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This study aimed to evaluate the utility of serum folic acid testing in children and adolescents in a developed country without mandatory folic acid food fortification and to identify patients at risk for folic acid deficiency. In this cross-sectional study, records from primary care and hospitals were reviewed for patients aged 0-18 years who underwent serum folic acid testing. Data were retrieved from the Leumit-Health-Services database over a ten-year period (January 2008 to December 2018). Clinical and laboratory data were compared between patients with folic acid deficiency to those with normal levels. Among 20,411 pediatric patients tested, 884 (4.3%) had folic acid deficiency, of whom only 26.3% had anemia. Only two patients (0.2%) had megaloblastic anemia. Multivariate analysis showed that male gender (odds ratio(OR)1.6, 95% CI 1.22-2.12), older age (OR 1.32, 95% CI 1.26-1.39), higher BMI percentile (OR 1.01, 95% CI 1-1.01), antipsychotic treatment (OR 3.23, 95% CI 1.52-6.84), celiac (OR 2.97, 95% CI 1.66-5.34), and Attention-Deficit-and-Hyperactivity-Disease (ADHD) treated with psychostimulants (OR 2.21, 95% CI 1.56-3.12) were associated with folic acid deficiency(all p < 0.01). Lower hemoglobin levels were independently associated with increased OR of folic acid deficiency (OR 0.77, 95% CI 0.66-0.90, p = 0.001), but anemia as a diagnosis was not., Conclusion: Pediatric folic acid deficiency rates were low in this nationwide cohort and not linked to megaloblastic anemia, likely due to concomitant iron deficiency anemia. Although retrospective, this might suggest low utility for routine serum folic acid testing in healthy children in developed countries, except in cases of celiac disease or specific medication use such psychostimulants or antipsychotics., What Is Known: • Folic acid deficiency is common among children in developing countries, causing megaloblastic anemia, growth delays, and cognitive impairments. In developed countries, the prevalence is considered low., What Is New: • Of 20,411 pediatric patients tested for serum folate, in a developed country, only 4.3% had folate deficiency. • Risk factors for deficiency included celiac, antipsychotics, and psychostimulant treatment for ADHD. • Routine folate testing in developed countries may have limited utility; Targeted screening is recommended., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Deficiency in vitamins B9 and B12 are common in general practice, due to their high prevalence in the population, especially among elderly patients. This article will present the clinical manifestations of vitamin B9 and B12 deficiencies, which can sometimes be insidious. We will discuss screening strategies, which are based on the presence of compatible symptoms as well as risk factors for deficiency. The choice of administration route for substitution depends both on severity and etiology; but the oral route has demonstrated similar effectiveness compared to intramuscular administration., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

A 25-year-old woman with childhood-onset refractory epilepsy and developmental delay experienced a gradually progressive marked deterioration in mobility and seizure control, with language regression. Investigation identified a homozygous deletion within the contactin-associated protein-like 2 gene ( CNTNAP2 ), underlying her early presentation, but also cerebral folate deficiency that most likely contributed to her later deterioration. Following antiseizure medication adjustment and treatment with folinic acid, she stabilised with improved seizure control and limited improvement in language and motor function; she has remained neurologically stable for more than a decade. That the previously observed neurological decline was halted by folinic acid replacement supports this being due to cerebral folate deficiency. Metabolic conditions are less well recognised in adults and can be under-diagnosed. They are potentially treatable and should be considered even in the presence of another cause, particularly when the presentation is not fully compatible., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Neural tube defects are among the most common congenital malformations in the US, with an estimated 3000 pregnancies affected each year. Many of these neural tube defects are caused by low folate levels in the body., Objective: The US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update on the benefits and harms of folic acid supplementation., Population: Persons who are planning to or could become pregnant., Evidence Assessment: The USPSTF concludes that, for persons who are planning to or could become pregnant, there is high certainty that folic acid supplementation has a substantial net benefit to prevent neural tube defects in their offspring., Recommendation: The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 μg) of folic acid. (A recommendation).

We investigated the prevalence of folate deficiency and associated factors in a large population of Korean women of reproductive age during the COVID-19 pandemic. We utilized different cut-offs and evaluated age, year of testing, geographical region, and the utilization of serum homocysteine levels. Out of the 27,758 women evaluated, the overall prevalence of folate deficiency was 12.5% (<4 ng/mL, metabolic indicator) and 5.4% (<3 ng/mL, hematologic indicator). Homocysteine testing was observed in 8.4% of women, with 2.7% having elevated homocysteine levels (>15.4 µmol/L). According to our multiple logistic regression analysis, younger women, particularly those aged 20 to 24 years, tested in 2020, and from Jeolla province, Gyeongsang province, and Jeju Island, were identified as being more prone to folate deficiency. Receiver operating characteristic curve analysis demonstrated that a cut-off of >8.4 µmol/L provided the most accurate definition of folate deficiency with serum folate levels <4 ng/mL, while a cut-off of >8.8 µmol/L best defined folate deficiency with serum folate levels <3 ng/mL, with both cut-offs being lower than 15.4 µmol/L. Our study emphasizes the prevalence of folate deficiency, associated factors, and the role of homocysteine in planning nutritional support programs in Korea.

Background: Neurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs. However, early treatment with folinic acid has been shown to stabilize or reverse neurological features. Approximately thirty patients have been described worldwide. Here, we report the first two cases with genetically proven cerebral folate transport deficiency from South-Eastern Europe, describe the effect of oral folinic acid therapy on clinical and neuroradiological features and review the literature., Results: Two siblings presented in childhood with clinical and radiological findings consistent with a hypomyelinating leukodystrophy. Exome sequencing revealed a novel homozygous pathogenic variant in FOLR1 (c.465&#95;466delinsTG; p.W156G), confirming the diagnosis of neurodegeneration due to cerebral folate transport deficiency. Folinic acid treatment was promptly initiated in both patients. The younger sibling was treated early in disease course at 2 years of age, and demonstrated complete recovery in clinical and MRI features. The older sibling, who was 8 years of age at the time of diagnosis and treatment, demonstrated partial but substantial improvements., Conclusion: We present the first account in the literature that early treatment initiation with oral folinic acid alone can result in complete neurological recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency. Moreover, through the report of these patients along with review of the literature, we provide information about the natural history of the disease with comparison of treatment effects at different stages of disease progression. This report also reinforces the importance of universal access to genetic testing to ensure prompt diagnoses for treatable disorders., (© 2023. The Author(s).)

