Severe Folate Deficiency Research Articles

Assessment of Vitamin D, Vitamin B12, and Folate Levels in Recently Identified Pregnant Females.

Background: Pregnancy is a critical period where optimal maternal and fetal health depends on adequate nutritional status. Deficiencies in essential vitamins, such as vitamin D, vitamin B12, and folate, can result in adverse health outcomes. Objective: This study aims to assess the serum levels of vitamin D, vitamin B12, and folate in early pregnancy. Methodology: This cross-sectional research was conducted at Kurdistan Private Hospital in Duhok, Kurdistan Region of Iraq, from September 2022 to October 2023. The study included 150 pregnant women, with ages ranging from 18 to 45 years. Serum levels of vitamin D, vitamin B12, and folate were measured using the Automatic Clinical Chemistry Analyzer COBAS e 411 (Roche Diagnostics, Basel, Switzerland). Results: The mean age of the participants was 29 years (standard deviation [SD] = 6.2 years), with ages ranging from 18 to 45 years. The average serum human chorionic gonadotropin (HCG) level was 4,292 mIU/mL (SD = 3,947 mIU/mL), with a range of 98 to 10,000 mIU/mL. The mean serum levels were 17.8 ng/mL (SD = 11.6) for vitamin D, 367 pg/mL (SD = 245) for vitamin B12, and 11.5 ng/mL (SD = 4.6) for folate. The prevalence of vitamin D deficiency was significant, with 92 participants (61.3%) having levels below 20 ng/mL, 39 participants (26%) having insufficient levels ranging from 20 to 29 ng/mL, and only 19 participants (12.7%) having sufficient levels between 30 and 100 ng/mL. No cases of vitamin D toxicity (>150 ng/mL) were observed. Regarding vitamin B12, 32 participants (21.3%) had deficient levels (<200 pg/mL), while 118 participants (78.7%) had normal levels. Folate analysis revealed that 3 participants (2%) had moderate deficiency (2-3 ng/mL), 14 participants (9.3%) had mild deficiency (3-6 ng/mL), and there were no cases of severe folate deficiency (<2 ng/mL). Pearson correlation analysis showed weak correlations between the study variables, with the strongest being a weak negative correlation between age and serum folate levels (-0.18). Conclusions: The study found a high prevalence of vitamin D deficiency among the pregnant women included in the study, while the levels of folate and vitamin B12 were comparable to worldwide estimates. These findings focus attention on the importance of monitoring and addressing nutritional deficiencies at the beginning and throughout pregnancy. They also underline the need for preventive health interventions to correct these deficiencies and achieve the best outcomes for both maternal and fetal health.

Veganism and hypercoagulable state - hyperhomocysteinemia presenting as pulmonary thrombo-embolism in a vegetarian living at high altitude

Hyperhomocysteinemia as a hypercoagulable state has been debatable, but when associated with other high-risk factors like severe vitamin B12 and folate deficiency, smoking, high altitude, and antiphospholipid syndrome can present with thromboembolism. Vegans are at high risk of severe B12 deficiency as the primary source is animal products. Right now, the total number of vegans, vegetarians, and all related categories, is close to 14 per cent of the world population. We here present a young vegan with severe B12 deficiency presenting with sub-massive thromboembolism.

A Very Rare Case of Severe Anemia Caused By Vitamin B 12 and Folate Deficiency with Non-Immune Intramedullary Hemolysis

