Identification of critical variants within SLC44A4, an ulcerative colitis susceptibility gene identified in a GWAS in north Indians.

SLC44A4 is one of the seven novel susceptibility genes that were discovered in the first ever genome-wide association study (GWAS) on ulcerative colitis (UC) in the genetically distinct north Indians. This gene seems to be functionally relevant to disease biology as it may contribute to the associated phenotype of Vitamin B1 deficiency among UC patients, hence playing a role in disease pathogenesis. A large number of single-nucleotide polymorphisms (SNPs) are known to be distributed throughout this gene, but the functional status of most are not known. Thus, an extensive investigation of structural and regulatory variants within this gene was undertaken in this study to identify the critical variants amongst them using a combination of fine mapping, in silico and in vitro approaches. A few intronic SNPs were predicted to have regulatory roles on the basis of in silico analysis, suggesting that they may be the critical variants within SLC44A4. This highlights the importance of this gene in UC biology, thus confirming the finding of the GWAS and also warranting additional studies.

Vitamin B1 deficiency inhibits the increased conversion of tryptophan to nicotinamide in severe food-restricted rats.

The conversion of tryptophan (Trp) → nicotinamide (Nam) is an important pathway for supplying vitamin niacin. We reported the following two phenomena: (1) severe food restriction led to an increase in the Trp → Nam conversion compared with free-access control group; (2) the conversion of Trp → Nam is also increased by vitamin B1 deficiency compared with free-access control group. The present study was done to clarify whether or not a true reason about an increase in the Trp → Nam conversion is a vitamin B1 deficiency or severe food restriction. The present results showed that vitamin B1 deficiency suppressed the increased conversion of Trp → Nam induced by severe food restriction, probably by suppressing 3-hydroxyanthranilic acid 3,4-dioxygenase protein synthesis in liver.

Formate: an essential metabolite, a biomarker, or more?

Plasma and urinary formate concentrations were recently found to be elevated during vitamin B12 and folate deficiencies. It was proposed that formate may be a valuable biomarker of impaired one-carbon metabolism. Formate is an essential intermediary metabolite in folate-mediated one-carbon metabolism and, despite its importance, our knowledge of its metabolism is limited. Formate can be produced from several substrates (e.g., methanol, branched chain fatty acids, amino acids), some reactions being folate-dependent while others are not. Formate removal proceeds via two pathways; the major one being folate-dependent. Formate is a potentially toxic molecule and we suggest that formate may play a role in some of the pathologies associated with defective one-carbon metabolism.

B-Vitamin dependent methionine metabolism and alcoholic liver disease.

Convincing evidence links aberrant B-vitamin dependent hepatic methionine metabolism to the pathogenesis of alcoholic liver disease (ALD). This review focuses on the essential roles of folate and vitamins B6 and B12 in hepatic methionine metabolism, the causes of their deficiencies among chronic alcoholic persons, and how their deficiencies together with chronic alcohol exposure impact on aberrant methionine metabolism in the pathogenesis of ALD. Folate is the dietary transmethylation donor for the production of S-adenosylmethionine (SAM), which is the substrate for all methyltransferases that regulate gene expressions in pathways of liver injury, as well as a regulator of the transsulfuration pathway that is essential for production of glutathione (GSH), the principal antioxidant for defense against oxidative liver injury. Vitamin B12 regulates transmethylation reactions for SAM production and vitamin B6 regulates transsulfuration reactions for GSH production. Folate deficiency accelerates the experimental development of ALD in ethanol-fed animals while reducing liver SAM levels with resultant abnormal gene expression and decreased production of antioxidant GSH. Through its effects on folate metabolism, reduced SAM also impairs nucleotide balance with resultant increased DNA strand breaks, oxidation, hepatocellular apoptosis, and risk of carcinogenesis. The review encompasses referenced studies on mechanisms for perturbations of methionine metabolism in ALD, evidence for altered gene expressions and their epigenetic regulation in the pathogenesis of ALD, and clinical studies on potential prevention and treatment of ALD by correction of methionine metabolism with SAM.