Classically, deficiencies of vitamin B 12 and folate are associated with megaloblastic anaemia. Additionally, vitamin B 12 is able to cause a haemolytic anaemia in the form of pseudo-thrombotic microangiopathy (pseudo-TMA). Here, we present a case of a middle-aged woman with a history of Roux-en-Y gastric bypass who presented with dyspnoea and fatigue and was found to have thrombocytopenia and a non-immune haemolytic anaemia. Work-up for haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, paroxysmal nocturnal haemoglobinuria, infection, malignancy and autoimmune conditions was unremarkable. Her haemolytic anaemia and thrombocytopenia resolved with folate replenishment. She was diagnosed as likely having pseudo-TMA secondary to folate deficiency., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Case presentation We report three cases of vitamin B12 and/or folic acid deficiencies presenting with non-immune hemolytic anemia and thrombocytopenia. This presentation, with features of a thrombotic microangiopathy (TMA), has earlier been described as 'pseudo-TMA'.

This is a case report of a 24-year-old woman at pregnancy week 30, who presented with abdominal pain, nausea, dizziness, fatigue, intermittent headaches, and hyperreflexia. Haemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome was suspected due to blood tests showing low haemoglobin- and thrombocyte levels, and elevated lactate dehydrogenase level. The baby was delivered by acute caesarean section shortly after hospitalization. After delivery, the patient's condition did not improve. Additional testing showed folic acid deficiency, probably contributing to the anaemia. Further anamnesis showed, that the patient had untreated coeliac disease, contributing to folic acid deficiency.

Folate metabolism disorders are known to have a potential involvement in the pathophysiology of mitochondrial diseases. Many researchers suggest that profound systemic folate deficiency may contribute to mitochondrial folate deficiency. Folic acid metabolism is closely related to vitamin B 1 2 and homocysteine. Considering that hereditary optic neuropathies (HON) are mitochondrial diseases, it is important to study the folate status, the content of vitamin B 1 2 and homocysteine in patients with this pathology., Objective: To compare the content of folic acid, vitamin B 1 2 and homocysteine in the blood serum of patients with Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON), optic neuropathy of other genesis, and the comparison group., Material and Methods: The study involved 58 patients with LHON and ARON, the control group of 49 patients with ischemic, inflammatory, traumatic and compressive optic neuropathies, and the comparison group of 20 healthy volunteers., Results: A decrease in blood folic acid levels was revealed (4.0±1.6 ng/mL) in patients with HON compared to the control group ( p =1.3·10 -8 ) and the comparison group ( p =1·10 -17 ). The content of vitamin B 1 2 in patients with HON was 380.8±168.1 pg/mL, which was significantly lower than in the comparison group ( p =0.0001). The homocysteine content was 14.1±5.6 μmol/L in patients with HON, which was significantly higher than in the control group ( p =0.0007) and the comparison group ( p =0.000003). At the same time, an increase in homocysteine level of more than 10 µmol/L was revealed in 75% of patients with HON. Similar metabolic disorders were found in groups with various mutations in mitochondrial and nuclear DNA., Conclusion: Patients with HON showed marked decrease in the levels of folic acid and vitamin B 12 , as well as hyperhomocysteinemia. It is very important to identify the causes of metabolic disorders in order to determine the role of folate deficiency in the development of HON, as well as the possibility of its pharmacological treatment.

Purpose: Since mandatory fortification of grain products with folic acid in the United States in 1998, folate deficiency has become rare. Some have suggested that serum folate levels should be tested rarely in countries with mandatory folic acid fortification, given low rates of deficiency, high cost per deficiency diagnosis, and low rates of supplementation for those diagnosed as deficient. Given persistent racial, ethnic, and socioeconomic disparities in folate deficiency, these suggestions may not apply to all populations. We examine the rate at which serum testing detected folate deficiency in an urban safety net hospital and the characteristics of folate-deficient patients., Methods: We reviewed the charts of all inpatients and emergency department patients with low serum folate results at a safety net hospital in Boston in 2018. We collected data concerning demographics, social determinants of health, clinical factors, and whether folate supplementation was prescribed. Finally, we performed a cost analysis., Results: Of 1368 patients tested, 76 (5.5%) met criteria for folate deficiency. Overall, 86.8% of these patients were anemic, and 17.1% had macrocytic anemia; 42% were diagnosed with malnutrition. Common social determinants in folate-deficient patients included birth outside of the United States, homelessness, and alcohol use disorder. Of folate-deficient patients, 88% were newly prescribed folic acid supplementation at discharge. The estimated charge per deficient test was $1278., Conclusion: Compared with a nearby institution, serum folate testing at our safety net hospital detected deficiency at a higher rate, incurred a lower charge per deficient test, and was more likely to impact management., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hereditary folate malabsorption (HFM) is a rare disorder of proton-coupled folate transporter deficiency. It is characterized by macrocytic anemia, recurrent infections, and epilepsy. A five-year-old girl presented with recurrent pneumonia, diarrhea, and mouth ulcers. On examination, pallor, microcephaly with spastic quadriparesis was noted. On investigations, leukopenia and thrombocytopenia with megaloblastic bone marrow picture and low folate levels was found. HFM was diagnosed at two years of age and the child was treated with folinic acid. Her diagnosis was confirmed by whole-exome sequencing which revealed a novel pathogenic homozygous frameshift insertion variation (c.620dupG) in the exon 2 of the SLC46A1 gene which was further confirmed by Sanger sequencing. The child improved significantly except for a partial improvement in neurological symptoms.

