Managing folate deficiency implies filling the gap between laboratory and clinical assessment.

The characterization of folate status in subjects at risk of deficiency and with altered vitamin homeostasis is crucial to endorse preventive intervention health policies, especially in developed countries. Several physiological changes (i.e. pregnancy), clinical situations and diseases have been associated to increased requirement, impaired intake and absorption of folate. However clinical practice guidelines (CPG) endorse folic acid supplementation generally discarding the use of its determination in serum to assess the risk of deficiency and/or its concentration at baseline. Poor confidence on the diagnostic accuracy of serum folate assays still persists in the current CPGs although recent standardization efforts have greatly improved inter-method variability and precision. In this review we critically appraise the methodological issues concerning laboratory folate determination and the evidence on the potential adverse effects of folic acid exposure. The final aim is to build a sound background to promote serum folate-based cost-effective health care policies by optimizing folic acid supplementation in subjects at risk of deficiency and with altered folate homeostasis. Our first result was to adjust in relation to current serum folate assays the thresholds reported by CPGs as index of folate status, defined on the association with metabolic and hematologic indicators. We identify a statistically significant difference between the estimated thresholds and accordingly show that the assessment of folate status actually changes in relation to the assay employed. The use of the method-dependent thresholds here reported may pragmatically endorse the stewardship of folic acid supplementation in clinical practice and increase the cost-effectiveness of health care policies.

Screening of folate-producing lactic acid bacteria and modulatory effects of folate-biofortified yogurt on gut dysbacteriosis of folate-deficient rats.

Folate deficiency is accompanied by gut dysbacteriosis. To understand dietary intervention in folate deficiency, a folate-deficient rat model was used to evaluate the modulatory effects of folate-producing lactic acid bacteria (LAB) and biofortified yogurt on gut dysbacteriosis. The high folate-producing strain was screened from 12 LABs, and its variant, namely Lactobacillus plantarum GSLP-7 V, with folate productivity in yogurt at 3.72 µg mL-1, was obtained by stressing with 5.0 mg L-1 methotrexate and 100.00 mg L-1 Ca2+. To our knowledge, this is the highest folate productivity in yogurt by LAB strains ever reported. To further examine the folate supplement effect in vivo, a folate-deficient rat model was established and fed a folate-free diet for 8 weeks. Also, the effects of L. plantrum GSLP-7 V, yogurt fermented with L. plantrum GSLP-7 V, plain yogurt, and chemical folic acid on folate deficiency and gut dysbacteriosis were examined. Analysis of the change in gut microbiota showed that the gut dysbacteriosis was significantly correlated with folate deficiency. Administration of L. plantrum GSLP-7 V and its fermented yogurt for 10 days restored the disrupted gut microbiota and recovered the serum folate and homocysteine to normal levels, while chemical folic acid worsened the gut dysbacteriosis. Chemical folic acid only enriched Akkermansia, while L. plantrum GSLP-7 V and its fermented yogurt modulated the gut microbiota comprehensively through 7 and 10 key genera, respectively. This study confirmed the effectiveness of dietary intervention with folate-biofortified yogurt through modulating gut microbiota, suggesting the potential of the folate-producing LAB as an agent for the treatment of folate-deficiency related diseases.

Folic acid deficiency and vision: a review.

Folic acid (FA), also termed folate, is an essential vitamin for health at all ages since it participates in the biosynthesis of nucleotides, amino acids, neurotransmitters, and certain vitamins. It is therefore crucial for rapidly growing tissues such as those of the fetus. It is becoming clear that FA deficiency and impaired folate pathways are implicated in many diseases of both early life and old age. FA can be transported into the cell by the folate receptor, the reduced folate transporter, and proton-coupled folate transporter. Folate transport proteins are present in certain eye tissues, which explains why FA plays an important role in eye development. The purpose of this literature review is to investigate the evidence relating FA deficiency to eye diseases.

Genetic mimics of cerebral palsy.

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.

Movement Disorders in Treatable Inborn Errors of Metabolism.

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.

A case of subacute combined degeneration of the spinal cord due to folic acid and copper deficiency.

