Vitamin B (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12-containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

The importance of folate in reproduction can be appreciated by considering that the existence of the vitamin was first suspected from efforts to explain a potentially fatal megaloblastic anemia in young pregnant women in India. Today, low maternal folate status during pregnancy and lactation remains a significant cause of maternal morbidity in some communities. The folate status of the neonate tends to be protected at the expense of maternal stores; nevertheless, there is mounting evidence that inadequate maternal folate status during pregnancy may lead to low infant birthweight, thereby conferring risk of developmental and long-term adverse health outcomes. Moreover, folate-related anemia during childhood and adolescence might predispose children to further infections and disease. The role of folic acid in prevention of neural tube defects (NTD) is now established, and several studies suggest that this protection may extend to some other birth defects. In terms of maternal health, clinical vitamin B12 deficiency may be a cause of infertility or recurrent spontaneous abortion. Starting pregnancy with an inadequate vitamin B12 status may increase risk of birth defects such as NTD, and may contribute to preterm delivery, although this needs further evaluation. Furthermore, inadequate vitamin B12 status in the mother may lead to frank deficiency in the infant if sufficient fetal stores of vitamin B12 are not laid down during pregnancy or are not available in breastmilk. However, the implications of starting pregnancy and lactation with low vitamin B12 status have not been sufficiently researched.

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Background: Elevated total homocysteine (tHcy) concentrations have been associated with cognitive impairment, but it is unclear whether low vitamin B-12 or folate status is responsible for cognitive decline. Objective: We examined the associations of cognitive decline with vitamin B-12 and folate status in a longitudinal cohort study performed from 1993 to 2003 in Oxford, United Kingdom. Design: Cognitive function was assessed with the Mini-Mental State Examination on ͧ3 occasions during 10 y and related to serum concentrations of vitamin B-12, holotranscobalamin (holoTC), tHcy, methylmalonic acid (MMA), and folate with the use of linear mixed models in 1648 participants who provided blood in 1995. Results: Cognitive function declined abruptly at younger ages in some participants but remained intact in others until very old age. In multivariate regression analyses after adjustment for established risk factors, concentrations of holoTC (a marker of reduced vitamin B-12 status), tHcy, and MMA predicted cognitive decline, but folate did not. A doubling in holoTC concentrations (from 50 to 100 pmol/L) was associated with a 30% slower rate of cognitive decline (Ҁ0.137 to Ҁ0.083), whereas a doubling in tHcy (from 10 to 20 mol/L) or MMA (from 0.25 to 0.50 mol/L) was associated with 50% more rapid cognitive decline (Ҁ0.090 to Ҁ0.169) and (Ҁ0.104 to Ҁ0.169), respectively. After adjustment for all vitamin markers simultaneously, the associations of cognitive decline with holoTC and MMA remained significant. Conclusions: Low vitamin B-12 status was associated with more rapid cognitive decline. Randomized trials are required to determine the relevance of vitamin B-12 supplementation for prevention of dementia.Am J Clin Nutr 2007;86:1384 -91.

Vitamin D deficiency is common among older Irish adults. These data indicate the need for targeted strategies within sections of the older population to improve vitamin D status.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.