Background: Repeated crises in children with sickle cell anaemia (SCA), which is a manifestation of disease severity, results in depletion of their minimal tissue folate stores, with higher likelihood of folate deficiency. The study aimed to determine the relationship between disease severity and the folate status of children with SCA attending University of Nigeria Teaching Hospital (UNTH), Enugu., Methods: This was a hospital based, cross-sectional study conducted between September 2018 and March 2019. One hundred participants were recruited, consisting of 50 children having sickle cell crisis and 50 age and gender matched haemoglobin AA genotype controls. Relevant information was documented using a pretested questionnaire. Sickle cell severity score was determined using frequency of crisis, admissions and transfusions in the preceding one year, degree of liver and splenic enlargement, life-time cummulative frequency of specific complications of SCA, leucocyte count and haematocrit., Results: Folate deficiency was observed in eight percent of the subjects and none of the controls. The difference was not significant (Fisher's exact = 4.167, p=0.117). The odds of being folate deficient was 8.5 times more likely during anaemic crisis than in vaso-occlusive crisis, though not significant (95% C.I 0.05 - 89.750, p = 0.075). The mean SCA severity score was 8.06 ± 3.64, signifying a moderate SCA severity in the study population. There was a no relationship between folate status and severity of SCA (Fisher's exact = 0.054, p = 0.949)., Conclusion: Folate status in children with SCA is not affected by their disease severity. Therefore, there may be no need for additional folate supplementation with increasing severity of sickle cell anaemia., (© 2021 Nnajekwu UC et al.)

Background: Little is known about the reference interval of serum folate concentration if using recently re-standardized assays traceable to the World Health Organization (WHO) international standard reference 03/178 in a Korean population. This study aimed to investigate serum folate levels in Korean subjects without macrocytic anemia or increased homocysteine, for the assessment of folate deficiency., Methods: We retrospectively reviewed data from Korean adults whose hemoglobin, mean corpuscular volume, and serum total homocysteine values were within reference limits., Results: The median (interquartile range) serum folate level was 7.8 (5.4 - 12.6) ng/mL in men and 10.2 (6.9 - 15.6) ng/mL in women. The reference interval for serum folate (2.5th and 97.5th percentiles) ranged from 2.9 to 38.0 ng/ mL. From among 723 Korean adults, the lower limit of reference intervals of serum folate for folate deficiency, defined as the 2.5th percentile, was 2.9 ng/mL. The prevalence of folate deficiency was higher in men (6.5%) than in women (1.2%, p < 0.05) when a cutoff value of 3.0 ng/mL was applied. Using the cutoff value of 4 ng/mL for folate deficiency, which is in accordance with the instructions from the manufacturer of the new assay and the WHO 2012 guideline for homocysteine as a metabolic indicator before assay standardization, about 5% of subjects were reclassified as folate deficient., Conclusions: Our study suggests that any change of reference limits using a re-standardized assay needs to be verified in clinical laboratories.

Cerebral folate deficiency (CFD) results in neurological alterations and a massive degeneration of the choroid/retina if left untreated, which limit the visual field and visual acuity. This article reports the case of a female patient with CFD, who developed autistic personal characteristics prior to reaching school age and first started to speak at the age of 3 years. At the age of 6 years she was presented because of unclear reduced visual acuity in the right eye. At that time mild bilateral peripheral chorioretinal atrophy was present, which subsequently became more pronounced. Additionally, a centrally emphasized chorioretinal atrophy further developed. Visual acuity of both eyes progressively deteriorated until stagnating at 0.1 at the age of 14 years. The causal assignment of the findings of the patient was not possible for many years. Choroideremia was excluded by molecular genetic testing (CHM gene with no mutations) and gyrate atrophy was ruled out by a normal ornithine level. The existence of a mitochondrial disease was almost completely excluded by exome sequencing. After the onset of further nonocular symptoms, e.g. neuromuscular disorders, electroencephalograph (EEG) alterations and autistic disorder, intensified laboratory diagnostics were performed in the treating pediatric hospital. Finally, an extremely low level of the folic acid metabolite 5‑methyltetrahydrofolate was detected in the cerebrospinal fluid (CSF) leading to the diagnosis of CFD. High-dose substitution treatment with folic acid was subsequently initiated. After excluding the presence of a pathogenic mutation of the FOLR1 gene for the cerebral folate receptor 1, a high titer blocking autoantibody against cerebral folate receptor 1 was detected as the cause.

Background and Aims: Abdominal aortic calcification (AAC) has been introduced as a good predictor of cardiovascular disease (CVD) events, but no previous study has investigated the relationship between folate levels and AAC. The present study aims to explore the relationship between red blood cell (RBC) folate, a better indicator reflecting long-term folate intake, and severe AAC in the United States (US) middle-aged and elderly population., Methods and Results: Cross-sectional data were derived from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 of 2818 men and women aged 40 years or older. Multivariable logistic regression models were used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for severe AAC of each RBC folate quintile category. The restricted cubic spline model was used for the dose-response analysis. A U-shaped dose-response relation between RBC folate and the odds of severe AAC was found after adjustment for multiple potential confounding factors, p for nonlinear = 0.0032. With the third quintile category of RBC folate as the reference, multivariable-adjusted ORs and 95% CIs of the lowest, second, fourth, and the highest quintile categories were 2.34 (1.37-4.00), 1.24 (0.70-2.19), 1.58 (0.92-2.70), and 2.26 (1.35-3.76), respectively., Conclusions: Individuals with either low or high levels of RBC folate were at increased risks of severe AAC in a representative sample of US adults. While folate deficiency is widely recognized as harmful, these results highlight the need to investigate the potential adverse health outcomes of high folate level., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

In order to propose a course of action to be taken in the face of any hyperhomocysteinemia, we have reported for the first time in a French journal the recommendations made within the framework of the European E-HOD project for the diagnosis and treatment of remethylation disorders. The remethylation route ensures homocysteine-methionine conversion. It is linked to the folate cycle and the intracellular metabolism of cobalamins. Remethylation disorders can be classified into three groups: 1) isolated disorders (cblD-HC, cblE, cblG) corresponding to an isolated deficit in the production of methylcobalamin, cofactor of methionine synthase; 2) combined disorders (cblC, cblD-MMA/HC, cblF, cblJ) corresponding to an alteration of the transport and intracellular metabolism of cobalamins, which causes a defect in the synthesis of the two functional forms of cobalamin: methylcobalamin and adenosylcobalamin, a cofactor for methyl malonylCoA mutase; 3) MTHFR deficit, an abnormality of the folate cycle. The biological anomalies observed are hyperhomocysteinemia and hypomethioninaemia associated in the case of disorders combined with increased urinary excretion of methylmalonic acid. The clinical presentation is however heterogeneous according to the remethylation disorder but also for the same pathology according to the age. Given the large number of pathologies grouped together in remethylation disorders, this point is illustrated by only two clinical cases concerning the same deficit (deficit in MTHFR) but with different discovery circumstances: a neonatal form and a late form.