Subacute combined degeneration of the spinal cord (SACD) is a rare neurologic disorder manifesting progressive symptoms of paresthesia and spastic paralysis. Herein we present an autopsy case of SACD caused by folic acid and copper deficiency. A 16-year-old male presented with gradually worsening unsteady gait, and bladder and rectal dysfunction. He had a medical history of T-cell acute lymphoblastic leukemia (T-ALL), diagnosed 1.5 years previously. The patient had undergone chemotherapy, including methotrexate, as well as allogeneic bone mallow transplantation. Laboratory tests revealed normal vitamin B12 and methylmalonic acid concentration, but reduced serum copper, ceruloplasmin and folic acid concentrations. Magnetic resonance imaging revealed symmetrical T2 signal hyperintensities in the posterior and lateral spinal cord. The patient was treated with oral copper, oral folate, and intravenous vitamin B12. A month after this treatment, the patient's symptoms were unchanged, and 2 months later he died of acute adrenal insufficiency. The pathological findings of the spinal cord were compatible with SACD. Because SACD is usually reversible with early treatment, it should be suspected in high-risk patients undergoing chemotherapy or those who are malnourished with characteristic symptoms of SACD, even in young patients.

Stable Liposome in Cosmetic Platforms for Transdermal Folic acid delivery for fortification and treatment of micronutrient deficiencies.

Oral folate fortification has been successful in many developed nations, however, developing countries still face low compliance and high incidence of folate deficiency associated with low birth weight infants and preterm deliveries. We report safe and efficient approach for transdermal systemic folate delivery using fluidising liposomes (120 ± 4 nm) stabilised within 3D matrix of naturally occurring cosmetic bases: Fuller's earth and henna with room temperature stability. The proof of stratum corneum fluidisation was established ex-vivo by Langmuir-Blodgett film, FTIR and confocal imaging in rat skin. In-vivo topical application in rats showed 11-fold increase in plasma folate within 2 hr, confirming systemic delivery through skin. Efficacy study in folate deficient rats over 4 weeks showed significantly higher plasma levels compared to oral delivery with significant skin depot. Sub-acute toxicity studies in rats at 750-fold higher doses showed safety after 4 weeks daily application. Primary irritation patch test on 25 healthy human volunteers proved non-irritant nature of the nutricosmetics. The technology is first demonstration of transdermal folate fortification with nanosized liposome incorporated in cosmetics, without synthetic surfactants/ethanol or need of external energy. The platform technology opens the possibility of delivering multiple nutrients systemically through skin and can be scaled for affordable community fortification.

A 2017 global update on folic acid-preventable spina bifida and anencephaly.

BACKGROUND: Spina bifida and anencephaly are largely preventable birth defects through mandatory folic acid fortification. Our objective was to estimate the proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented worldwide through mandatory fortification of wheat and/or maize flour with folic acid during the year 2017. METHODS: Using existing data, we identified countries with mandatory fortification policies that added at least 1.0 ppm folic acid to wheat and/or maize flour and had information on percentage of industrially milled flour that is fortified. We assumed mandatory folic acid fortification at 200 µg/day of folic acid fully protects against FAP SBA, reducing the prevalence of spina bifida and anencephaly to 0.5 per 1,000 live births. RESULTS: Overall, 59 countries met our criteria for implementing mandatory folic acid fortification of wheat and/or maize flour in 2017. These countries prevented about 50,270 out of 280,500 FAP SBA births in 2017. Thus, we have only achieved 18% prevention of FAP SBA worldwide. Several countries in Africa and Asia with a high number of FAP SBA-affected births do not have mandatory fortification. CONCLUSION: About 230,000 children unnecessarily developed FAP SBA globally in 2017. There is an urgent need for all countries to implement mandatory folic acid fortification, a proven, safe public health intervention that saves money and prevents infant mortality and disability. Prevention of FAP SBA can play an important role in helping countries to achieve their Sustainable Development Goals for health.

Folic acid, dietary habits, and homocysteine levels in relation to neural tube defects: A case-control study in North India.