Effects of ethanol consumption on the B-group vitamin contents of liver, blood and urine in rats.

Several studies have shown that blood vitamin levels are lower in alcoholic patients than in control subjects. Acute ethanol exposure enhances the release of vitamins from liver cells in vitro. The aim of the present study is to confirm the effects of ethanol consumption on vitamin contents in vivo. We compared the contents of B-group vitamins in the liver, blood and urine between ethanol-fed and control rats fed a diet containing a sufficient- and low-vitamin mixture. The experimental rats were fed a 15 % ethanol solution freely for 28 d, and then 24 h urine samples were collected, after which the animals were killed. The B-group vitamin contents in the liver, blood and urine were measured. No differences in liver, blood and urine contents were observed between the control and ethanol-fed rats fed a diet containing a sufficient-vitamin mixture. On the contrary, in rats fed a diet containing a low-vitamin mixture, consumption of ethanol caused a decrease in the contents of vitamins B1, B2 and pantothenic acid in the liver; however, the contents of the other vitamins did not decrease. In the blood, the contents of vitamins B1, B2, B6 and pantothenic acid were lower in the ethanol-fed rats than in the controls. Urinary excretion of the B-group vitamins, except for niacin, was lower in the ethanol-fed rats. These results show that ethanol consumption affects the absorption, distribution and excretion of each of the vitamins in rats fed a diet containing a low-vitamin mixture.

Muscle carnitine deficiency: adult onset lipid storage myopathy with sensory neuropathy.

Muscle carnitine deficiency usually results in a lipid storage myopathy, but more rarely, neuropathy occurs in this condition. We report herein a 29-year-old man with muscle carnitine deficiency who developed not only a lipid storage myopathy, but also a severe sensory neuropathy. Oral therapy with levo-carnitine (3 g per day) for 3 months produced a remarkable improvement of the myopathy and sensory neuropathy. Six months later, he remained in good condition under strict dietary control. This report emphasizes that severe neuropathy may occur in some patients with muscle carnitine deficiency, and highlights the need for the neurologist's familiarity with those afflicted to achieve optimal clinical management.

[Neurological pathology associated with vitamin B group deficiency: thiamine, folate and cobalamin]. / Patología neurológica por déficit de vitaminas del grupo B: tiamina, folato y cobalamina.

The "fragility" of the nervous system, especially concerning to its nutrition and metabolism, explains why vitamin deficits are an important cause of neurological pathology. Some deficiency diseases, which can be very severe and irreversible, are still present in our environment; diagnosis, which must be early so as not to delay treatment, can be difficult if we do not have them in mind. In this review we address the most relevant neurological diseases associated with thiamine, folate and cobalamin deficiency, and we focus especially combined subacute degeneration and Wernicke-Korsakoff syndrome.

La "fragilidad" del sistema nervioso, en especial en lo referente a su nutrición y metabolismo, explica que los déficits vitamínicos sean una causa importante de patología neurológica. Algunas enfermedades carenciales, que pueden ser muy graves e irreversibles, aún se presentan en nuestro entorno. Su diagnóstico, que debe ser precoz para no retrasar el tratamiento, puede ser complicado si no las tenemos en mente. En esta revisión abordamos las enfermedades neurológicas más relevantes asociadas al déficit de tiamina, folatos y cobalamina, deteniéndonos especialmenteen la degeneración combinada subaguda y el síndrome de Wernicke-Korsakoff.

Five lipoxygenase hypomethylation mediates the homocysteine effect on Alzheimer's phenotype.

