Vitamin B6 deficiency cooperates with oncogenic Ras to induce malignant tumors in Drosophila.

Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5'-phosphate (PLP), is a crucial cofactor for DNA and amino acid metabolism. The inverse correlation between vitamin B6 and cancer risk has been observed in several studies, although dietary vitamin B6 intake sometimes failed to confirm this association. However, the molecular link between vitamin B6 and cancer remains elusive. Previous work has shown that vitamin B6 deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, suggesting that genome instability may correlate the lack of this vitamin to cancer. Here we provide evidence in support of this hypothesis. Firstly, we show that PLP deficiency, induced by the PLP antagonists 4-deoxypyridoxine (4DP) or ginkgotoxin (GT), promoted tumorigenesis in eye larval discs transforming benign RasV12 tumors into aggressive forms. In contrast, PLP supplementation reduced the development of tumors. We also show that low PLP levels, induced by 4DP or by silencing the sgllPNPO gene involved in PLP biosynthesis, worsened the tumor phenotype in another Drosophila cancer model generated by concomitantly activating RasV12 and downregulating Discs-large (Dlg) gene. Moreover, we found that RasV12 eye discs from larvae reared on 4DP displayed CABs, reactive oxygen species (ROS) and low catalytic activity of serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme involved in thymidylate (dTMP) biosynthesis, in turn required for DNA replication and repair. Feeding RasV12 4DP-fed larvae with PLP or ascorbic acid (AA) plus dTMP, rescued both CABs and tumors. The same effect was produced by overexpressing catalase in RasV12 DlgRNAi 4DP-fed larvae, thus allowing to establish a relationship between PLP deficiency, CABs, and cancer. Overall, our data provide the first in vivo demonstration that PLP deficiency can impact on cancer by increasing genome instability, which is in turn mediated by ROS and reduced dTMP levels.

Seizures due to pyridoxine deficiency in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized not only by its hallmark motor symptoms but also by a myriad of non-motor manifestations, including cognitive decline, autonomic manifestations, and gastrointestinal disturbances. Amidst these, a lesser-known but critical aspect is the increased risk of functional deficiency of pyridoxine (vitamin B6) in patients with PD, which is linked to an increased risk of seizures. This review investigates the intersection of PD, new-onset seizures, and pyridoxine deficiency, aiming to elucidate the significance of these associations and their contributions to the neurologic burden in PD. Case reports documenting the occurrence of seizures in patients with PD, particularly in the context of high-dose dopaminergic therapy and the subsequent revelation of pyridoxine deficiency were included. These cases, which often featured extensive workups revealing unremarkable findings aside from pyridoxine deficiency, underscore the multifaceted nature of PD and its treatment-related complications. The findings in these case reports suggest that dietary insufficiencies, gastrointestinal dysfunctions, and drug-nutrient interactions may eventually precipitate pyridoxine deficiency, which in turn may lead to seizures by disrupting GABAergic neurotransmission. This sheds the light on the need for increased clinical awareness and routine monitoring of pyridoxine levels in patients with PD, especially those undergoing significant therapeutic adjustments or exhibiting comorbidities that might interfere with their dietary intake such as gastrointestinal manifestations or depression. Such proactive measures could potentially mitigate the impact of this complication in patients with PD, ultimately enhancing patient care and quality of life.

A retrospective analysis of vitamin B6 deficiency and associated changes of gut microbes in Crohn's disease.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) are at risk of micronutrient deficiencies, particularly during flares. Vitamin B6 is required for the proper development of brain, nerves, and many other parts of the body. However, limited studies are available to describe the prevalence, relevance and consequences of vitamin B6 deficiencies in IBD. We aim to estimate the prevalence of vitamin B6 deficiencies in Crohn's disease (CD) patients, to identify associated risk factors and to explore the alteration of intestinal microbiota related to vitamin B6 status. METHODS: A total of 360 CD patients and 55 ulcerative colitis (UC) patients from Shanghai Tenth People's Hospital of Tongji University were included. Serum vitamin B6 concentrations were collected from the computerized laboratory data. The logistic regression was used for statistical analysis. Fecal-associated microbiota was also analyzed using 16S rRNA sequencing in another 20 CD patients (10 of vitamin B6 normal, 10 of vitamin B6 deficiency). RESULTS: The prevalence of vitamin B6 abnormality was significantly higher in CD than in UC patients. Logistic regression analysis showed that small bowel lesion, ileocolonic lesion (L3), extraintestinal manifestations, ileal resection, and usage of immunosuppressor were independently associated with abnormal vitamin B6 in CD. Interestingly, the microbial structure presented significant differences between two CD groups. PICRUSt2 prediction revealed that some enzymes and metabolic pathways between the two groups were significantly different. CONCLUSIONS: Collectively, our analysis showed that vitamin B6 reduction occurred frequently in patients with CD and affected the intestinal flora of patients.

Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation.

BACKGROUND AND AIMS: We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5'-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). METHODS: We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. RESULTS: In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. CONCLUSIONS: Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. IMPACT AND IMPLICATIONS: We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.

Vitamin B6 in Health and Disease.

Vitamin B6 is a fascinating molecule involved in the vast majority of changes in the human body because it is a coenzyme involved in over 150 biochemical reactions. It is active in the metabolism of carbohydrates, lipids, amino acids, and nucleic acids, and participates in cellular signaling. It is an antioxidant and a compound with the ability to lower the advanced glycation end products (AGE) level. In this review, we briefly summarize its involvement in biochemical pathways and consider whether its deficiency may be associated with various diseases such as diabetes, heart disease, cancer, or the prognosis of COVID-19.

Effects of Dietary Vitamin B6 Restriction on Hepatic Gene Expression Profile of Non-Obese and Obese Mice.

Although vitamin B6 is contained in various foods, its deficiency is one of the most common micronutrient deficiencies worldwide. Furthermore, patients with obesity and cardiovascular disease are more likely to have suboptimal vitamin B6 status than healthy people. Therefore, we investigated the effects of dietary vitamin B6 restriction on hepatic gene expression and function in obese mice. C57BL/6J male mice were fed a low-fat (LF) or high-fat (HF) diet in combination with sufficient (7 mg pyridoxine/kg diet) or insufficient (1 mg) amounts of vitamin B6 for 16 weeks. Analysis of microarray data revealed that expressions of 4000 genes were significantly altered by the experimental diets (LF7, LF1, HF7, and HF1). The effects of dietary fat content on gene expressions were markedly greater than vitamin B6 content. Only three differentially expressed genes (DEGs) were overlapped between the LF1/LF7 and HF1/HF7 comparison. In the LF1/LF7 comparison, 54 upregulated DEGs were enriched in gene ontology (GO) terms associated with the sterol metabolic process and 54 downregulated DEGs were enriched in GO terms associated with immune response. In HF1/HF7 comparison, 26 upregulated DEGs were enriched in GO terms associated with amino acid catabolic process. High-fat consumption downregulated gene expressions associated with vitamin B6-dependent pathways. In conclusion, our data suggest that obesity may differentially regulate vitamin B6-associated metabolic pathways in the body.

Vitamin B6, Inflammation, and Cardiovascular Outcome in a Population-Based Cohort: The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study.

BACKGROUND: a large number of studies have linked vitamin B6 to inflammation and cardiovascular disease in the general population. However, it remains uncertain whether vitamin B6 is associated with cardiovascular outcome independent of inflammation. METHODS: we measured plasma pyridoxal 5'-phosphate (PLP), as an indicator of vitamin B6 status, at baseline in a population-based prospective cohort of 6249 participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study who were free of cardiovascular disease. As indicators of low-grade systemic inflammation, we measured high-sensitivity C-reactive protein and GlycA; Results: median plasma PLP was 37.2 (interquartile range, 25.1-57.0) nmol/L. During median follow-up for 8.3 (interquartile range, 7.8-8.9) years, 409 non-fatal and fatal cardiovascular events (composite outcome) occurred. In the overall cohort, log transformed plasma PLP was associated with the composite outcome, independent of adjustment for age, sex, smoking, alcohol consumption, body mass index (BMI), estimated glomerular filtration rate (eGFR), total cholesterol:high-density lipoprotein (HDL)-cholesterol ratio, and blood pressure (adjusted hazard ratio per increment of log plasma PLP, 0.66; 95% confidence interval (CI), 0.47-0.93). However, adjustment for high-sensitivity C-reactive protein and GlycA increased the hazard ratio by 9% and 12% respectively, to non-significant hazard ratios of 0.72 (95% confidence interval, 0.51-1.01) and 0.74 (95% confidence interval, 0.53-1.05). The association of plasma PLP with cardiovascular risk was modified by gender (adjusted Pinteraction = 0.04). When stratified according to gender, in women the prospective association with cardiovascular outcome was independent of age, smoking, alcohol consumption, high-sensitivity C-reactive protein, and GlycA (adjusted hazard ratio, 0.50, 95% confidence interval, 0.27-0.94), while it was not in men (adjusted hazard, 0.99, 95% confidence interval, 0.65-1.51). CONCLUSIONS: in this population-based cohort, plasma PLP was associated with cardiovascular outcome, but this association was confounded by traditional risk factors and parameters of inflammation. Notably, the association of low plasma PLP with high risk of adverse cardiovascular outcome was modified by gender, with a stronger and independent association in women.

Vitamin B6 Deficiency in Patients With Parkinson Disease Treated With Levodopa/Carbidopa.