Background: Current guidelines pertaining to diagnosing macrocytic anemia in association with vitamin B12 and folate deficiency recommend that vitamin B12, folate, homocysteine, and methylmalonic acid assays should be assessed concurrently due to their close relationship in metabolism. We aimed to investigate the completion of these assays in local clinics and hospitals without in-house clinical laboratories in Korea., Methods: We retrospectively reviewed data from the laboratory information system between September 25, 2017, and June 30, 2019, to investigate usage rates of vitamin B12, folate, homocysteine, and methylmalonic acid assays in patients with macrocytic anemia., Results: During the study period, 14 894 Korean adults among 109 524 (13.6%) total hemoglobin-tested subjects underwent concurrent erythrocyte mean corpuscular volume (MCV) tests. Among these 14,894 adults, 265 (1.2%) from 94 local clinics or hospitals without in-house clinical laboratories in Korea had macrocytic anemia. Furthermore, among these 265 adults, only one woman underwent serum vitamin B12 and folate assay and one man underwent serum homocysteine testing during the study period. No patients among the 265 individuals with macrocytic anemia received erythrocyte folate or methylmalonic acid testing (with either serum, plasma, random urine, or 24-hour collected urine)., Conclusions: The results of this study provide basic information regarding utilization rates of assays in association with vitamin B12 and folate deficiency. Making more data available is expected to improve rates of testing in patients with macrocytic anemia in local clinics and hospitals without in-house clinical laboratories in Korea., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Purpose: The value of testing for folate deficiency has been scrutinized recently given low prevalence of deficiency with widespread dietary fortification. Numerous studies have shown folate testing to be low yield overall. However, the value of such testing in the inpatient cancer population has not been defined., Methods: We queried all folate tests performed during 2017 at our center on admitted cancer patients. We used diagnosis codes and manual chart review to assess risk factors for folate deficiency. Descriptive statistics were used to summarize characteristics of patients undergoing folate testing, the frequency of vitamin B12 co-testing, and repeat folate testing. Fisher's exact test was used to compare the proportion of deficient vs. not deficient tests based on the presence of risk factors. A Cox proportional hazards model was fit to examine the association between folate deficiency and survival., Results: In total, 937 patients had 1065 tests performed during 2017. Among all tests, 7.0% indicated folate deficiency. In patients who underwent two folate tests in a single hospitalization, 89% were deficient neither instance. Risk factors for folate deficiency were equally common in instances with deficient compared with replete testing (25.3 vs. 20.4%, P = 0.334). Folate deficiency was associated with higher risk for death (HR 1.49, 95% CI 1.10-2.03, P = 0.01)., Conclusion: Folate deficiency was present in 7% of hospitalized cancer patients and associated with shorter overall survival. Repeat testing in the same patient over time was low yield. Traditional risk factors for folate deficiency do not appear to apply in this patient population.

Background Maternal folic acid supplementation (FAS) reduces the risk of neural tube defects in offspring. However, its effect on congenital heart disease (CHDs), especially on the severe ones remains uncertain. This study aimed to assess the individual and joint effect of first-trimester maternal FAS and multivitamin use on CHDs in offspring. Methods and Results This is a case-control study including 8379 confirmed CHD cases and 6918 controls from 40 healthcare centers of 21 cities in Guangdong Province, China. Adjusted odds ratios (aORs) of FAS and multivitamin use between CHD cases (overall and specific CHD phenotypes) and controls were calculated by controlling for parental confounders. The multiplicative interaction effect of FAS and multivitamin use on CHDs was estimated. A significantly protective association was detected between first-trimester maternal FAS and CHDs among offspring (aOR, 0.69; 95% CI, 0.62-0.76), but not for multivitamin use alone (aOR, 1.42; 95% CI, 0.73-2.78). There was no interaction between FAS and multivitamin use on CHDs ( P =0.292). Most CHD phenotypes benefited from FAS (aORs ranged from 0.03-0.85), especially the most severe categories (ie, multiple critical CHDs [aOR, 0.16; 95% CI, 0.12-0.22]) and phenotypes (ie, single ventricle [aOR, 0.03; 95% CI, 0.004-0.21]). Conclusions First-trimester maternal FAS, but not multivitamin use, was substantially associated with lower risk of CHDs, and the association was strongest for the most severe CHD phenotypes. We recommend that women of childbearing age should supplement with folic acid as early as possible, ensuring coverage of the critical window for fetal heart development to prevent CHDs.