PURPOSE: The present study attempts to understand the complex contribution of biochemical (plasma homocysteine) and nutritional parameters (dietary pattern and folate supplementation) to the neural tube defects (NTDs) affected pregnancies and controls in North Indian population. METHODS: Case-control study design was adopted to assess the role of folic acid, dietary habits, and homocysteine in relation to NTD births. The subjects comprised of 130 mothers of affected children (cases) and 233 mothers of healthy children (controls), who were either carrying NTD fetus or gave birth to NTD child. RESULTS: The mean homocysteine levels were elevated in cases (15.71 ± 8.35 µmol/L) as compared to controls (12.87 ± 5.95 µmol/L) but were lower among the non-vergetarians (13.55 ± 6.64 µmol/L) than the vegetarians (14.78 ± 7.93 µmol/L). Vegetarian dietary habit increased the NTD risk by 1.6 fold (95% CI = 1.0-2.7) while folic acid supplementation demonstrated a protective effect for conceptions (OR = 0.59; 95% CI = 0.3-0.9). Consumption of folic acid with non-vegetarian diet witnessed lowering of homocysteine in cases (12.88 ± 6.81 µmol/L) and in controls (11.85 ± 5.54 µmol/L), with an odds ratio depicting a 3.1 fold risk for consuming vegetarian diet without folic acid supplementation during the peri-conceptional period. CONCLUSION: It is suggested that plasma hyperhomocysteinemia bears negative impact on child-bearing women group, of north Indian ancestry, in modulating the risk of NTDs. Efforts should be made to enhance awareness regarding folic acid and vitamin B12 (non-vegetarian diet) supplementations alongwith proper nutritional intake among women, especially those consuming vegetarian diet to control homocysteine levels in order to reduce the risk of NTDs.

The unusual nutritional and toxin-related underproduction anemias: approaching the riddle beyond iron, cobalamin, and folate.

"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.

Thiamin and folic acid deficiency accompanied by resistant electrolyte imbalance in the re-feeding syndrome in an elderly patient.

INTRODUCTION: Re-feeding Syndrome (RS) is a deadly complication, which can be encountered during "refeeding" of malnourished patients. In these patients, thiamin deficiency may develop and "risk awareness" is the most significant factor in the management of these patients. In this case report, the treatment is presented of an elderly patient who was diagnosed with RS and followed-up in the intensive care unit (ICU) due to resistant fluidelectrolyte imbalance. CASE: An 87-year-old elderly woman was admitted to the hospital due to aspiration pneumonia. On day 4, during parenteral nutrition (30 kcal/kg/day), severe electrolyte imbalance developed. Total parenteral nutrition (TPN) was stopped, and enteral feeding together with potassium (90 mmol/day, i.v.) were started. During follow-up, plasma potassium values remained less than 3 mmol/L. Despite replacement therapy, hypoalbuminemia, hypomagnesemia, hypocalcemia, and hypophosphatemia persisted. Considering the parenteral nutrition (30 kcal/kg/day) during the hospitalization period, a diagnosis of RS was made. On day 10, thiamin (200 mg/day, i.v.) and folic acid (5 mg/day) were added, and the patient subsequently responded to electrolyte replacement treatment. The patient was discharged on day26 with a home-care plan. CONCLUSION: In patients with malnutrition, thiamin replacement should be given before starting nutrition to prevent RS. Energy intake should be 10kcal/kg/day at the start, and be gradually increased between days 4-10. Hemodynamic-laboratory parameters should be closely monitored. All these measures may be life-saving for patients at high risk.

Déficit de ácido fólico y vitamina B12 en niños y adolescentes hospitalizados por un trastorno psiquiátrico / Folic acid and vitamin B12 deficit in children and adolescents hospitalized due to a psychiatric disorder