Introduction: Macrocytic anemia can be associated with chronic alcohol use, vitamin B12 and folic acid deficiency. However, it is very uncommon to see severe anemia in developed world, especially in a young healthy patient without any medical issues. Folate deficiency is rarely reported to cause hemolytic anemia. We present an interesting case report of a young female with severe anemia from vitamin B12, folate deficiency and nonimmune intramedullary hemolysis. Case: 40-year-old Caucasian female with no significant past medical history, who has not seen a doctor in the last 20 years presented to our emergency department complaining of worsening shortness of breath and bilateral lower limb swelling for the last 6 months prior to admission. Shortness of breath had been worsening in the last 2 months to a point that she can barely walk about 6 feet. Patient also reported non-bloody diarrhea for the last few weeks, reports looking pale by her coworkers. She is a nonsmoker, drinks about 2 drinks a day, no illicit drug use and works as a state trooper police officer. Patient had stable vital signs with tachycardia of heart rates in 90s, physical exam showed scleral icterus and pallor and 2 + bilateral lower limb pitting edema. Blood work showed hemoglobin 2.2 mg/dl, hematocrit 6.9, MCV 153.3, MCH 48.9, MCHC 31.9, platelet count 62, reticulocyte 2.1%, low vitamin B12 of 159pg/ml, low serum folate, elevated LDH and low haptoglobin. Negative direct combs test, Negative Celiac antibodies, normal iron panel, negative HIV, hepatitis A, B and C serologies, EBV, normal methylmalonic acid level, elevated homocysteine level, negative PNH panel. Patient had a normal EGD and colonoscopy, and negative stool studies including C.diff, shigella, salmonella, vibrio, and E.coli. Patient received 5 units of packed red blood cells and 1 unit of FFP. Hemoglobin improved with 5 units packed red blood cells, IV folic acid and IM vitamin B12 injections. Patient was discharged home on oral folic acid and vitamin B 12 replacement. Conclusion: Severe anemia from isolated folate and vitamin B 12 although uncommon in young healthy patients but should be considered in the differential diagnosis. Intramedullary hemolysis is a rare presentation of severe folate deficiency with limited literature. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An infantile case of hereditary folate malabsorption with sudden development of pulmonary hemorrhage: a case report

BackgroundHereditary folate malabsorption—a rare disorder caused by impairment of the folate transporter—can develop into severe folate deficiency manifesting as megaloblastic anemia and occasionally thrombocytopenia. Reportedly, megaloblastic anemia can manifest with hemorrhagic episodes, possibly due to ineffective platelet production and platelet dysfunction. However, life-threatening hemorrhage events in hereditary folate malabsorption have not been well investigated.Case presentationA 3-month-old Japanese boy was transferred to our hospital due to thrombocytopenia and severe megaloblastic anemia. During a thorough examination of hematopoietic abnormalities, the patient suddenly went into cardiac arrest due to pulmonary hemorrhage. Although intravenous folate supplementation was started soon after the identification of folate deficiency, the patient died of circulatory defect and multiple organ failure. The cause of pulmonary hemorrhage, such as respiratory infection, could not be confirmed. Genetic investigation revealed a mutation in the SLC46A1 gene to be the cause of the hereditary folate malabsorption.ConclusionWe report an infantile case of hereditary folate malabsorption that progressed to lethal pulmonary hemorrhage before folate deficiency was identified. Clinicians should consider that megaloblastic anemia could lead to severe bleeding without warning, and that nutrient supplementation should be initiated as soon as possible.