MTHFD1 is a trifunctional protein containing 10-formyltetrahydrofolate synthetase, 5,10-methenyltetrahydrofolate cyclohydrolase and 5,10-methylenetetrahydrofolate dehydrogenase activities. It is encoded by MTHFD1 and functions in the cytoplasmic folate cycle where it is involved in de novo purine synthesis, synthesis of thymidylate and remethylation of homocysteine to methionine. Since the first reported case of severe combined immunodeficiency resulting from MTHFD1 mutations, seven additional patients ascertained through molecular analysis have been reported with variable phenotypes, including megaloblastic anemia, atypical hemolytic uremic syndrome, hyperhomocysteinemia, microangiopathy, infections and autoimmune diseases. We determined the level of MTHFD1 expression and dehydrogenase specific activity in cell extracts from cultured fibroblasts of three previously reported patients, as well as a patient with megaloblastic anemia and recurrent infections with compound heterozygous MTHFD1 variants that were predicted to be deleterious. MTHFD1 protein expression determined by Western blotting in fibroblast extracts from three of the patients was markedly decreased compared to expression in wild type cells (between 4.8 and 14.3% of mean control values). MTHFD1 expression in the fourth patient was approximately 44% of mean control values. There was no detectable methylenetetrahydrofolate dehydrogenase specific activity in extracts from any of the four patients. This is the first measurement of MTHFD1 function in MTHFD1 deficient patients and confirms the previous molecular diagnoses., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Megaloblastic anemia causes macrocytic anemia from ineffective red blood cell production and intramedullary hemolysis. The most common causes are folate (vitamin B 9 ) deficiency and cobalamin (vitamin B 12 ) deficiency. Megaloblastic anemia can be diagnosed based on characteristic morphologic and laboratory findings. However, other benign and neoplastic diseases need to be considered, particularly in severe cases. Therapy involves treating the underlying cause-eg, with vitamin supplementation in cases of deficiency, or with discontinuation of a suspected medication., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

Objectives: To evaluate the odds of vitamin B12 and folate deficiencies among Zambian clinic attendees with distal symmetric polyneuropathy (DSP) and age, sex, and HIV matched controls., Methods: Cases were adults from clinics in urban/peri-urban Zambia. Controls were enrolled among persons not seeking personal medical care, such as a caregiver or person collecting antiretrovirals without a medical complaint. Participants underwent structured interviews, physician examination, and assessments of complete blood count, renal and liver profiles, serum vitamin B12 and folate, erythrocyte folate, plasma total homocysteine and methylmalonic acid. HIV testing and CD4 counts were performed when appropriate., Results: Among 107 consenting matched case-control pairs, 65% were female, 52% HIV positive, with mean age of 47.6 (SD 13.5) years. Among HIV positive participants, mean CD4 count was 484 (SD 221) and 482 (SD 236) for cases and controls, respectively (p = .93). DSP symptoms and severity did not differ by HIV status (p's > 0.05). Height, history of tuberculosis treatment, alcohol use, education, asset index, dietary diversity, and nutritional supplement use did not differ between cases and controls (p's > 0.05). DSP cases had at least 3:1 odds of having low serum folate (p = .0001), severely low erythrocyte folate (p = .014), and elevated total homocysteine (p = .001) levels compared to controls. Markers of vitamin B12 deficiency were not associated with case status (p's > 0.05)., Conclusion: Markers of folate deficiency are highly associated with DSP among Zambian clinic attendees. Future studies should consider a broader range of comorbid nutritional deficiencies, and strategies for interventions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Oral manifestations of deficiency of iron, vitamin B12 and folic acid are thought to be common. Prevalence of these deficiencies among patients with compatible symptoms is not well known. The goal of this study was to summarize evidence from a dental practice of iron, vitamin B12 and folic acid deficiency in patients presenting with compatible oral manifestations., Methods: 250 patients who presented with burning mouth syndrome, angular cheilitis, recurrent aphthous stomatitis, papillar atrophy of the tongue dorsum or mucosal erythema were identified. Patients underwent clinical examination, and the blood samples were taken., Results: 250 patients (208 females; 42 males, mean age 44.1 years) with at least one corresponding symptom or sign were identified. The nutritional deficiency of one or more nutrients was found in 119 patients (47.6%). Seven times more females than males were noted to have one type of deficiency (104 females, 15 males). Iron deficiency as defined was diagnosed in 62 patients (24.8%), vitamin B12 or folic acid deficiency in 44 patients (17.6%) and both deficiencies (iron + vitamin B12/folic acid) in 13 patients (5.2%). The only predictive factor was gender and only for iron deficiency. The presence of more than one deficiency was noted in 10 patients (4.9%)., Conclusion: The most commonly observed deficiency in dental practice over the course of 11 years was an iron deficiency in the female population. Age, diet and reported co-morbidities did not show statistically significant predictable value in recognizing these deficiencies.

Background: Within Cambodia, micronutrient deficiencies continue to be prevalent in vulnerable groups, such as women and children. Fortification of staple foods such as rice could be a promising strategy for Cambodia to improve micronutrient status., Objective: Our objective was to investigate the impact of multiple-micronutrient fortified rice (MMFR), distributed through a World Food Program school-meals program (WFP-SMP) on serum zinc concentrations and folate status in a double-blind, cluster-randomized, placebo-controlled trial., Methods: Sixteen schools were randomly assigned to receive one of three different types of extruded-fortified rice (UltraRice Original (URO), UltraRice New (URN), or NutriRice) or unfortified rice (placebo) six days a week for six months. A total of 1950 schoolchildren (6-16 years old) participated in the study. Serum zinc (all groups) and folate (only in NutriRice and placebo group) concentrations were assessed from morning non-fasting antecubital blood samples and were measured at three time points (baseline and after three and six months)., Results: After six months of intervention, serum zinc concentrations were significantly increased in all fortified rice group compared to placebo and baseline (0.98, 0.85 and 1.40 µmol/L for URO, URN and NutriRice, respectively) (interaction effect: p < 0.001 for all). Children in the intervention groups had a risk of zinc deficiencies of around one third (0.35, 039, and 0.28 for URO, URN, and NutriRice, respectively) compared to the placebo ( p < 0.001 for all). The children receiving NutriRice had higher serum folate concentrations at endline compared to children receiving normal rice (+ 2.25 ng/mL, p = 0.007)., Conclusions: This study showed that the high prevalence of zinc and folate deficiency in Cambodia can be improved through the provision of MMFR. As rice is the staple diet for Cambodia, MMFR should be considered to be included in the school meal program and possibilities should be explored to introduce MMFR to the general population., Competing Interests: The authors declare no conflict of interest.

