Cystathionine β-synthase (CBS)-deficient patients develop premature
arteriosclerosis and
thrombosis leading to a high risk of a vascular event before the age of 30 years. In
CBS deficiency the transsulfuration pathway is impaired, leading to markedly elevated levels of
homocysteine and
methionine, and severely decreased levels of
cystathionine and
cysteine. Through autooxidation these elevated levels of
homocysteine might induce excessive production of
reactive oxygen species (ROS). ROS are involved in endothelial damage and are neutralized by
antioxidants. In humans the main
antioxidant is
glutathione (GSH). Its production mainly depends on the amount of available
cysteine. Since
cysteine levels in
CBS deficiency are decreased, GSH production is presumed to be low. Accordingly, all CBS-deficient patients receive
cysteine supplements, which supposedly stimulate GSH synthesis. However, data on the effect of
cysteine dosage on GSH synthesis in CBS-deficient patients are lacking. Therefore, in a CBS-deficient
pyridoxine non-responsive female patient, concentration and fractional synthesis rate (FSR) of erythrocyte GSH were measured by infusion of l-[3,3-(2)H2]
cysteine tracer during prolonged
cysteine supplementation with 88 and 40 mg/kg per day. Erythrocyte GSH concentration and its FSR at
cysteine supplementation with 88 versus 40 mg/kg per day were 1.25 versus 1.30 mmol/L and 230 versus 254% per day, respectively. These data suggest that in a CBS-deficient patient exogenous supply of 40 mg
cysteine/kg per day is sufficient to maintain GSH synthesis in erythrocytes. Further studies in larger patient groups should be initiated to measure the effects on GSH metabolism to further elucidate the correct dose of
cysteine supplements in CBS-deficient patients.