The association of serum folate levels with schizophrenia symptoms

To evaluate the association of serum folate levels with schizophrenia and its clinical characteristics in patients from a Russian sample. Ninety-three patients with schizophrenia and 60 healthy volunteers were examined. Determination of serum folate levels was performed by chemiluminescent immunoassay on microparticles (Architect, Abbott Lab SA). Symptoms of schizophrenia were assessed with the Positive and Negative Syndrome Scale, the Calgary Schizophrenia Depression Scale, the Snight-Hamilton Anhedonia Scale, the Brief Assessment of Cognition in Schizophrenia, the Personal and Social Performance Scale, the Scale for Therapy Side-Effects assessment, Simpson-Angus scales, abnormal involuntary movements scale, Barnes akathisia rating scale. Statistical analysis was performed using the Statistica 6.0. Since the data distribution was different from normal, non-parametric criteria were used. Patients had significantly lower folate levels than healthy controls (p=0.00053), mainly in women (p=0.0025). At the same time, in all the subgroups (including healthy ones), the vast majority of the participants had folate levels below the median (9.95 ng/ml) and in the lower quartile of the reference values. In patients, folate levels are inversely correlated with the severity of most negative symptoms and directly correlated with all measures of cognitive functions. Patients with folate levels below the reference values differed from other patients by a greater severity of the total score of negative symptoms (p=0.023), Marder's factors of negative symptoms (p=0.046) and disorganized thinking (p=0.033), a greater severity of general side effects of therapy (p=0.021) and all measures of cognitive functions except for verbal memory. Smoking has a significant effect on serum folate levels in all participants (p=0.016). There was also an inverse association of folate levels with the selectivity of antipsychotics (p=0.035), and more severe folate deficiency in inpatients than outpatients (p=0.0063). The results obtained in the Russian sample on the association of folate deficiency with schizophrenia and a wide range of clinical indicators, including those affecting the prognosis of schizophrenia, indicate the high relevance of further study of this topic and the introduction of approaches to augmentation of antipsychotic therapy for schizophrenia with folates.

First Report of Severe Folate Deficiency in Women Treated with Olaparib for Relapsed Ovarian Cancer

Introduction: Folate deficiency has been widely reported in association with several physiologic and pathologic conditions such as pregnancy, malnutrition, chronic hemolysis, inflammatory bowel disease, alcoholism, and cancer, as well as in conjunction with the administration of several drugs and drug classes including anti-folates (e.g. methotrexate), anticonvulsants and contraceptives. (1) We identified new-onset severe folate deficiency in a patient receiving olaparib for treatment of relapsed ovarian cancer. Olaparib (Lynparza™) is a poly-ADP ribose polymerase (PARP) inhibitor approved for the treatment of relapsed ovarian cancer in BRCA 1 and 2 mutation carriers. It is reported to cause decreased hemoglobin in 90% of patients, with 15% experiencing grade 3-4 anemia. (2) The etiology of anemia in the setting of PARP inhibitor therapy is currently unknown. To our knowledge, this is the first report of severe folate deficiency induced by olaparib.Methods: We performed a chart review of patients in our practice with relapsed ovarian cancer undergoing treatment with olaparib to determine the incidence of folic acid deficiency in this population. Patients found to be folate deficient were started on oral folic acid supplementation with close follow up. We assessed the response of folic acid supplementation on anemia. We also assessed the impact of anemia on olaparib dosing.Results: We identified a total of six patients who were on active olaparib therapy for treatment of relapsed ovarian cancer. Five out of six patients developed a decrease in baseline hemoglobin after the initiation of olaparib. Four out of six patients (67%) had severe folate deficiency (<1.6 ng/mL, normal range 7-31.4 ng/mL) after taking olaparib for at least four weeks. None of these patients reported emesis to account for dietary folate deficiency. Three out of six patients required dose-reductions of olaparib due to the development of transfusion-dependent anemia, with a mean time of 39 days from the initiation of olaparib to hemoglobin nadir. In those found to have folate deficiency, folic acid supplementation was started at a range of 1 mg daily to 2 mg TID, with subsequent improvement of serum folate level and anemia. Subsequently, all four patients were able to continue olaparib therapy without further dose reductions and were also able to avoid additional blood transfusions.Conclusion: In our small case series, we discovered that folate deficiency occurred in a majority of patients within weeks of initiating olaparib treatment. We plan to confirm our findings in a larger prospective trial in the coming months. We are also planning to study a potential association between PARP inhibition, BRCA mutations, and folate pathway. Once these findings are confirmed, we think that identifying and treating folate deficiency in this population is warranted, and may improve dose delivery and safety of olaparib therapy.