Periconceptional folic acid (FA) supplementation is recommended to prevent neural tube defects (NTDs), but little information is known about its use in Vietnam. It is important that FA supplements start to be taken when planning a pregnancy and continued through the first trimester to prevent NTDs, as the neural tube closes in the first month of pregnancy. However, FA supplementation in Vietnam is usually recommended to commence from the first antenatal visit, which is usually at 16 weeks, and very few women take FA before their first visit. This multicenter study aimed to determine the prevalence of FA supplement use and associated maternal characteristics in Vietnam. FA supplementation was assessed in 2030 singleton pregnant women between 2015 and 2016. In total, 654 (32.2%) women reported taking either supplements containing FA alone or multivitamins containing FA, and 505 (24.9%) reported correctly taking supplements containing FA alone. Women who were aged 30 years or over, had low education levels, had formal employment, and whose current pregnancy was first or unplanned were less likely to supplement with FA. Education programs are needed to encourage FA supplementation when contemplating pregnancy., Competing Interests: The authors declare no conflict of interest. The sponsors had no role in the design, execution, interpretation, or writing of the study.

Objective: To investigate the current situation of anaemia among children aged 6-23 months in a rural county in China, and to explore the influencing factors and the main causes of anaemia., Design: A cross-sectional study., Setting: Huzhu County in Qinghai Province, China PARTICIPANTS: We selected 38 sampled villages using Proportional to Population Size sampling method. We obtained the name list of children aged 6-23 months in each sampled village and planned to survey all the eligible children aged 6-23 months and their caregivers., Primary and Secondary Outcomes Measures: The prevalence of anaemia, the influencing factors of anaemia, the laboratory tests for biological causes of anaemia, including serum ferritin, soluble transferrin receptor, folic acid, homocysteine and vitamin B12., Results: A total of 754 children aged 6-23 months and their caregivers were surveyed, and 183 anaemic children aged 12-23 months were collected venous blood sample. The anaemia prevalence of children aged 6-23 months in Huzhu County was 59.1%. Children of younger age (OR=0.968, 95% CI 0.940 to 0.998), Tibetan nationality (OR=3.123, 95% CI 1.473 to 6.623) and not introducing meat (OR=0.698, 95% CI 0.499 to 0.976) were more likely to be anaemic. More than 80% of children with anaemia were due to iron deficiency (ID), and 20.2% of them had both iron and folic acid deficiencies., Conclusions: The anaemia prevalence of children aged 6-23 months in Huzhu County was high and children of younger age, Tibetan nationality and not introducing meat were more likely to be anaemic. The main cause of anaemia was nutritional anaemia, with the vast majority being ID. Interventions of feeding counselling and nutrients supplements are appropriate and should be further strengthened., Trial Registration Number: ChiCTRPRC12002444., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cerebral folate deficiency is typically defined as a deficiency of the major folate species 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) in the presence of normal peripheral total folate levels. However, it should be noted that cerebral folate deficiency is also often used to describe conditions where CSF 5-MTHF is low, in the presence of low or undefined peripheral folate levels. Known defects of folate transport are deficiency of the proton coupled folate transporter, associated with systemic as well as cerebral folate deficiency, and deficiency of the folate receptor alpha, leading to an isolated cerebral folate deficiency associated with intractable seizures, developmental delay and/or regression, progressive ataxia and choreoathetoid movement disorders. Inborn errors of folate metabolism include deficiencies of the enzymes methylenetetrahydrofolate reductase, dihydrofolate reductase and 5,10-methenyltetrahydrofolate synthetase. Cerebral folate deficiency is potentially a treatable condition and so prompt recognition of these inborn errors and initiation of appropriate therapy is of paramount importance. Secondary cerebral folate deficiency may be observed in other inherited metabolic diseases, including disorders of the mitochondrial oxidative phosphorylation system, serine deficiency, and pyridoxine dependent epilepsy. Other secondary causes of cerebral folate deficiency include the effects of drugs, immune response activation, toxic insults and oxidative stress. This review describes the absorption, transport and metabolism of folate within the body; analytical methods to measure folate species in blood, plasma and CSF; inherited and acquired causes of cerebral folate deficiency; and possible treatment options in those patients found to have cerebral folate deficiency., (© 2019 SSIEM.)

In this case report, a 26-year-old pregnant woman presented with headache, visual disturbances, mega-loblastic anaemia, thrombocytopenia and proteinuria in her third trimester. These symptoms were initially misinterpreted as HELLP-syndrome, but due to normal blood pressure and liver function the patient was diagnosed with severe folate deficiency despite her daily supplements of folate to avoid neural tube defects and deficiency. The reason was onset of coeliac disease during pregnancy. Careful examination may help discriminate HELLP-syndrome from folate deficiency and thus avoid preterm delivery.

The term "cerebral palsy mimic" is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have specific disease-modifying treatment. In this article, we discuss clinical features that should alert the clinician to the possibility of a cerebral palsy mimic, provide a practical framework for selecting and interpreting neuroimaging, biochemical, and genetic investigations, and highlight selected conditions that may present with predominant spasticity, dystonia/chorea, and ataxia. Making a precise diagnosis of a genetic disorder has important implications for treatment, and for advising the family regarding prognosis and genetic counseling. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