INTRODUCCIÓN: A pesar de que diferentes déficits nutricionales como el de ácido fólico se han asociado a la esquizofrenia y a otros trastornos psiquiátricos, se sabe poco sobre los posibles déficits de ácido fólico y vitamina B12 en niños y adolescentes con trastornos psiquiátricos. OBJETIVO: Describir los valores y posibles déficits de ácido fólico y vitamina B12 en niños y adolescentes hospitalizados por un trastorno psiquiátrico y comparar las posibles diferencias existentes según diagnóstico. MÉTODO: Se revisaron de forma retrospectiva las historias clínicas de los pacientes ingresados durante el 2015 en el Servicio de Psiquiatría y Psicología del Hospital Clinic de Barcelona. Se midieron los niveles de ácido fólico y vitamina B12 al ingreso, se registraron los datos sociodemográficos y la categoría diagnóstica, según criterios DSM-IV-TR. RESULTADOS: Se incluyeron 278 pacientes, de edad media: 14,8 años y 64% chicas. Los niveles medios de vitamina B12 fueron: 420.5±152.4 pg/ mL, significativamente menores en adolescentes que en niños y en chicos que en chicas. Se observaron diferencias significativas entre pacientes con un trastorno depresivo (381.3±107.5 pg/mL) vs. Trastornos de la conducta alimentaria (TCA) (523.1 ±229.6 pg/mL) (p = 0.002). La media de ácido fólico fue: 8±4.8 ng/mL, significativamente menor en adolescentes que en niños. Los pacientes con trastornos psicóticos (5,9±2.2ng/mL) presentaron niveles significativamente menores que los pacientes con TCA (8.1±3.6ng/mL) (p = 0.019). 11,2% de los pacientes tenían un déficit de uno o de ambos nutrientes. CONCLUSIONES: Alrededor de un 11% de la muestra presentaba un déficit de vitamina B12, de ácido fólico o de ambos, con diferencias significativas en algunas categorías diagnósticas. Sería interesante poder estudiar mejor estos déficits, debido a la importancia y posible repercusión clínica de los mismos en niños y adolescentes

INTRODUCTION: Despite different nutritional deficits such as folic acid have been associated with schizophrenia and other psychiatric disorders, little is known about the possible nutritional deficits in children and adolescents with psychiatric disorders. OBJECTIVE: To describe folic acid and vitamin B12 values and possible deficits of children and adolescents hospitalized due to psychiatric disorders and compared them between diagnostic categories. METHODS: We retrospectively reviewed the charts of patients hospitalized during 2015 in the Child and Adolescent Psychiatry and Psychology Department, Hospital Clínic in Barcelona, Spain. Levels of folic acid and vitamin B12 were registered as well as sociodemographic data and diagnostic category, according to DSM-IV-TR criteria. RESULTS: 278 patients were reviewed, mean age: 14.8 years, 64% females. Vitamin B12 mean value was 420.5±152.4 pg/mL, with significant lower levels in adolescent vs children and males vs females. We also found significant differences between patients with depressive (381.3±107.5 pg/mL) vs. eating disorders (523.1 ±229.6pg/mL) (p = 0.002). Folic acid mean value was 8±4.8 ng/mL, with significant lower levels in adolescents compared to children. Significant differences between patients with psychotic (5,9±2.2ng/mL) vs. eating disorders were also observed (8.1±3.6ng/mL) (p = 0.019). 11.2% patients had deficit of vitamin B12, folic acid or both. CONCLUSIONS: Around 11% of our sample had deficit of vitamin B12, folic acid or a combination of them, with some significant differences among diagnostic categories. It would be interesting to deeply study this issue due to the importance of these deficits in the paediatric population

Nutrition, One-Carbon Metabolism and Neural Tube Defects: A Review.

Neural tube defects (NTDs) are a group of severe congenital malformations, induced by the combined effects of genes and the environment. The most valuable finding so far has been the protective effect of folic acid supplementation against NTDs. However, many women do not take folic acid supplements until they are pregnant, which is too late to prevent NTDs effectively. Long-term intake of folic acid-fortified food is a good choice to solve this problem, and mandatory folic acid fortification should be further promoted, especially in Europe, Asia and Africa. Vitamin B2, vitamin B-6, vitamin B-12, choline, betaine and n-3 polyunsaturated fatty acids (PUFAs) can also reduce the NTD risk by interacting with the one-carbon metabolism pathway. This suggest that multivitamin B combined with choline, betaine and n-3 PUFAs supplementation may have a better protective effect against NTDs than folic acid alone. Genetic polymorphisms involved in one-carbon metabolism are associated with NTD risk, and gene screening for women of childbearing age prior to pregnancy may help prevent NTDs induced by the risk allele. In addition, the consumption of alcohol, tea and coffee, and low intakes of fruit and vegetable are also associated with the increased risk of NTDs, and should be avoided by women of childbearing age.