Severe folate deficiency anemia associated with the use of a PARP inhibitor (olaparib) in a patient with fallopian tube cancer

Treatment of cancer patients with olaparib (PARP inhibitor) is associated with an increased risk of anemia, which is seen in a majority of treated patients. However, symptomatic anemia requiring transfusion is rare. Olaparib-induced anemia can be secondary to bone marrow suppression, hemolysis or folate deficiency. We report a case of new onset severe folic acid deficiency anemia in a patient with breast and relapsed fallopian tube cancer being treated with olaparib. Complete blood count on admission showed a hemoglobin of 4.2 g/dl and serum folate was undetectable (&lt; 1.6 ng/ml; reference range 7-31.4 ng/ml). This is the second report of olaparib-induced folate deficiency anemia. She received three units packed red cell transfusion and parenteral folic acid supplementation and improved symptomatically. This case highlights the importance of recognizing folate deficiency as a reversible cause of anemia with PARP inhibitor therapy.

Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience.

Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.

Olaparib-induced severe folate deficiency in women with relapsed ovarian cancer: First report and case series.

e17540Background: We discovered severe folate deficiency in a patient taking the Poly (ADP-Ribose) Polymerase (PARP)-inhibitor olaparib (Lynparza) for relapsed ovarian cancer (OC). Discovery of nea...

Regulation of Reduced Folate Carrier (RFC) by Vitamin D Receptor at the Blood-Brain Barrier.

Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major folate transport systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα), known to be regulated by ligand-activated nuclear receptors, such as vitamin D receptor (VDR). Folate uptake at the choroid plexus, which requires the actions of both FRα and PCFT, is critical to cerebral folate delivery. Inactivating FRα or PCFT mutations cause severe cerebral folate deficiency resulting in early childhood neurodegeneration. The objective of this study was to investigate the role of RFC in folate uptake at the level of the blood-brain barrier (BBB) and its potential regulation by VDR. We detected robust expression of RFC in different in vitro BBB model systems, particularly in immortalized cultures of human cerebral microvascular endothelial cells (hCMEC/D3) and isolated mouse brain capillaries. [3H]-methotrexate uptake by hCMEC/D3 cells at pH 7.4 was inhibited by PT523 and pemetrexed, antifolates with high affinity for RFC. We also showed that activation of VDR through calcitriol (1,25-dihydroxyvitamin D3) exposure up-regulates RFC mRNA and protein expression as well as function in hCMEC/D3 cells and isolated mouse brain capillaries. We further demonstrated that RFC expression could be down-regulated by VDR-targeting siRNA, further confirming the role of VDR in the direct regulation of this folate transporter. Together, these data suggest that augmenting RFC functional expression could constitute a novel strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by loss of FRα or PCFT function.

Epidemiological determinants of Folate deficiency among pregnant women of district Dehradun

BackgroundFolate deficiency has been found to be associated with congenital birth defects like spina bifida, anencephaly, etc. Pregnant women have an increased need for folic acid (600μg/day) to support the growth of the placenta and foetus and prevent birth defects. ObjectivesThe present study was conducted to assess deficiency of serum folate among pregnant women and its epidemiological determinants. MethodsA cross-sectional study was conducted in the Doiwala block of Uttarakhand state, a hilly state of the country, and a total of 95 pregnant women participated. Pregnant women were randomly selected from antenatal clinics organized at sub-centres and primary health centres. Blood samples were analyzed for serum folate by competitive immunoassay using direct chemiluminescent technology. Fully automated ADVIA Centaur XP Immunoassay system was used for analysis. ResultsAnalysis of data showed that mean serum folate level among pregnant women was 10.1±5.9ng/ml (95% confidence interval 8.9–11.2). As per World Health Organization cut-off levels, a total of 28 (29.4%), 95% CI (20.2–38.5), women were having folate deficiency (≤5.9ng/ml), and out of them 3 were having folate levels below 3ng/ml (severe folate deficiency). 9 (9.4%) women had elevated levels (>20ng/ml). 57 (60%) women were in the normal range (6–20ng/ml).Out of various biosocial determinants considered, education and economic status have shown significant association with folate deficiency. A significant difference was observed in the mean serum folate level among pregnant women living in joint and nuclear type of family. Mean serum folate levels showed a slight negative correlation with body mass index (Spearman's rho=−0.22, p=0.03900) and gestational age (correlation coefficient: r=−0.26, p=0.009). ConclusionIt is concluded that higher level of education, living in joint family during pregnancy and availability of designated APL (Above Poverty Line) or BPL (Below Poverty Line) card are important determinants for better serum folate level and lower chances of folate deficiency.

Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies.

Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5–25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency.

Severe experimental folate deficiency in a human subject - a longitudinal investigation of red-cell folate immunoassay errors as megaloblastic anaemia develops.

BackgroundThe few published studies comparing results between commercial red-cell folate immunoassays have found significant differences. None have provided longitudinal data during the development of megaloblastic anaemia from severe folate deficiency. The objective was to produce longitudinal data, comparing results between three commercial immunoassays for red-cell folate, generated by means of severe experimental folate deficiency.MethodsThis 58 year old male, initially replete in folate, used a folate-deficient diet to severely deplete himself of folate until overt megaloblastic anaemia developed. The Siemens Advia Centaur, Roche Elecsys 2010 and Beckman UniCel DxI 800 Access immunoassay systems were used, by different clinical pathology laboratories, to perform weekly assays for red-cell folate throughout the depletion stage. The results were analysed graphically four ways: comparison with lines of equality; number of standard deviations difference against the means; number of standard deviations difference over time; variation over time.ResultsThere were very significant differences, varying with time and folate concentration, between the results reported by the three laboratories. The differences were greatest, up to 17 standard deviations, between the Siemens Advia Centaur and each of the other two systems. Of the 85 results comparing the Siemens Advia Centaur and the Roche Elecsys 2010, two were within the 99.9% confidence interval. Of the 91 results comparing the Siemens Advia Centaur and the Beckman UniCel DxI 800 Access, 22 were within the 99.9% confidence interval. Of the 83 results comparing the Beckman UniCel DxI 800 Access and the Roche Elecsys 2010, 37 were within the 99.9% confidence interval.ConclusionsComparative longitudinal data from clinical pathology laboratories, produced during experimental folate deficiency, have exposed very significant differences in results between commercial red-cell folate immunoassays. One immunoassay, the Roche Elecsys 2010, failed to detect overt megaloblastic anaemia of severe folate deficiency.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-441) contains supplementary material, which is available to authorized users.

Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops.

BackgroundThe currently accepted theory, that the human liver store of folate is limited to about four months, is based on the findings of Victor Herbert and others of the era before folate fortification of food. A recent model, developed by Lin et al., predicts far greater liver folate storage capacity than reported by Herbert. The conflict between Herbert’s and Lin’s models needs to be resolved experimentally, however current research is restricted because ethical considerations prevent such risky experimentation on patients or healthy human volunteers. The objective was to provide a detailed record of the biochemical and haematological responses to the development of severe experimental folate deficiency in an initially replete human subject.MethodsThis 58 year old male severely depleted himself of folate, using a folate-deficient diet, until overt megaloblastic anaemia developed. The biochemical and haematological responses were monitored by routine blood tests. Daily intake of dietary supplements prevented deficiencies of other relevant nutrients.ResultsThe rate of change of all analytes was significantly slower, and the delay before any change for several analytes was significantly longer, than reported for previous experiments. The time before reporting of abnormal biochemical and haematological results was therefore very significantly longer than reported by Herbert, but was consistent with the recent model of Lin et al. Serum folate and red-cell folate became abnormally low after 219 and 413 days respectively. Macrocytic anaemia was produced after 469 days, and megaloblastic anaemia was confirmed by bone marrow biopsy on day 575. Folate starvation ceased on day 586, and recovery was complete on day 772.ConclusionsThe currently accepted four month time scale for development of megaloblastic anaemia from folate deficiency, based on the early work of Herbert and others, is not consistent with the results from this study. The > 300 day liver folate storage time, predicted by the model of Lin et al., is supported by this experiment. Self-experimentation has produced a detailed record of the biochemical and haematological responses to severe experimental folate deficiency, whereas using patients or healthy volunteers as subjects would be unethical.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-442) contains supplementary material, which is available to authorized users.