There are several hundred single-gene disorders that we classify as inborn errors of metabolism. Inborn errors of metabolism are often rare and highly heterogeneous multisystem diseases with non-neurological and neurological manifestations, commonly with onset during childhood. Movement disorders are among the most common neurological problems in inborn errors of metabolism, but, in many cases, remain poorly defined. Although movement disorders are usually not the only and often not the presenting symptom, their recognition can facilitate a diagnosis. Movement disorders contribute substantially to the morbidity in inborn errors of metabolism and can have a significant impact on quality of life. Common metabolic movement disorders include the monoamine neurotransmitter disorders, disorders of amino and organic acid metabolism, metal storage disorders, lysosomal storage disorders, congenital disorders of autophagy, disorders of creatine metabolism, vitamin-responsive disorders, and disorders of energy metabolism. Importantly, disease-modifying therapies exist for a number of inborn errors of metabolism, and early recognition and treatment can prevent irreversible CNS damage and reduce morbidity and mortality. A phenomenology-based approach, based on the predominant movement disorder, can facilitate a differential diagnosis and can guide biochemical, molecular, and imaging testing. The complexity of metabolic movement disorders demands an interdisciplinary approach and close collaboration of pediatric neurologists, neurologists, geneticists, and experts in metabolism. In this review, we develop a general framework for a phenomenology-based approach to movement disorders in inborn errors of metabolism and discuss an approach to identifying the "top ten" of treatable inborn errors of metabolism that present with movement disorders-diagnoses that should never be missed. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: For women of reproductive age, a population-level red blood cell (RBC) folate concentration below the threshold 906 nmol/L or 400 ng/mL indicates folate insufficiency and suboptimal neural tube defect (NTD) prevention. A corresponding population plasma/serum folate concentration threshold for optimal NTD prevention has not been established., Objective: The aim of this study was to examine the association between plasma and RBC folate concentrations and estimated a population plasma folate insufficiency threshold (pf-IT) corresponding to the RBC folate insufficiency threshold (RBCf-IT) of 906 nmol/L., Methods: We analyzed data on women of reproductive age (n = 1673) who participated in a population-based, randomized folic acid supplementation trial in northern China. Of these women, 565 women with anemia and/or vitamin B-12 deficiency were ineligible for folic acid intervention (nonintervention group); the other 1108 received folic acid supplementation for 6 mo (intervention group). We developed a Bayesian linear model to estimate the pf-IT corresponding to RBCf-IT by time from supplementation initiation, folic acid dosage, methyltetrahydrofolate reductase (MTHFR) genotype, body mass index (BMI), vitamin B-12 status, or anemia status., Results: Using plasma and RBC folate concentrations of the intervention group, the estimated median pf-IT was 25.5 nmol/L (95% credible interval: 24.6, 26.4). The median pf-ITs were similar between the baseline and postsupplementation samples (25.7 compared with 25.2 nmol/L) but differed moderately (±3-4 nmol/L) by MTHFR genotype and BMI. Using the full population-based baseline sample (intervention and nonintervention), the median pf-IT was higher for women with vitamin B-12 deficiency (34.6 nmol/L) and marginal deficiency (29.8 nmol/L) compared with the sufficient group (25.6 nmol/L)., Conclusions: The relation between RBC and plasma folate concentrations was modified by BMI and genotype and substantially by low plasma vitamin B-12. This suggests that the threshold of 25.5 nmol/L for optimal NTD prevention may be appropriate in populations with similar characteristics, but it should not be used in vitamin B-12 insufficient populations. This trial was registered at clinicaltrials.gov as NCT00207558., (Published by Oxford University Press on behalf of the American Society for Nutrition 2019.)

Background: Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring., Methods: We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones., Results: There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271-13.258; OR = 3.333, 95%CI: 1.068-10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070-3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023-3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361-11.308)., Conclusion: Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.

Background: Cognitive disorders in old age have a serious impact on the health and social aspects of patients and their families., Objective: The scope of this paper is to explore the role of cobalamin and folate that has been linked to cognitive decline, not only as a deficiency state depending on malnutrition, but also a determinant in cognitive impairment., Methods: A 6-year observational, retrospective study was conducted by collecting the routine blood analyses and cognitive screening scores of patients aged 60 years or older, followed at our Centre for the Diagnosis and Treatment of Cognitive Disorders., Results: In a linear regression with a multi-vitamin model, higher folate concentrations were correlated with better cognitive performances through MMSE score, even after correction for sex, age, and years of education (beta = 0.144, p = 0.001). Estimated MMSE marginal means for folate versus homocysteine showed that folate deficiency was associated with worse cognitive performances, with a more severe cognitive impairment when hyperhomocysteinemia was present., Conclusion: The assessment of B-vitamin status among elderly adults can contribute to an economic and practical approach to the prevention and management of cognitive decline. Future studies focused to define optimal vitamin status are warranted.

Folate (vitamin B 9 ) plays a crucial role in fundamental cellular processes, including nucleic acid biosynthesis, methyl group biogenesis and amino acid metabolism. The detection and correction of folate deficiency prevents megaloblastic anaemia and reduces the risk of neural tube defects. Coexisting deficiencies of folate and vitamin B 12 are associated with cognitive decline, depression and neuropathy. Folate deficiency and excess has also been implicated in some cancers. Excessive exposure to folic acid, a synthetic compound used in supplements and fortified foods, has also been linked to adverse health effects. Of at least three distinct laboratory markers of folate status, it is the total abundance of folate in serum/plasma that is used by the majority of laboratories. The analysis of folate in red cells is also commonly performed. Since the folate content of red cells is fixed during erythropoiesis, this marker is indicative of folate status over the preceding ~4 months. Poor stability, variation in polyglutamate chain length and unreliable extraction from red cells are factors that make the analysis of folate challenging. The clinical use of measuring specific folate species has also been explored. 5-Methyltetrahydrofolate, the main form of folate found in blood, is essential for the vitamin B 12 -dependent methionine synthase mediated remethylation of homocysteine to methionine. As such, homocysteine measurement reflects cellular folate and vitamin B 12 use. When interpreting homocysteine results, age, sex and pregnancy, specific reference ranges should be applied. The evaluation of folate status using combined markers of abundance and cellular use has been adopted by some laboratories. In the presence of discordance between laboratory results and strong clinical features of deficiency, treatment should not be delayed. High folate status should be followed up with the assessment of vitamin B 12 status, a review of previous results and reassessment of folic acid supplementation regime., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Retinal vascular occlusions are uncommon in young people and require more in-depth investigation into the cause. Studies have revealed that a high level of circulating homocysteine poses a risk for retinal vaso-occlusive events across a wide age range. This case report reflects on how the interplay of genetic mutation and vitamin deficiency can cause a pathological level of homocysteine with resultant branch retinal artery occlusion in a young patient., Case Presentation: A 16-year-old boy presented to eye casualty with acute inferior visual field loss in the left eye. Visual acuity remained normal at 6/6 each eye and the event was painless. Initial assessment, and retinal photography revealed a left superior hemi-field branch retinal artery occlusion with macular sparing. Given the patient's age, extensive investigation into the cause was carried out. Positive findings were of an elevated level of homocysteine as a result of vitamin B12 and folic acid deficiency as well as a genetic mutation in the MTHFR gene (encoding MTHFR enzyme which is vital in normal homocysteine metabolism). Vitamin B12 and folic acid were replaced which in turn normalized the patient's homocysteine levels. At two months, the patient's visual fields had also improved, and no further vascular event had occurred., Conclusions: This case report has highlighted the link between hyperhomocysteinaemia and retinal artery occlusion. However, despite vitamin replacement being shown to normalize homocysteine levels, no evidence exists to date as to whether this will reduce the risk of further retinal vascular occlusion.

