levoleucovorin and Hyperhomocysteinemia

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Topics: Anemia, Megaloblastic; Cells, Cultured; Fatal Outcome; Female; Folic Acid; Folic Acid Deficiency; Humans; Hyperhomocysteinemia; Infant; Infant, Newborn; Leucovorin; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Minor Histocompatibility Antigens; Severe Combined Immunodeficiency; Young Adult

Various regimens of folic acid-based and vitamin B12 (Vit B12) supplementations have been tried for lowering plasma homocysteine (Hcy) levels in uremic patients. However, the therapeutic potency of low-dose folic acid and Vit B12 alone is not properly understood. In this study, seventy-five patients on chronic hemodialysis (HD) therapy were randomized into three groups. The FNA group received intravenous (IV) supplementation with folinic acid 3 mg weekly; the Vit B12 group received IV supplementation with vitamin B12 1 mg weekly; and the combination group received IV supplementation with both agents weekly. Blood levels of Hcy, folic acid, and Vit B12 were measured monthly for three months. After three months of treatment, plasma levels of Hcy decreased significantly in all three groups when compared with their baselines (all p < 0.05). The final Hcy level was significantly lower in the combination group (11.5 +/- 2.3 micromol/L) when compared with that of the FNA group (15.9 +/- 5.6 micromol/L, p < 0.05) but not with the Vit B12 group (15.9 +/- 11.6 micromol/L), although their baseline levels were similar. The percentage decreases of tHcy at the end of the treatment in the FNA group, Vit B12 group, and combination group were 16.4%, 29.3%, and 38.9% respectively. Our study showed that IV pharmacologic dose of Vit B12 alone is as effective as low-dose folic acid in correcting hyperhomocysteinemia in chronic HD patients, and combining both drugs in low doses may have added effects.

Topics: Drug Therapy, Combination; Female; Humans; Hyperhomocysteinemia; Leucovorin; Male; Middle Aged; Prospective Studies; Renal Dialysis; Vitamin B 12; Vitamin B Complex

In a recent uncontrolled retrospective report we suggested that the long-term supplementation of high-dose, i.v. folinic acid combined with high-dose i.v. pyridoxine was highly effective in correcting plasma total homocysteine (tHcy) concentrations in haemodialysis patients. To confirm these findings, we conducted a randomized, controlled trial aimed at evaluating whether i.v. or oral folinic acid provided improved tHcy-lowering efficacy in haemodialysis patients compared with oral folic acid.. In a 6-month prospective, randomized, controlled trial, 60 chronic haemodialysis patients, matched for age, gender, dialysis duration, and average screening pre-treatment-fasting tHcy levels, were given either 50 mg/week of i.v. calcium folinate (group 1), 50 mg/week of oral calcium folinate (group 2), or 45 mg/week oral folic acid (group 3). All 60 patients also received 750 mg/week of i.v. vitamin B6 and 3 mg/week of oral vitamin B12.. Fasting tHcy decreased significantly and to a similar extent in the three groups after 2 months of treatment and remained stable at 4 and 6 months (16.6+/-3.5, 18.3+/-4, and 19.1+/-3.1, in groups 1, 2, and 3, respectively, P=NS). Mean percentage reduction at 6 months was also similar in the three treatment groups (46, 43, and 42% in groups 1, 2, and 3, respectively, P=NS).. These findings show that the tHcy-lowering effects of high-dose i.v. folinic acid, oral folinic acid, or oral folic acid were comparable, suggesting that the hyperhomocysteinaemia observed in haemodialysis patients is not due to abnormal folate metabolism. Furthermore, they are compatible with the view that other abnormalities are also involved in the impaired clearance of homocysteine in uraemic patients.

Topics: Administration, Oral; Aged; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Folic Acid; Hematinics; Humans; Hyperhomocysteinemia; Injections, Intravenous; Leucovorin; Male; Middle Aged; Prospective Studies; Renal Dialysis; Time Factors; Vitamin B 12; Vitamin B 6

The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid (FA). We evaluated whether a high-dose L-folinic acid-based regimen provided improved total homocysteine (tHcy)-lowering efficacy in chronic hemodialysis patients, as suggested by a recent uncontrolled report.. We block-randomized 48 chronic, stable hemodialysis patients based on their screening predialysis tHcy levels, sex, and dialysis center into two groups of 24 subjects treated for 12 weeks with oral FA at 15 mg/day or an equimolar amount (20 mg/day) of oral L-folinic acid (FNA) [L-5-formyltetrahydrofolate]. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12.. The mean percentage (%) reductions (with 95% CIs) in predialysis tHcy were not significantly different [FNA = 22.1% (11.8 to 31.4%), FA = 20.7% (11.7 to 30.5%), P = 0.950 by paired t test]. Final on-treatment values (mean with 95% CI) were as follows: FNA, 15.9 micromol/L (14.0 to 18.0); FA, 16.9 micromol/L (14.8 to 18.8). Moreover, in those subjects with baseline tHcy levels >/=14 micromol/L, neither treatment resulted in "normalization" of tHcy levels (that is, final on-treatment values <12 micromol/L) among a significantly different or clinically meaningful number of patients [FNA = 2 out of 22 (9.1%); FA = 2 out of 24 (8.3%); Fisher's exact test of between groups difference, P = 1.000].. Relative to high-dose FA, high-dose oral L-folinic acid-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (that is,> 90%) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen.

