Hyperhomocysteinaemia in young patients with non-arteritic anterior ischaemic optic neuropathy.

BACKGROUND/AIM: Elevated plasma homocysteine is a newly identified vascular risk factor among patients under age 55 years with cerebrovascular, cardiovascular, or peripheral vascular disease. This study sought to evaluate retrospectively the plasma homocysteine status among healthy younger patients with ischaemic optic disc disease. METHODS: 12 non-diabetic patients who had been diagnosed with non-arteritic anterior ischaemic optic neuropathy (NAION) before the age of 50 years were identified from chart review. None had experienced previous ischaemic cerebrovascular, cardiovascular, or peripheral vascular events. Plasma homocysteine, CBC, renal function, vitamin B6, vitamin B12, and folate levels were sampled in the fasting state. RESULTS: Two of 12 patients (17%) had hyperhomocysteinaemia. Both had experienced NAION in both eyes with recurrent episodes. Neither patient was hypertensive nor had a smoking history. One of these two patients had mild hypercholesterolaemia which did not warrant medication. CONCLUSIONS: Elevated plasma homocysteine may be associated with NAION. An evaluation for hyperhomocysteinaemia should be considered in patients with NAION who do not have the typical risk factor such as older age, diabetes, hypertension, or tobacco use. It should also be considered in young patients with bilateral or recurrent attacks of NAION.

Characterisation of five missense mutations in the cystathionine beta-synthase gene from three patients with B-6-nonresponsive homocystinuria

Homocystinuria, due to a deficiency of the enzyme cystathionine beta-synthase (CBS), is an inborn error of sulphur-amino acid metabolism, This is an autosomal recessive disease which results in hyperhomocysteinaemia and a wide range of clinical features, including optic lens dislocation, mental retardation, skeletal abnormalities and premature thrombotic events, We report the identification of 5 missense mutations in the protein-coding region of the CBS gene from 3 patients with pyridoxine-nonresponsive homocystinuria. Reverse-transcription PCR was used to amplify CBS cDNA from each patient and the coding region was analysed by direct sequencing, The mutations detected included 3 novel (1058C --> T, 992C --> A and 1316G --> A) and 2 previously identified (430G --> A and 833C --> T) base alterations in the CBS cDNA, Each of these mutations predicts a single amino acid substitution in the CBS polypeptide, Appropriate cassettes of patient CBS cDNA, containing each of the above defined mutations, were used to replace the corresponding cassettes of normal CBS cDNA sequence within the bacterial expression vector pT7-7. These recombinant mutant and normal CBS constructs were expressed in Escherichia coli cells and the catalytic activities of the mutant proteins were compared with normal. All of the mutant proteins exhibited decreased catalytic activity in vitro, which confirmed the association between the individual mutation and CBS dysfunction in each patient.

Effects of creatine supplementation on homocysteine levels and lipid peroxidation in rats

Hyperhomocysteinaemia is an independent risk factor for CVD. Recent data show a relationship between homocysteine (Hcy) and free radical formation. Since creatine synthesis is responsible for most of the methyl group transfers that result in Hcy formation, creatine supplementation might inhibit Hcy production and reduce free radical formation. The present study investigated the effects of creatine supplementation on Hcy levels and lipid peroxidation biomarkers. Thirty rats were divided into three groups: control group; diet with creatine group (DCr; 2% creatine in the diet for 28 d); creatine overload plus diet with creatine group (CrO + D; 5 g creatine/kg by oral administration for 5 d + 2 % in the diet for 23 d). Plasma Hcy was significantly lower (P<0.05) in DCr (7.5 (SD 1.2) mu mol/l) and CrO + D (7.2 (SD 1.7) mu mol/l) groups compared with the control group (12.4 (SD 2.2) mu mol/l). Both plasma thiobarbituric acid-reactive species (TBARS) (control, 10 (SD 3.4); DCr, 4.9 (So 0.7); CrO + D, 2.4 (SD 1) mu mol/l) and plasma total glutathione (control, 4.3 (SD 1.9); DCr, 2.5 (SD 0.8); CrO + D, 1.8 (SD 0.5) mu mol/l) were lower in the groups that received creatine (P<0.05). In addition, Hcy showed significant negative correlation (P<0.05) with plasma creatine (r - 0.61) and positive correlation with plasma TBARS (r 0.74). Plasma creatine was negatively correlated with plasma TBARS (r - 0.75) and total peroxide (r - 0.40). We conclude that creatine supplementation reduces plasma Hcy levels and lipid peroxidation biomarkers, suggesting a protective role against oxidative damage. Modulating Hcy fort-nation may, however, influence glutathione synthesis and thereby affect the redox state of the cells.

