Homocystinuria Due to Cystathionine Synthase Deficiency

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Abstract
Homocystinuria is characterized by mental retardation, ectopis lentis, bony abnormalities, cardiovascular abnormalities with thrombo-embolic episodes, fine fair hair, malar flush, fatty liver changes, elevated blood plasma concentrations of methionine and homocystine, and an abnormal amount of urinary homocystine. Assays of liver tissue extracts from 4 homocystinuric patients showed markedly deficient cystathionine synthase activities (about 3% of mean control value), not increased by pyridoxal phosphate addition (in vitro) and differing from control liver specimen activities. In 2 families, each parent had 33-43% of mean control hepatic cystathionine synthase activity, without clinical stigmata or homocystinuria. Thus the fundamental defect may be inherited as an autosomally recessive deficiency of cystathionine synthase activity, with the asymptomatic parents representing the heterozygous, and affected offspring the homozygous, states. A post-mortem brain tissue extract from a homocystinuric patient showed a selective cystathionine synthase deficiency. Liver tissue from a mentally retarded cystathioninuric patient had 5% of mean control hepatic cystathionase activity, representing a 2nd defect in transsulfuration associated with disturbed brain function. Normal man converts about 80% of the S from an oral L-methionine load to urinary inorganic sulfate. Although 2 cystathionine synthase deficient patients had reduced ability to accomplish this conversion, they had unimpaired ability to convert cysteine S to inorganic sulfate. The cystathionine synthase reaction is thus a step in the major human methionine metabolic pathway and steps beyond this reaction are not significantly disturbed. Unidentified S-containing compounds appear in the urine of an affected patient fed L-methionine in much greater amounts than control subjects and in amounts greater than the urine homocystine. The patient also retained an abnormal amount of a methionine dose, excreting it abnormally slowly. A clinical test for marked cystathionine synthase deficiency is proposed.