Topics: Aged; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Leucovorin; Male; Middle Aged; Renal Dialysis; Treatment Outcome

The effectiveness of intravenous folinic acid or intravenous folic acid for the treatment of hyperhomocysteinemia of hemodialysis patients is unknown. In a randomized, controlled, double-blind trial, 66 hemodialysis patients were administered either 15 mg of folic acid or an equimolar amount (16.1 mg) of folinic acid intravenously three times weekly. Normalization of total homocysteine (tHcy) plasma levels after 4 weeks of treatment was achieved in 10 patients (30.3%) in the folic-acid group and 6 patients (18.2%; P: = 0.389) in the folinic-acid group (normalization at any time during the study period in 39.4% and 33.3% of the patients; P: = 0.798). The relative reduction in tHcy plasma levels at week 4 was 32.2% in the folic-acid group and 34.1% in the folinic-acid group. A high baseline tHcy plasma concentration (P: = 0.00001), methylenetetrahydrofolate reductase (MTHFR) 677TT/1298AA genotype (P: = 0.03540), and low red blood cell folate concentrations (P: = 0.02285) were associated with a better relative response to treatment. Normalization of tHcy plasma levels was dependent on a lower baseline tHcy level (P: = 0.01976), younger age (P: = 0.00896), and MTHFR 677TT/1298AA or 677CT/1298AC genotypes (P: = 0.00208 and P: = 0.02320, respectively). A 4-week course of intravenous folinic acid is not superior to intravenous folic acid in reducing elevated tHcy plasma levels in hemodialysis patients. The response to treatment is predicted by tHcy plasma level, red blood cell folate content, and MTHFR genotype.

Topics: Double-Blind Method; Drug Administration Schedule; Erythrocytes; Female; Folic Acid; Genotype; Homocysteine; Humans; Hyperhomocysteinemia; Infusions, Intravenous; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Oxidoreductases Acting on CH-NH Group Donors; Pyridoxine; Renal Dialysis; Treatment Outcome; Vitamin B 12

Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy.. Folic acid supplementation is only partially efficacious in correcting moderate elevation of plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD) patients. Experimental and clinical data have suggested that this partial efficacy may be due to impairment of folic acid metabolism to 5-methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD patients.. In a cohort of 37 patients on intermittent HD treatment, plasma tHcy concentrations were determined before and during i.v. supplementation of folinic acid (50 mg once per week), together with i.v. pyridoxine (250 mg 3 times per week), to prevent vitamin deficiency, particularly in those treated by recombinant erythropoietin.. Folinic acid and pyridoxine i.v. supplementation was given for 11.2 +/- 2.45 months (range 7.5 to 17 months). The mean plasma tHcy levels decreased significantly from 37. 3 +/- 5.8 microM at baseline to 12.3 +/- 5.4 microM on folinic acid treatment (P < 0.001). Moreover, 29 of the 37 patients (78%) had normal plasma tHcy levels at the end of follow-up (that is, <14.1 microM, mean 9.8 microM, range 6.2 to 13 microM). No adverse effects attributable to folinic acid treatment were observed during this time.. Intravenous folinic acid therapy (50 mg) once per week associated with pyridoxine supplementation appears to be an effective and safe strategy to normalize plasma tHcy levels in the majority of chronic HD patients.

Topics: Adult; Aged; Erythrocytes; Female; Humans; Hyperhomocysteinemia; Injections, Intravenous; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Pyridoxine; Renal Dialysis; Tetrahydrofolates; Vitamin B 12

Topics: Aged; Betaine; Female; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Psychotic Disorders; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Topics: Endothelium, Vascular; Humans; Hyperhomocysteinemia; Kidney Diseases; Leucovorin; Renal Dialysis; Stroke; Tetrahydrofolates; Vitamin B 12; Vitamin B 6

Cardiovascular diseases are the leading cause of death in haemodialysis patients. Hyperhomocysteinaemia is an independent risk factor. Basic research has provided strong evidence that oxidation of low-density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Oxidative stress, lipid metabolism alterations, and hyperhomocysteinaemia observed in haemodialysis patients could induce increases in LDL oxidation. This study was designed to determine the effect of folinic acid on hyperhomocysteinaemia and to assess the antioxidant efficacy of folinic acid. The antioxidant effect of folinic acid was compared with that of vitamin E.. Sixteen stable patients (11 men, five women; mean age 54.3+/-6.32 years) on standard haemodialysis received 400 mg of vitamin E, orally, at the end of each haemodialysis session for 3 months. After a 1-month wash-out, they received 10 mg of folinic acid, intravenously, at the end of each haemodialysis session for an additional 3 months. Blood samples were drawn in the morning after an overnight fast and before dialysis. Plasma vitamin E was analysed by high-pressure liquid chromatography. Malondialdehyde (MDA) was determined using a fluorimetric method and plasma copper oxidized anti-LDL antibodies (Ab-LDLox) were measured with an ELISA method using native LDL and oxLDL as antigens. Plasma homocysteine was determined by an FPIA method.. Folinic acid supplements significantly reduced hyperhomocysteinaemia (-44%), MDA concentrations (-40%), and IgG-LDLox titres (-13%).. Treatment with folinic acid lowers plasma homocysteine levels and, like vitamin E, affords antioxidant protection, which prevents lipid peroxidation. This lowering of lipid peroxidation may reduce the risk of atherosclerosis and prevent or delay cardiovascular complications in HD patients.

Topics: Antioxidants; Female; Humans; Hyperhomocysteinemia; Immunoglobulin G; Leucovorin; Lipid Peroxides; Lipoproteins, LDL; Male; Malondialdehyde; Middle Aged; Renal Dialysis; Vitamin E