PMM.74 Are We Forgetting The Folates?

Folate deficiency causes macrocytic anaemia and pancytopenia. In severe cases it may also be associated with neurological signs and symptoms such as memory loss and irritability. Poor nutrition, alcoholism or...

Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency.

Pancytopenia due to severe folate deficiency

Internal Medicine JournalVolume 42, Issue 9 p. 1063-1064 LETTERS TO THE EDITOR† Pancytopenia due to severe folate deficiency N. Bhatnagar, N. Bhatnagar Department of Haematology, The Royal Free Hospital, London, UKSearch for more papers by this authorA. Wechalekar, A. Wechalekar Department of Haematology, The Royal Free Hospital, London, UKSearch for more papers by this authorC. McNamara, C. McNamara Department of Haematology, The Royal Free Hospital, London, UKSearch for more papers by this author N. Bhatnagar, N. Bhatnagar Department of Haematology, The Royal Free Hospital, London, UKSearch for more papers by this authorA. Wechalekar, A. Wechalekar Department of Haematology, The Royal Free Hospital, London, UKSearch for more papers by this authorC. McNamara, C. McNamara Department of Haematology, The Royal Free Hospital, London, UKSearch for more papers by this author First published: 03 June 2015 https://doi.org/10.1111/j.1445-5994.2012.02849.xCitations: 3 Clinical-scientific notes Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume42, Issue9September 2012Pages 1063-1064 RelatedInformation

A folate receptor alpha double-mutated haplotype 1816delC–1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels

Folate is crucial for various cellular functions. Several transport mechanisms allow folate to enter the intracellular compartment with folate receptor-α being the major high-affinity receptor. Rare genetic variations in exons of the FR-α gene, FOLR1, were recently shown to cause severe folate deficiency accompanied by neurological and other disturbances. So far, similar effects by genetic variation in noncoding parts of the FOLR1 gene have not been identified. The aim of our study was to determine biochemically the haplotype structure of two linked polymorphisms in the FOLR1 gene, 1816delC and 1841G>A, the prevalences of the mutated alleles across Eurasia, and their possible effects on physiological folate levels in vivo. For this purpose we employed allele-specific PCR and Pyrosequencing technology and performed genotyping in 738 subjects from Spain, 387 from Sweden, 952 from Estonia, and 47 from Korea. We demonstrate the presence of an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, with the prevalence of the mutated allele being highest among Koreans (q=0.074), lower in Estonians (q=0.017), Spaniards (q=0.0061), and the lowest among Swedes (q=0.0026). Erythrocyte folate levels were studied in the Spanish population sample, where subjects carrying the double-mutated FOLR1 haplotype had significantly reduced levels by 27% (P=0.039), adjusted for serum vitamin B(12) levels and MTHFR 677C>T genotype, while the mean serum folate levels were only 20% lower among the carriers (P=0.11). Plasma homocysteine and cobalamin levels did not differ. Thus, we have demonstrated by molecular haplotyping an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, spread over the whole Eurasian continent, which may be of functional importance for uptake of folate in red blood cells.

Pneumocystis jiroveci Pneumonia in an Infant With Severe Folate Deficiency

Pneumocystis jiroveci pneumonia is rare in immunocompetent children. Severe folate deficiency affects T cell function, potentially increasing susceptibility to opportunistic pathogens. We report the case of an 11-month-old child who developed P. jiroveci pneumonia in the setting of severe nutritional folate deficiency and review the literature regarding the influence of folate on immunity.

Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency

Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.