A rationale for cystine supplementation in severe homocystinuria

Previous studies have shown that the thiol redox, as measured by the ratio of free/bound cyst(e)ine in unaffected individuals, remains relatively constant. In severe homocystinuria (HCU) where cyst(e)ine moieties are significantly reduced, this redox is only restored when homocyst(e)ine moieties are also taken into account. This appears to stem from an increase in the free/bound homocyst(e)ine ratio with free homocystine acting as a surrogate for free cystine. We examined these ratios in 47 patients (two with a cobalamin C defect, two with methylenetetrahydrofolate reductase deficiency, 16 with pyridoxine-responsive HCU and 27 with pyridoxine-nonresponsive HCU). Comparing free/bound homocyst(e)ine ratios to the total cysteine concentration indicates a relative increase of free homocystine as total cysteine concentrations fall below 170 μmol/L. This provides a rationale and treatment algorithm for cyst(e)ine supplementation in homocystinuria.