Environmental and genetic risk factors are implicated in the pathogenesis of Alzheimer's disease (AD). However, how they interact and influence its pathogenesis remains to be investigated. High level of homocysteine (Hcy) is an AD risk factor and associates with an up-regulation of the ALOX5 gene. In the current paper we investigated whether this activation is responsible for the Hcy effect on the AD phenotype and the mechanisms involved. Triple transgenic mice were randomized to receive regular chow diet, a diet deficient in folate and B vitamins (Diet), which results in high Hcy, or the Diet plus zileuton, a specific ALOX5 inhibitor, for 7 months. Compared with controls, Diet-fed mice had a significant increase in Hcy levels, memory and learning deficits, up-regulation of the ALOX5 pathway, increased Aß levels, tau phosphorylation, and synaptic pathology, which were absent in mice treated with zileuton. In vivo and vitro studies demonstrated that the mechanism responsible was the hypomethylation of the ALOX5 promoter. Our findings demonstrate that the up-regulation of the ALOX5 is responsible for the Hcy-dependent worsening of the AD phenotype in a relevant mouse model of the disease. The discovery of this previously unknown cross-talk between these two pathways could afford novel therapeutic opportunities for treating or halting AD.

One carbon metabolism and bone homeostasis and remodeling: A review of experimental research and population studies.

Homocysteine (HCY) is a degradation product of the methionine pathway. The B vitamins, in particular vitamin B12 and folate, are the primary nutritional determinant of HCY levels and therefore their deficiencies result in hyperhomocysteinaemia (HHCY). Prevalence of hyperhomocysteinemia (HHCY) and related dietary deficiencies in B vitamins and folate increase with age and have been related to osteoporosis and abnormal development of epiphyseal cartilage and bone in rodents. Here we provide a review of experimental and population studies. The negative effects of HHCY and/or B vitamins and folate deficiencies on bone formation and remodeling are documented by cell models, including primary osteoblasts, osteoclast and bone progenitor cells as well as by animal and human studies. However, underlying pathophysiological mechanisms are complex and remain poorly understood. Whether these associations are the direct consequences of impaired one carbon metabolism is not clarified and more studies are still needed to translate these findings to human population. To date, the evidence is limited and somewhat conflicting, however further trials in groups most vulnerable to impaired one carbon metabolism are required.

Cardiac manifestations in disorders of fat and carnitine metabolism in infancy.

The prognosis of patients with cardiomyopathy associated with hypocarnitinemia is uncertain. Cardiac hemodynamics, histologic findings and response to oral L-carnitine therapy were retrospectively evaluated in 11 children with cardiomyopathy associated with abnormal carnitine metabolism. Three had systemic carnitine deficiency, two familial hypocarnitinemia with neutropenia, three transient neonatal hypocarnitinemia and three a carnitine insufficiency syndrome. Six had a hypertrophic and five a dilated cardiomyopathy. Hypotonia was present in seven (64%). The cardiothoracic ratio was greater than 0.60 in eight (73%). The most frequent abnormality on the electrocardiogram was ST-T wave inversion in the left precordial leads with various degrees of left ventricular hypertrophy. Echocardiographically, two patients with hypertrophic cardiomyopathy had decreased left ventricular function and two patients with dilated cardiomyopathy had increased thickness of the left ventricular wall. Histologic evaluation (two autopsies and one endomyocardial biopsy) revealed striking lipid accumulation within hypertrophied myocytes. Six of eight patients on carnitine replacement therapy had improvement echocardiographically during a 3 month to 2 year follow-up period. In summary, both hypertrophic and dilated cardiomyopathy can result from abnormal carnitine metabolism. The determination of plasma carnitine concentrations and fatty acid metabolism by-products should be performed in all patients with either form of cardiomyopathy of unknown etiology because carnitine supplementation may lead to improvement.

Mode of Bioenergetic Metabolism during B Cell Differentiation in the Intestine Determines the Distinct Requirement for Vitamin B1.

Bioenergetic metabolism varies during cell differentiation, but details of B cell metabolism remain unclear. Here, we show the metabolic changes during B cell differentiation in the intestine, where B cells differentiate into IgA(+) plasma cells (PCs). Naive B cells in the Peyer's patches (PPs) and IgA(+) PCs in the intestinal lamina propria (iLP) both used the tricarboxylic acid (TCA) cycle, but only IgA(+) PCs underwent glycolysis. These metabolic differences reflected their dependencies on vitamin B1, an essential cofactor for the TCA cycle. Indeed, the diminished activity of the TCA cycle after dietary vitamin B1 depletion decreased the number of naive B cells in PPs without affecting IgA(+) PCs in the iLP. The maintenance of naive B cells by dietary vitamin B1 was required to induce-but not maintain-intestinal IgA responses against oral antigens. These findings reveal the diet-mediated maintenance of B cell immunometabolism in organized and diffuse intestinal tissues.