Background: In our study, we aimed to evaluate the serum homocysteine levels, pyridoxine, folate and vitamin B12 levels in children with attention deficit hyperactivity disorders (ADHD)., Subjects and Methods: This study included 30 newly diagnosed drug-naive children with ADHD (23 males and 7 female, mean age 9.3±1.8 years) and 30 sex-and age matched healthy controls. The diagnosis of ADHD was made according to DSM-V criteria. Children and adolescents were administered the Schedule for Affective Disorders and Schizophrenia for School Aged Children, Present and Lifetime Version, the Conners' Parent Rating Scale-Revised, Long Form, the Conners' Teacher Rating Scale and the Wechsler Intelligence Scale for Children Revised (WISC-R) for all participants. Homocysteine, pyridoxine, folate and vitamin B12 levels were measured with enzyme-linked immunosorbent assay., Results: Homocysteine, pyridoxine, folate and vitamin B12 levels were significantly lower in children with ADHD compared with their controls (p<0.05). A positive significant correlation was observed between the all WISC-R scores and vitamin B12 level in patients (r=0.408, p=0.025)., Conclusions: The results obtained in this study showed that reduced homocysteine, pyridoxine, folate and vitamin B12 levels could be a risk factor in the etiology of ADHD.

Purpose: The red blood cell (RBC) folate test is a laboratory test with limited clinical utility. Previous attempts to reduce physician ordering of unnecessary laboratory tests, including folate levels, have resulted in only modest success. The objective of this study was to assess the effectiveness and impacts of restricting RBC folate ordering in the electronic health record (EHR)., Methods: This was a retrospective observational study that took place from January 2010 to December 2016 at a large academic healthcare network in Toronto, Canada. All inpatients and outpatients who underwent at least 1 RBC folate or vitamin B12 test during the study period were included. Ordering an RBC folate test was restricted to clinicians in gastroenterology and hematology. The option to order the test was removed from other physicians' computerized order entry screens in the EHR in June 2013., Results: RBC folate testing decreased by 94.4% during the study, from a mean of 493.0 ± 48.0 tests per month prior to intervention to 27.6 ± 10.3 tests per month after intervention (P < .001)., Conclusions: Restricting RBC folate ordering in the EHR resulted in a large and sustained reduction in RBC folate testing. Significant cost savings, estimated at more than a quarter of a million Canadian dollars over 3 years, were achieved. There was no significant clinical impact of the intervention on the diagnosis of folate deficiency., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cobalamin and folate are crucial micronutrients during infancy and they are required for growth and cognitive development. Due to the monotonous and predominantly vegetarian-based complementary feeding and poor maternal micronutrient status, infants from low- and middle-income countries are susceptible to cobalamin deficiency. However, data on plasma cobalamin and folate and the functional markers methylmalonic acid and total homocysteine from breastfed infants in Nepal are still needed. We collected plasma samples from 316 6⁻11-month-old breastfed infants with a length-for-age of less than minus one z -score and analyzed blood for plasma folate, cobalamin, methylmalonic acid and total homocysteine concentrations. Cobalamin deficiency (plasma cobalamin 10 µmol/L) and methylmalonic acid (>0.28 µmol/L) indicating functional cobalamin deficiency were found among 53% and 75% of the infants, respectively. Based on a combined indicator of cobalamin status, 58% were found to have low cobalamin status. However, folate deficiency (.

Introduction: Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits., Study Aims and Methods: Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous families homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding., Results: Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5-6 weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy., Discussion: Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene abnormality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The intrauterine environment is critical for fetal growth and organ development. Evidence from animal models indicates that the developing kidney is vulnerable to suboptimal maternal nutrition and changes in health status. However, evidence from human studies are yet to be synthesised. Therefore, the aim of the current study was to systematically review current research on the relationship between maternal nutrition during pregnancy and offspring kidney structure and function in humans. A search of five databases identified 9501 articles, of which three experimental and seven observational studies met the inclusion criteria. Nutrients reviewed to date included vitamin A ( n = 3), folate and vitamin B12 ( n = 2), iron ( n = 1), vitamin D ( n = 1), total energy ( n = 2) and protein ( n = 1). Seven studies were assessed as being of "positive" and three of "neutral" quality. A variety of populations were studied, with limited studies investigating maternal nutrition during pregnancy, while measurements of offspring kidney outcomes were diverse across studies. There was a lack of consistency in the timing of follow-up for offspring kidney structure and/or function assessments, thus limiting comparability between studies. Deficiencies in maternal folate, vitamin A, and total energy during pregnancy were associated with detrimental impacts on kidney structure and function, measured by kidney volume, proteinuria, eGFR cystC and mean creatinine clearance in the offspring. Additional experimental and longitudinal prospective studies are warranted to confirm this relationship, especially in Indigenous populations where the risk of renal disease is greater.

"Anemias beyond iron, vitamin B12, and folate deficiencies" covers a wide array of everything which lies beyond commonly seen anemias caused by deficiencies of three micronutrients. Although anemias due to deficiencies of iron, B12, and folate are common in daily practice and account for at least one-third of anemia etiologies in older adults, it is not uncommon to encounter other nutritional and toxin-induced underproduction anemias. The combination of thorough clinical examination, careful peripheral blood smear review, and judicious selection of supporting laboratory studies is typically sufficient to make an assertive diagnosis of those cases. Moreover, the recognition of overlapping features with primary hematologic disorders and the diagnostic limitations of conventional testing are important for clinicians to determine when to refer to a hematologist. Herein, we discuss clinical features and diagnostic approaches to unusual underproduction anemias due to deficiencies of vitamin B6 and copper, and toxic effects of alcohol and lead.