Moderate elevations of total plasma homocysteine (tHcy) are risk-factors for premature thrombovascular disease (PVD) and neural-tube defects (NTD). In humans, homocysteine is metabolized in two pathways, transulfuration by cystathionine beta-synthase (CBS) and remethylation by methionine synthase (MS). Because carriers for homocystinuria caused by these enzyme deficiencies have half the normal gene dosage of either CBS or MS, they are expected to have increased tHcy either after a standard methionine load, or at fasting, respectively, heterozygotes for CBS deficiency from controls. Obligate heterozygotes have tHcy concentrations which overlap with those of controls, but the investigators found that ratios of homocysteine-related metabolites can provide discrimination. The etiology of NTD is multifactorial. Elevated tHcy is found in woman carrying NTD. Both folate and cobalamin deficiencies are independent risk factors for NTD, cause elevated tHcy, and participate in the reaction of MS, which remethylates homocysteine, using the methyl group from 5-methyl tetrahydrofolate. Cobalamin is the cofactor for methionine synthase. They hypothesize that deficiencies in either cobalamin, or folate, affect this reaction, by decreasing either the activity or the reaction velocity, respectively, of MS. Biochemicals discrimination of NTD from non NTD pregnancies using concentrations of individual metabolites has also not been successful. Although they found lowered median cobalamin in the amniotic fluid from NTD pregnancies compared with controls, only ratios of MS-related metabolites provided biochemical discrimination of NTD pregnancies from controls. The gene for MS was recently sequenced and reported. No information exists about the heterozygotes or MS deficiency. Anecdotal evidence supports increased NTD and PVD in the one family with MS deficiency they manage. They hypothesize that ratios of MS metabolites will discriminate carriers from noncarriers int his large family. This CAP proposal is a three-pronged effort to begin to investigate homocysteine metabolic pathways in intact humans, to develop molecular-based laboratory support, and to further develop hypothesis based clinical DNA basic science investigation of homocysteine metabolism. First, the CAP will develop biochemical discriminants for carriers of CBS deficiency, by extending our pilot study to the nine CBS deficiency patients and their extended families in our care, which will result int he direct investigation of the CBS enzyme. Second, the CAP will develop biochemical discriminants for women at increased risk for NTD by extending and confirming our pilot study of NTD. Third, the CAP will begin the direct study of MS by developing biochemical discriminants for MS carriers in a rare large family with MS deficiency, and will result in the initiation of direct investigation of the enzyme.
| Singh, Rani H; Kruger, Warren D; Wang, Liqun et al. (2004) Cystathionine beta-synthase deficiency: effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria. Genet Med 6:90-5 |
| Kruger, W D; Wang, L; Jhee, K H et al. (2003) Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. Hum Mutat 22:434-41 |