Effect of physical activity on thiamine, riboflavin, and vitamin B-6 requirements.

Because exercise stresses metabolic pathways that depend on thiamine, riboflavin, and vitamin B-6, the requirements for these vitamins may be increased in athletes and active individuals. Theoretically, exercise could increase the need for these micronutrients in several ways: through decreased absorption of the nutrients; by increased turnover, metabolism, or loss of the nutrients; through biochemical adaptation as a result of training that increases nutrient needs; by an increase in mitochondrial enzymes that require the nutrients; or through an increased need for the nutrients for tissue maintenance and repair. Biochemical evidence of deficiencies in some of these vitamins in active individuals has been reported, but studies examining these issues are limited and equivocal. On the basis of metabolic studies, the riboflavin status of young and older women who exercise moderately (2.5-5 h/wk) appears to be poorer in periods of exercise, dieting, and dieting plus exercise than during control periods. Exercise also increases the loss of vitamin B-6 as 4-pyridoxic acid. These losses are small and concomitant decreases in blood vitamin B-6 measures have not been documented. There are no metabolic studies that have compared thiamine status in active and sedentary persons. Exercise appears to decrease nutrient status even further in active individuals with preexisting marginal vitamin intakes or marginal body stores. Thus, active individuals who restrict their energy intake or make poor dietary choices are at greatest risk for poor thiamine, riboflavin, and vitamin B-6 status.

Hereditary carnitine deficiency of muscle.

An eight-year-old boy with slowly progressive muscle weakness was found to have Oil red O positive vacuoles in predominanty type i muscle fibers. Subsequent studies demonstrated markedly reduced skeletal muscle carnitine (0.24 mumoles per gram; normal 1.64 to 3.34). Serum carnitine was normal. Although both parents were clinically normal, muscle carnitine levels were low in both (mother 0.60; father 0.90 mumoles). There was no clinical evidence of cardiac disease but the patient had ventricular hypertrophy by electrocardiography, vectorcardiography, and echocardiography. Treatment with prednisone resulted in clinical improvement but no change in muscle histology. Our studies suggest that the carnitine deficiency of muscle in this case may be due to impaired carnitine entry into muscle and that this form of disease can be inherited as an autosomal recessive disorder.

The bone marrow in nutritional deficiencies.

The overwhelming majority of nutritional deficiencies that affect the bone marrow and blood are due to the lack of vitamin B12, folic acid, or iron or combinations thereof. The two vitamins are closely related in DNA synthesis, whereas iron is the most abundant heavy metal in the body and is chiefly utilized for hemoglobin synthesis. Concomitant conditions of vitamin B12 and/or folate deficiency along with iron deficiency are not infrequent, and one type of anemia may mask the other. It is important to establish the correct diagnoses, as therapy directed at the wrong deficiency may hide the real deficiency with disastrous results. Specific diagnostic tests are now available to determine definitive diagnoses, and specific therapy is readily available to restore and maintain a normal nutrient status.

Effects of methylcobalamin on vitamin B1- and B-deficient encephalopathy in rats.

Vitamin B1- and B-deficient encephalopathy was produced in adult Wistar rats and the effect of methylcobalamin was studied. These experiments were performed in vitamin B1- or B-deficient rats with or without the administration of guanidine, a magnesium antagonist. These encephalopathic rats showed symmetrical lesions in the pontine tegmentum. No pathological changes in the brainstem were seen in guanidine-administered rats. This suggests that guanidine itself doesn't produce these brainstem lesions. Moderate to severe pathological changes occurred in vitamin B-deficient rats with guanidine administration, whereas these pathological changes were milder in vitamin B1-deficient rats with guanidine administration and in vitamin B1- and B-deficient rats with the combination of the guanidine and methylcobalamin administrations. These facts suggest that vitamin B12, methylcobalamin, plays an important preventive role in the development of the pontine lesions in this experiment.