Difference in the homocysteine-lowering effect of folic acid in haemodialysis patients with and without occlusive vascular disease.

BACKGROUND: Hyperhomocysteinaemia has been identified as an independent cardiovascular risk factor and is found in more than 85% of patients on maintenance haemodialysis. Previous studies have shown that folic acid can lower circulating homocysteine in dialysis patients. We evaluated prospectively the effect of increasing the folic acid dosage from 1 to 6 mg per dialysis on plasma total homocysteine levels of haemodialysis patients with and without a history of occlusive vascular artery disease (OVD). METHODS: Thirty-nine stable patients on high-flux dialysis were studied. Their mean age was 63 +/-11 years and 17 (43%) had a history of OVD, either coronary and/or cerebral and/or peripheral occlusive disease. For several years prior to the study, the patients had received an oral post-dialysis multivitamin supplement including 1 mg of folic acid per dialysis. After baseline determinations, the folic acid dose was increased from 1 to 6 mg/dialysis for 3 months. RESULTS: After 3 months, plasma homocysteine had decreased significantly by approximately 23% from 31.1 +/- 12.7 to 24.5 +/- 9 micromol/l (P = 0.0005), while folic acid concentrations had increased from 6.5 +/- 2.5 to 14.4+/-2.5 microg/l (P < 0.0001). However, the decrease of homocysteine was quite different in patients with and in those without OVD. In patients with OVD, homocysteine decreased only marginally by approximately 2.5% (from 29.0 +/- 10.3 to 28.3 +/- 8.4 micromol/l, P = 0.74), whereas in patients without OVD there was a significant reduction of approximately 34% (from 32.7+/-14.4 to 21.6+/-8.6 micromol/l, P = 0.0008). Plasma homocysteine levels were reduced by > 15% in three patients (18%) in the group with OVD compared with 19 (86%) in the group without OVD (P = 0.001), and by > 30% in none of the patients (0%) in the former group compared with 13 (59%) in the latter (P = 0.001). CONCLUSIONS: These results indicate that the homocysteine-lowering effect of folic acid administration appears to be less effective in haemodialysis patients having occlusive vascular disease than in those without evidence of such disease.

Homocysteine and cardiovascular disease in renal disease

Elevated homocysteine (hyperhomocysteinaemia) in renal patients is a major concern for physicians. Although cause and effect between homocysteine and cardiovascular disease (CVD) has not been established in either the general population or renal patients, there is much evidence that this relationship does exist. Purported mechanisms that may explain this effect include increases in endothelial injury, smooth muscle cell proliferation, low-density lipoprotein oxidation and changes in haemostatic balance. Renal patients have a much greater incidence of hyperhomocysteinaemia and this may be explained by decreases in either the renal or extrarenal metabolism of the compound. We conclude that data from long-term placebo-controlled trials are urgently required to determine whether hyperhomocysteinaemia in renal patients is a cause of CVD events and requires therapeutic targeting.

Efficacy of B vitamins in lowering homocysteine in older men - Maximal effects for those with B-12 deficiency and hyperhomocysteinemia

Background and Purpose - A higher plasma concentration of total homocysteine (tHcy) is associated with a greater risk of cardiovascular events. Previous studies, largely in younger individuals, have shown that B vitamins lowered tHcy by substantial amounts and that this effect is greater in people with higher tHcy and lower folate levels. Methods - We undertook a 2-year, double-blind, placebo-controlled, randomized trial in 299 men aged >= 75 years, comparing treatment with a daily tablet containing 2 mg of folate, 25 mg of B-6, and 400 mu g of B-12 or placebo. The study groups were balanced regarding age (mean +/- SD, 78.9 +/- 2.8 years), B vitamins, and tHcy at baseline. Results - Among the 13% with B12 deficiency, the difference in mean changes in treatment and control groups for tHcy was 6.74 mu mol/L (95% CI, 3.94 to 9.55 mu mol/L) compared with 2.88 mu mol/L (95% CI, 0.07 to 5.69 mu mol/L) for all others. Among the 20% with hyperhomocysteinaemia, the difference between mean changes in treatment and control groups for men with high plasma tHcy compared with the rest of the group was 2.8 mu mol/L (95% CI, 0.6 to 4.9 mu mol/L). Baseline vitamin B12, serum folate, and tHcy were significantly associated with changes in plasma tHcy at follow-up (r = 0.252, r = 0.522, and r = -0.903, respectively; P = 0.003, <0.001, and <0.001, respectively) in the vitamin group. Conclusions - The tHcy-lowering effect of B vitamins was maximal in those who had low B12 or high tHcy levels. Community-dwelling older men, who are likely to be deficient in B12 or have hyperhomocysteinemia, may be most likely to benefit from treatment with B vitamins.