821 INHERITED DEFICIENCY OF ETF DEHYDROGENASE (DH) IS A CAUSE OF GLUTARIC ACIDEMIA TYPE II (GA2) AND ETHYLMALONIC-ADIPIC ACIDEMIA (EMA)

Abstract

GA2 is an inborn error characterized by nonketotic hypoglycemia, metabolic acidosis and accumulation of substrates of flavo-protein dehydrogenases that transfer electrons to the respiratory chain via ETF and ETF DH. EMA is a mild form of GA2, with a later onset and a more attenuated course.

We have previously shown absence of immunoreactive ETF DH in fibroblasts from some GA2 patients, and partial deficiency of ETF in others. We have extended these results using a catalytic assay for ETF DH, measuring comproportionation of fully reduced and oxidized ETF to ETF semiquinone; activity in 8 control fibroblast lines was 16±3 mU/mg protein. Four GA2 lines deficient in immunoreactive ETF DH had undetected activity (≤0.1 mU/mg), and 2 with decreased immunoreactive ETF but apparently normal ETF DH had activities of 12 and 13. Lines from parents of 2 ETF DH^- patients had activities of 8,6,4, and 5, i.e. intermediate between control and GA2 values. Four mild GA2/EMA lines were examined, showing activities of 0.7,2,3, and 7. All severely ETF DH^- patients had congenital anomalies, at least renal cysts ± dysplasia; it is not known if anomalies correlate best with site or degree of the block in electron transport.

We conclude: (a) ETF DH deficiency is the primary defect in some GA2 and (probably) EMA patients; (b) it is inherited as an autosomal recessive trait. The condition is a model of disordered morphogenesis caused by deficiency of a single known protein.

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