Pathology of the neuromuscular junction.

Diagnosis of neuromuscular disease by the study of motor endplate structure in the light and electron microscopes is probably one of the most specialized examinations in the field of neuropathology. The classical means of staining endplates using gold, silver or methylene blue are described as well as more modern techniques suitable for light microscopy. Specific abnormalities in patterns of terminal innervation after methylene blue staining are noted. Techniques for localizing endplates suitable for electron microscopic study are given and some of the typical changes that occur in endplate structure in some neuromuscular diseases are indicated.

Patología neurológica por déficit de vitaminas del grupo B: tiamina, folato y cobalamina / Neurological pathology associated with vitamin B group deficiency: thiamine, folate and cobalamin

La "fragilidad" del sistema nervioso, en especial en lo referente a su nutrición y metabolismo, explica que los déficits vitamínicos sean una causa importante de patología neurológica. Algunas enfermedades carenciales, que pueden ser muy graves e irreversibles, aún se presentan en nuestro entorno. Su diagnóstico, que debe ser precoz para no retrasar el tratamiento, puede ser complicado si no las tenemos en mente. En esta revisión abordamos las enfermedades neurológicas más relevantes asociadas al déficit de tiamina, folatos y cobalamina, deteniéndonos especialmente en la degeneración combinada subaguda y el síndrome de Wernicke-Korsakoff

The "fragility" of the nervous system, especially concerning to its nutrition and metabolism, explains why vitamin deficits are an important cause of neurological pathology. Some deficiency diseases, which can be very severe and irreversible, are still present in our environment; diagnosis, which must be early so as not to delay treatment, can be difficult if we do not have them in mind. In this review we address the most relevant neurological diseases associated with thiamine, folate and cobalamin deficiency, and we focus especially combined subacute degeneration and Wernicke-Korsakoff syndrome

S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice.

Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer's disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer's disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease.

Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency.

We have previously shown that a nutritional model of B vitamin deficiency and homocysteine cycle alteration could lead to increased amyloid ß deposition, due to PSEN1 and BACE over-expression and consequent increase in secretase activity. We hypothesize that nutritional factors causing homocysteine cycle alterations (i.e. hyperhomocysteinemia) could induce sequence-specific DNA hypomethylation and "aberrant" gene activation. Aim of present study was to analyze the methylation pattern of PSEN1 promoter in SK-N-BE neuroblastoma cells and TgCRND8 mice, in a B vitamin (folate, B12 and B6) deficiency paradigm. PSEN1 methylation status has been evaluated through bisulphite modification and genomic sequencing. We demonstrate that B vitamin deficiency induces hypomethylation of specific CpG moieties in the 5'-flanking region; S-adenosylmethionine has been supplemented as methyl donor to reverse this effect. PSEN1 promoter methylation status is correlated with gene expression. These findings pinpoint a direct relationship between B vitamin-dependent alteration of homocysteine cycle and DNA methylation and also indicate that PSEN1 promoter is regulated by methylation of specific CpG moieties.

[Wernicke's encephalopathy in chronic alcoholics]. / Wernicke-sjúkdómur medal áfengissjúkra.

Wernicke's encephalopathy (WE) is caused by thiamine (vitamin B1) deficiency and most commonly found in individuals with chronic alcoholism and malnutrition. Clinically, its key features are mental status disorders and oculomotor abnormalities as well as stance and gait ataxia. The diagnosis of WE is frequently missed although delay of appropriate treatment can lead to death or Korsakoff's amnestic syndrome. It is therefore crucial in suspected cases of WE, not to await confirmation of diagnosis, but immediately administer high-dose intravenous thiamine and simultaneously treat magnesium deficiency. Alcoholics at risk of WE should on admission receive immediate prophylactic therapy with parenteral thiamine.