Vitamin B6 Responsive Homocystinuria

Abstract

In homocystinuria, in inborn error due to deficiency of cystathionine synthase activity, methionine and homocystine accumulate in plasma and urine, and cystine disappears. Massive doses of vitamin B6 (pyridoxine) have corrected these amino acid abnormalities in some homocystinuric patients but not in others. The present studies were undertaken to define the mechanism of this vitamin response. Two homocystinuric males, ages 16 and 18 years, were studied while on diets of known, constant methionine and cystine content. Their plasma and urinary methionine and homocystine concentrations fell to normal within 5 days of B6 administration (500 mg/day) and, concurrently, cystine appeared. As little as 25 mg of B6 daily resulted in correction of plasma amino acid abnormalities in one patient, but a larger dose was required in the second. Since B6 is a cofactor for cystathionine synthase, these observations suggested enhanced synthase activity. Additional studies failed to support this thesis. Urinary sulfate excretion during methionine loading was not increased when the patients were receiving B6. Furthermore, cystathionine synthase activity in cell-free extractions of cultured skin fibroblasts was absent and was unaffected by addition of pyridoxine or pyridoxal phosphate to the growth medium or the in vitro assay system, respectively. These results imply that B6 responsiveness in homocystinuria involves activation of alternate pathways of sulfur amino acid metabolism rather than correction of the basic metabolic block. This mechanism is unique among the known vitamin-dependent inherited diseases and has important bio-chemical and therapeutic implications.