Laboratory evaluation of homocysteine remethylation disorders and classic homocystinuria: Long-term follow-up using a cohort of 123 patients

The homocystinurias, caused by defects of remethylation and cystathionine-beta-synthase (CBS) deficiency, are characterized by elevated homocysteine and abnormal methionine levels. Various treatments, including injectable hydroxycobalamin and oral betaine, aim to reduce homocysteine toxicity and normalize methionine, but only limited biochemical data has been reported assessing biochemical response to treatment. We analyzed laboratory results in 812 plasma samples from 56 patients with remethylation disorders and 67 patients with CBS deficiency. Total plasma homocysteine (tHcys) decreased with therapy, but rarely normalized regardless of treatment, with highest levels seen in CBS (116 +/- 79 mu mol/L) and MTHFR (102 +/- 56 mu mol/L) deficiencies. In CBS deficiency, tHcys correlated positively with methionine (rs = 0.51, p < 0.0001) and inversely with cystine (rs = -0.57, p < 0.0001) consistent with a metabolic block downstream of homocysteine. In patients with remethylation disorders, methionine was mostly normal on therapy, and inversely correlated with tHcys (rs = 0.57, p < 0.0001) demonstrating effectiveness of hydroxycobalamin and/or betaine in stimulating tHcys remethylation. Betaine also significantly increased sarcosine from its pre-treatment level on average 19-fold in remethylation disorders and 3-fold in CBS deficiency, with sarcosine > 5 mu mol/L being 97% sensitive and 95% specific for betaine therapy. These results show that existing therapies improve sulfur amino acid metabolism without completely normalizing it and that sarcosine can determine compliance to betaine supplementation.