Folate Insufficiency Due to Celiac Disease in a 49-Year-Old Woman of Southeast Asian-Indian Ethnicity.

The clinical presentation of celiac disease has evolved from chronic diarrhea and malnutrition to mild nutrient insufficiencies. Recently diagnosed adults with celiac disease should be assessed for micronutrient deficiencies because early institution of a gluten-free diet (GFD) prevents morbidity and reduces the incidence of gastrointestinal malignant neoplasms and osteoporosis. In this report, we present the case of a 49-year-old woman of Southeast Asian-Indian descent living in the United States who had folate insufficiency, as manifested by low serum and red blood cell (RBC) folate levels. Further investigation, including serologic testing and intestinal biopsy, confirmed a diagnosis of celiac disease and other nutrient deficiencies. Managing the condition of this patient with folate supplements and implementation of a recommended GFD reversed the folate insufficiency. In conclusion, when serum and/or RBC levels are low in a person of Southeast Asian-Indian descent living in a country with folate fortification of the grain supply, such as the United States, the medical team needs to look for an organic cause, as in our patient, to diagnose and manage celiac disease early and, hopefully, forestall complications.

[Treatable Dementia due to Vitamin B12 and Folate Deficiency].

Vitamin deficiency is one of the major causes of treatable dementia. Specifically, patients suffering from dementia frequentry display low serum levels of vitamin B(12). There is a close metabolic interaction between folate and vitamin B(12). Folate deficiency causes various neuropsychiatric symptoms, which resemble those observed in vitamin B(12) deficiency. This review summarizes, the basic pathophysiology of vitamin B(12) and folate deficiency, its clinical diagnosis, associated neuropsychiatric symptoms such as subacute combined degeneration and dementia, and epidemiological studies of cognitive decline and brain atrophy.

Treatable Inborn Errors of Metabolism Due to Membrane Vitamin Transporters Deficiency.

B vitamins act as cofactors for strategic metabolic processes. The SLC19 gene family of solute carriers has a significant structural similarity, transporting substrates with different structure and ionic charge. Three proteins of this family are expressed ubiquitously and mediate the transport of 2 important water-soluble vitamins, folate, and thiamine. SLC19A1 transports folate and SLC19A2 and SLC19A3 transport thiamine. PCFT and FOLR1 ensure intestinal absorption and transport of folate through the blood-brain barrier and SLC19A25 transports thiamine into the mitochondria. Several damaging genetic defects in vitamin B transport and metabolism have been reported. The most relevant feature of thiamine and folate transport defects is that both of them are treatable disorders. In this article, we discuss the biology and transport of thiamine and folate, as well as the clinical phenotype of the genetic defects.

Isolated folate deficiency causing profound pancytopenia in pregnancy.

New-onset pancytopenia in pregnancy is challenging in the clinical setting particularly as the management and outcome of pregnancy are entirely dependent on the underlying aetiology. In the absence of increased peripheral destruction, for example, hypersplenism, bone marrow (BM) failure should be considered as the cause of pancytopenia. Profound folate or B12 deficiency may result in BM failure and are relatively easy to diagnose and manage. Other causes include aplastic anaemia (AA), infiltration by a haematological malignancy and other non-haematological disorders. We report a 26-year-old woman presenting with severe pancytopenia due to folate deficiency with complete recovery observed after folic acid replacement. This case highlights the importance of recognising folate deficiency as a reversible cause of pancytopenia, since prompt replacement can lead to rapid normalisation of counts with no subsequent clinical sequelae. We also consider the indications for measuring serum folate in pregnancy.

[Vitamin B9]. / Vitamine B9.

Vitamin B9 is represented by the group of folate, whose structure is derived from folic acid. The biologically active form is reduced tetrahydrofolates, serving as an essential cofactor in methylation reactions, including the vitamin B12-dependent formation of methionine from homocysteine, and as a carrier of one-carbon units involved in the synthesis of purines and pyrimidines. Folate deficiency is associated with hyperhomocysteinemia, megaloblastic anemia, leuco- and thrombocytopenia, cardiovascular disease, embryonic defects, in particular neural tube defects, and, possibly, malignancies, depression and cognitive impairment.