Biochemical discrimination of heterozygotes for cystathionine β-synthase (CβS) deficiency

Abstract

Direct metabolite analyses would be a useful screen to discriminate CβS heterozygotes from non-carriers. We recently found that homocysteine-related metabolite ratios discriminated obligate heterozygotes for CβS deficiency from a control population. In the current study, samples from 55 first and second-degree relatives of probands with CβS deficiency were analyzed for total plasma homocysteine (tHcy), cysteine (tCys), folate (fol), cobalamin (B12), after fasting for 8 hours, and after 100 mg/kg methionine load (PL). Vitamin & smoking histories were obtained. Molecular genotypes were determined and compared to respective biochemical phenotypes.

Metabolite differences, between genotyped carriers (n=26) and non-carriers (n=29) were: folate, [(9.7 +/- 1.5 vs 15.6 +/- 1.9μM, p<0.02), erythrocyte folate (efol) (581 +/- 49 vs 372 +/- 48μM, p=0.004) and tHcy [(fasting) and (PL)], [(13.9 +/- 1.1 versus 10.4 +/-1.0 μM, p=0.01) and (58.8 +/- 2.9 vs 34.5 +/- 1.9μM, p=0.013)]. The ratio of [tHcy / (efol X tCys)] after an oral methionine load, provided 100% discrimination of carriers from noncaniers (102 +/- 14.5 vs 30 +/- 2.3, p=0.0001), in non vitamin-takers. Smoking elevated ratios of carriers and noncaniers (159 +/- 19 vs 40 +/- 5, p=0.0002). Smoking increased the sensitivity and specificity of this ratio, and negated the confounding effects of vitamins. Conclusion: the ratio of [tHcy / (efol X tCys)] can discriminate carriers from noncaniers of CβS deficiency.