some with facial dysmorphism and renal cystic dysplasia). Fatty infiltration of the liver, renal tubules, and heart and skeletal muscle are consistent findings at autopsy. Those with incomplete defects of ETF and ETF:QO can survive well into adult life. Milder disease, sometimes call ethylmalonic—adipic aciduria, can persist with Reye syndrome-like episodes in childhood, or with skeletal muscle weakness beginning in childhood or adolescence (Goodman & Frerman et al., 1984).

Diagnosis

Organic acid analysis usually shows increased ethylmalonic, glutaric, 2-hydroxyglutaric and 3-hydroxyglutaric acids, together with C6, C8 and C10 dicarboxylic acids and isovalerylcarnitine. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) may show increased glutarylcarnitine, isovalerylcarnitine, and C4, C8, C10, C10:1 and C12 carnitine esters. Serum carnitine is usually low, and serum sarcosine is often increased in patients with mild disease. Enzyme or immunoblot analysis, if necessary, will show that some patients are deficient in ETF, and that others are deficient in ETF:QO. Severe forms of the disease have been diagnosed in utero by demonstrating increased amounts of glutaric acid in amniotic fluid (Mitchell et al., 1983; Jacobs et al., 1884), and in some cases renal cysts have been seen in the fetus on ultrasound examination (kjaergaard et al, 1998).

Treatment

As in other fatty acid oxidation disorders, effective treatment relies on the avoidance of fasting, sometimes with continuous intragastric feeding, and carnitine administration to replenish lost stores. Riboflavin is usually given, and appears to have helped some patients.