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1.
Serum Homocysteine, Pyridoxine, Folate, and Vitamin B12 Levels in Migraine: Systematic Review and Meta-Analysis.
Liampas, I, Siokas, V, Mentis, AA, Aloizou, AM, Dastamani, M, Tsouris, Z, Aslanidou, P, Brotis, A, Dardiotis, E
Headache. 2020;(8):1508-1534
Abstract
BACKGROUND Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies. OBJECTIVE The present study aims to review and meta-analyze data from studies investigating the difference of serum Hcy and Hcy lowering vitamins between migraine patients and healthy controls (HC), as well as between patients with MA and migraine without aura (MO). METHODS Literature search involved MEDLINE, Embase, CENTRAL, Google Scholar, and trial registries. The Newcastle-Ottawa Scale was used to evaluate the quality of the retrieved studies. Standardized mean differences (SMDs) and 95% confidence intervals (95%CIs) were calculated. Funnel-plots were utilized for the evaluation of publication bias. RESULTS Overall, 29 (28 case-control and 1 cross-sectional) studies were retrieved. Meta-analysis was indicative of higher Hcy concentration in migraine patients vs HC overall [adults and children: 16 studies, I2 = 81%, SMD = 0.41, 95%CI = (0.20, 0.61)]. Hcy was consistently elevated in adults with migraine [adults: 12 studies, I2 = 76%, SMD = 0.35, 95%CI = (0.15, 0.54); children: 1 study, SMD = 0.37, 95%CI = (-0.05, 0.79)]. Subgroup analyses reproduced the results for both adults with MA [7 studies, I2 = 83%, SMD = 0.37, 95%CI = (0.03, 0.71)] and MO [5 studies, I2 = 84%, SMD = 0.46, 95%CI = (0.03, 0.89)]. Figures for serum folate were lower in the overall comparison of migraine patients with HC [adults and children: 11 studies, I2 = 87%, SMD = -0.36, 95%CI = (-0.68, -0.05); adults: 8 studies, I2 = 6%, SMD = -0.11, 95%CI = (-0.22, 0.01); children: 1 study, SMD = -0.71, 95%CI = (-1.14, -0.29); MA adults: 4 studies, I2 = 44%, SMD = -0.16, 95%CI = (-0.35, 0.04); MO adults: 4 studies, I2 = 47%, SMD = -0.17, 95%CI = (-0.44, 0.10)]. Serum vitamin B12 levels were not different between migraine patients and HC [adults and children: 11 studies, I2 = 88%, SMD = -0.24, 95%CI = (-0.57, 0.09); adults: 8 studies, I2 = 57%, SMD = -0.10, 95%CI = (-0.28, 0.08); children: 1 study, SMD = 0.29, 95%CI = (-0.13, 0.71); MA adults: 4 studies, I2 = 63%, SMD = -0.14, 95%CI = (-0.48, 0.20); MO adults: 4 studies, I2 = 59%, SMD = -0.15, 95%CI = (-0.45, 0.15)]. Serum Hcy was lower in MO than MA [adults and children: 10 studies, I2 = 39%, SMD = 0.30, 95%CI = (0.14, 0.46), adults: 6 studies, I2 = 29%, SMD = 0.21, 95%CI = (0.09, 0.36), children: 1 study, SMD = 0.51, 95%CI = (0.22, 0.80)]. Serum folate and vitamin B12 did not differ between MA and MO. CONCLUSIONS Our results suggest that there is a possible link between migraine, mainly MA, and elevated serum Hcy.
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2.
Vitamin B12, B6, or Folate and Cognitive Function in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis.
Zhang, C, Luo, J, Yuan, C, Ding, D
Journal of Alzheimer's disease : JAD. 2020;(2):781-794
Abstract
BACKGROUND Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults. OBJECTIVE To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis. METHODS Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity. RESULTS Twenty-one observational studies with sample sizes ranging from 155-7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61-0.97) and folate concentration (OR = 0.68, 95% CI = 0.51-0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship. CONCLUSION The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals.
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3.
Folic acid and vitamin B12 supplementation in subjects with type 2 diabetes mellitus: A multi-arm randomized controlled clinical trial.
