Homocystinuria due to cystathionine β‐synthase deficiency: Novel biochemical findings and treatment efficacy

To explore the pathogenesis of cystathionine β‐synthase (CBS) deficiency and to test the efficacy of pharmacological therapy we examined a panel of metabolites in nine homocystinuric patients under treated and/or untreated conditions. Off pharmacological treatment, the biochemical phenotype was characterized by accumulation of plasma total homocysteine (median 135 µmol/L) and blood S‐adenosylhomocysteine (median 246 nmol/L), and by normal levels of guanidinoacetate and creatine. In addition, enhanced remethylation was demonstrated by low serine level (median 81 µmol/L), and by increased concentration of methionine (median 76 µmol/L) and N‐methylglycine (median 6.8 µmol/L). Despite the substantially blocked transsulphuration, which was evidenced by undetectable cystathionine and severely decreased total cysteine levels (median 102 µmol/L), blood glutathione was surprisingly not depleted (median 1155 µmol/L). In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 µmol/L after withdrawal versus 33 µmol/L under treatment conditions), total cysteine levels (139 versus 211 µmol/L) and plasma serine levels (53 versus 103 µmol/L) on and off treatment demonstrated the efficacy of long‐term pyridoxine/betaine administration (p