Studies of the mechanism of pyridoxine-responsive homocystinuria.

Abstract

Extract: Pharmacologie doses of pyridoxine corrected plasma amino acid abnormalities in two boys (JK and EY) with homocystinuria caused by cystathionine synthase deficiency. Pyridoxine responsiveness was dose-dependent but differed in the two patients. JK required 25 mg pyridoxine per day for correction of plasma methionine, homocystine, and cystine concentrations; EY required more than 50 mg pyridoxine per day. Cystathionine synthase assays on extracts of cultured skin fibroblasts were carried out to explore this apparent clinical difference. Under basal conditions, synthase activity in extracts from both patients was less than 5% of normal. Addition of saturating concentrations of pyridoxal phosphate to the assay mixture stimulated synthase activity fourfold in extracts from JK's cells. No detectable increase in enzyme activity was noted in extracts of EY's cells under identical conditions. These in vivo and in vitro differences suggest that JK's pyridoxine responsiveness is mediated by partial correction of his underlying synthase deficiency and that EY's response to pyridoxine may be produced by another mechanism, perhaps stimulation of alternate pathways of sulfur-amino acid metabolism. Speculation: Can pyridoxine responsiveness in homocystinuria always be equated with stimulation of defective cystathionine synthase activity? Our results suggest a negative answer to this question and emphasize the need for further clinical and biochemical investigation of such patients.