Satapathy, S, Bandyopadhyay, D, Patro, BK, Khan, S, Naik, S
Complementary therapies in medicine. 2020;:102526
Abstract
OBJECTIVE This study was conducted to investigate and compare the effects of add-on folic acid and vitamin B12 supplementation on glycaemic control, insulin resistance and serum lipid profile in subjects with type 2 diabetes mellitus. STUDY DESIGN & INTERVENTION This study was a randomized, multi-arm, open-label clinical trial. 80 patients with type 2 diabetes and on stable oral antidiabetics were enrolled and 20 patients each were randomly allocated to one of the four groups - Group A: add-on Folic acid (5 mg/day); Group B: add-on Methylcobalamin (500 mcg/day); Group C: add-on Folic acid (5 mg/day) + Methylcobalamin (500 mcg/day) and Group D: Standard oral anti-diabetic drugs. The patients were followed up after 8 weeks. RESULTS HbA1c improved significantly in Groups B and C [median changes from baseline - 1.2 % (- 13 mmol/mol) and - 1.5 % (- 16 mmol/mol) respectively, p values 0.04 and 0.02 respectively] compared to Group D. Groups B and C also showed significant improvements in plasma insulin, insulin resistance and serum adiponectin compared to Group D. Serum homocysteine declined significantly in all three groups with add-on supplementation compared to standard treatment. No improvement in the lipid profile was noted in any of the groups. CONCLUSIONS Add-on supplementation with vitamin B12 improved glycaemic control and insulin resistance in patients with type 2 diabetes mellitus.
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Genetic, epigenetic and genomic mechanisms of methionine dependency of cancer and tumor-initiating cells: What could we learn from folate and methionine cycles.
Guéant, JL, Oussalah, A, Zgheib, R, Siblini, Y, Hsu, SB, Namour, F
Biochimie. 2020;:123-128
Abstract
Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy.
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5.
Early neurodevelopmental characterization in children with cobalamin C/defect.
Ricci, D, Martinelli, D, Ferrantini, G, Lucibello, S, Gambardella, M, Olivieri, G, Chieffo, D, Battaglia, D, Diodato, D, Iarossi, G, et al
Journal of inherited metabolic disease. 2020;(2):367-374
Abstract
Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy. Children up to the age of 4 years with a visual acuity ≥1/10 were evaluated using the Griffiths' Mental Development Scales. Eighteen children were enrolled (age range 12-48 months). Four were diagnosed by newborn screening (NBS); in the others mean age at diagnosis was 3.5 months (range 0.3-18 months). Eight had seizures: three in the first year, and five after the second year of life. Fourteen had brain lesions on magnetic resonance imaging (MRI). Neurovisual assessment evidenced low visual acuity (<3/10) in 4/18. NBS diagnosed patients had higher general and subquotients neurodevelopmental scores, normal brain MRI, and no epilepsy. The others showed a progressive reduction of the developmental quotient with age and language impairment, which was evident after 24 months of age. Our findings showed a progressive neurodevelopmental deterioration and a specific fall in language development after 24 months in cblC defect. The presence of brain lesions and epilepsy was associated with a worst neurodevelopmental outcome. NBS, avoiding major disease-related events and allowing an earlier treatment initiation, appeared to have a protective effect on the development of brain lesions and to promote a more favorable neurodevelopment.
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6.
Effect of Vitamin B12 Levels on the Association Between Folic Acid Treatment and CKD Progression: A Post Hoc Analysis of a Folic Acid Interventional Trial.
Li, Y, Spence, JD, Wang, X, Huo, Y, Xu, X, Qin, X
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2020;(3):325-332
Abstract
RATIONALE & OBJECTIVE In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression. STUDY DESIGN A post hoc analysis of an interventional trial. SETTING & PARTICIPANTS This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption. INTERVENTIONS Assignments to a double-blinded daily treatment of enalapril, 10mg, and folic acid, 0.8mg; or enalapril, 10mg, alone. OUTCOMES The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of<60mL/min/1.73m2 if baseline eGFR was≥60mL/min/1.73m2; or a decrease in eGFR≥50% if baseline eGFR was<60mL/min/1.73m2; or kidney failure). RESULTS Mean baseline eGFR in this study was 86.1±20.5 (SD) mL/min/1.73m2. Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248pmol/L), compared to enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels<248pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001). LIMITATIONS The analysis is post hoc and event rate is low. CONCLUSIONS Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels. FUNDING Government funding (National Key Research and Development Program of China).
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7.
Alterations in Sulfur Amino Acids as Biomarkers of Disease.
Stabler, SP
The Journal of nutrition. 2020;(Suppl 1):2532S-2537S
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Abstract
Homocysteine (Hcy) is methylated by methionine synthase to form methionine with methyl-cobalamin as a cofactor. The reaction demethylates 5-methyltetrahydrofolate to tetrahydrofolate, which is required for DNA and RNA synthesis. Deficiency of either of the cobalamin (Cbl) and/or folate cofactors results in elevated Hcy and megaloblastic anemia. Elevated Hcy is a sensitive biomarker of Cbl and/or folate status and more specific than serum vitamin assays. Elevated Hcy normalizes when the correct vitamin is given. Elevated Hcy is associated with alcohol use disorder and drugs that target folate or Cbl metabolism, and is a risk factor for thrombotic vascular disease. Elevated methionine and cystathionine are associated with liver disease. Elevated Hcy, cystathionine, and cysteine, but not methionine, are common in patients with chronic renal failure. Higher cysteine predicts obesity and future weight gain. Serum S-adenosylhomocysteine (AdoHcy) is elevated in Cbl deficiency and chronic renal failure. Drugs that require methylation for catabolism may deplete liver S-adenosylmethionine and raise AdoHcy and Hcy. Deficiency of Cbl or folate or perturbations of their metabolism cause major changes in sulfur amino acids.
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Macro vitamin B12: an underestimated threat.
Soleimani, R, Favresse, J, Roy, T, Gruson, D, Fillée, C
Clinical chemistry and laboratory medicine. 2020;(3):408-415
Abstract
Background The correct identification of the macro-B12 interference (macroforms) is paramount to avoid potential erroneous clinical decisions. Our objectives were to determine whether immunoassays are affected by the presence of macro-B12 and to validate a polyethylene glycol (PEG) precipitation procedure to detect it. Methods Sixty-two serum samples obtained from healthy volunteers were analyzed to determine recovery and reference intervals (RIs) following PEG precipitation. Thereafter, 50 serum samples with very high levels of B12 (>1476 pmol/L) were randomly selected to search for macro-B12 interferences. Serum samples obtained from healthy volunteers and related PEG aliquots were analyzed on a Cobas® immunoassay. Patients' samples were analyzed on both Cobas® and Architect® immunoassays. Finally, samples suspected to contain macro-B12 were analyzed by size-exclusion chromatography (SEC) to confirm the presence of macro-B12. Results Recovery and post-PEG RIs determined on a Cobas 8000® in healthy volunteers ranged from 68.3% to 108.4% and from 122.1 to 514.4 pmol/L, respectively. Fifteen samples (30%) were found to show macro-B12 while using the recovery criteria, and nine samples (18%) while using the post-PEG RI. The other immunoassay ran on the Architect i2000® was also affected by the presence of macro-B12. Size-exclusion chromatography studies confirmed the presence of macro-B12 (immunoglobulin-B12 complexes). Conclusions The prevalence of macro-B12 in elevated B12 samples is high. We suggest to systematically screen for the presence of macro-B12 with PEG precipitation procedure in samples with elevated B12 levels to avoid potential misdiagnosis or harmful clinical consequences.
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Fallacies of clinical studies on folic acid hazards in subjects with a low vitamin B12 status.
van Gool, JD, Hirche, H, Lax, H, Schaepdrijver, L
Critical reviews in toxicology. 2020;(2):177-187
Abstract
A 2016 plea for revision of the 1 mg/day upper level of folic acid intake prompted us to comprehensively review the 1945-2017 literature on folic acid hazards in subjects with low cyanocobalamin. The concept of folic acid treatment 'masking' the anemia in undiagnosed cyanocobalamin deficiency, thereby delaying the diagnosis of neuropathy, does not account for the dissociation between the deficiency's hematologic and neurologic manifestations. Possible risks of this concept were addressed by 1963-1971 FDA rulings, classifying all folic acid preparations as prescription-only drugs, delivering ≤1 mg daily. The neuropathy in folic acid trials for 'pernicious anemia' is due to the singular use of folic acid-neuropathy improved or disappeared with replacement of folic acid by liver extract or cyanocobalamin. The hypothesis that cognitive impairment in 'subclinical' cyanocobalamin deficiency is folate-mediated is untenable. Of 6 papers specifically investigating this, none could prove that increased cognitive impairment was related to high folate intake. This review fully supports the safety of the 1 mg/day upper level for folic acid intake.
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Assessment of cellular cobalamin metabolism in Gaucher disease.
Basgalupp, SP, Siebert, M, Ferreira, C, Behringer, S, Spiekerkoetter, U, Hannibal, L, Schwartz, IVD
BMC medical genetics. 2020;(1):12
Abstract
BACKGROUND Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B12) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. METHODS Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. RESULTS Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. CONCLUSIONS Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell- and compartment-specific vitamin B12 metabolism in Gaucher disease.