OBJECTIVE: The aim of the study was to investigate the role of L-DOPA/carbidopa (CD) therapy on vitamin B6 levels in patients with Parkinson disease (PD). METHODS: This is a cross-sectional retrospective study of vitamin B6 plasma levels in 24 patients with PD treated with L-DOPA/CD for 3 or more years, orally or intraduodenally. Vitamin B6 levels in plasma were measured by ELISA. RESULTS: All patients treated with intraduodenal L-DOPA/CD (6 of 6) and 13 of 18 patients receiving L-DOPA/CD orally had low plasma levels of vitamin B6. Eight of the 19 patients with low vitamin B6 levels had symptoms of hypovitaminosis B6. Patients with low vitamin B6 had been treated with larger doses of L-DOPA/CD, although the differences did not have statistical significance. Patients treated with intraduodenal L-DOPA/CD have vitamin B6 levels significantly lower than those treated with oral L-DOPA/CD. The variables that most correlated with vitamin B6 levels were the cumulative annual doses of CD (r = -0.36) and L-DOPA (r = -0.33) during the year preceding the study and the time to develop dyskinesias or fluctuations (r = +0.43). CONCLUSIONS: Vitamin B6 could play an important role in PD and its levels seem to be influenced by L-DOPA/CD. Plasma vitamin B6 levels should be monitored in patients receiving high L-DOPA/CD doses, especially those treated with intraduodenal infusion.

The effectiveness of correcting abnormal metabolic profiles.

Inborn errors of metabolism cause disease because of accumulation of a metabolite before the blocked step or deficiency of an essential metabolite downstream of the block. Treatments can be directed at reducing the levels of a toxic metabolite or correcting a metabolite deficiency. Many disorders have been treated successfully first in a single patient because we can measure the metabolites and adjust treatment to get them as close as possible to the normal range. Examples are drawn from Komrower's description of treatment of homocystinuria and the author's trials of treatment in bile acid synthesis disorders (3ß-hydroxy-Δ5 -C27 -steroid dehydrogenase deficiency and Δ4 -3-oxosteroid 5ß-reductase deficiency), neurotransmitter amine disorders (aromatic L-amino acid decarboxylase [AADC] and tyrosine hydroxylase deficiencies), and vitamin B6 disorders (pyridox(am)ine phosphate oxidase deficiency and pyridoxine-dependent epilepsy [ALDH7A1 deficiency]). Sometimes follow-up shows there are milder and more severe forms of the disease and even variable clinical manifestations but by measuring the metabolites we can adjust the treatment to get the metabolites into the normal range. Biochemical measurements are not subject to placebo effects and will also show if the disorder is improving spontaneously. The hypothesis that can then be tested for clinical outcome is whether getting metabolite(s) into a target range leads to an improvement in an outcome parameter such as abnormal liver function tests, hypokinesia, epilepsy control etc. The metabolite-guided approach to treatment is an example of personalized medicine and is a better way of determining efficacy for disorders of variable severity than a randomized controlled clinical trial.

Vitamin B-6 Status Correlates with Disease Activity in Rheumatoid Arthritis Patients During Treatment with TNFα Inhibitors.

BACKGROUND: A frequent observation in inflammatory conditions, including rheumatoid arthritis (RA), is low circulating amounts of pyridoxal 5'-phosphate (PLP), the metabolically active form of vitamin B-6. Recently, a functional marker of vitamin B-6 status, the ratio of 3-hydroxykynurenine (HK): xanthurenic acid (XA) in plasma (HK: XA), was proposed. OBJECTIVE: We investigated vitamin B-6 status in patients with RA before and after established treatment with TNFα inhibitors. METHODS: We performed a longitudinal study of RA patients (n = 106, 36% men, median age 54 y) starting first treatment with a TNFα inhibitor (infliximab, etanercept, adalimumab, golimumab, or certolizumab). Clinical assessment (Disease Activity Score for 28 standard joints, DAS28), joint ultrasonography, and blood draw were performed at baseline and after 3 mo treatment. Plasma concentrations of PLP, HK, and XA were measured by liquid chromatography-tandem mass spectrometry. Associations of changes in vitamin B-6 markers with change in DAS28 were assessed by generalized additive models regression and with European League Against Rheumatism (EULAR) response categories by linear regression. RESULTS: At baseline PLP was inversely correlated with CRP (ρ = -0.27, P = 0.007), whereas HK: XA correlated with DAS28 (ρ = 0.46, P < 0.001), CRP (ρ = 0.36, P < 0.001), and ultrasonography scores (ρ = 0.29-0.35, P ≤ 0.003). After 3 mo treatment, the change (a 33% overall reduction) in DAS28 was related to changes in both PLP (ß = -0.28, P = 0.01) and HK: XA (ß = 0.33, P < 0.001). Good responders (45%) according to EULAR criteria experienced a 31% increase in PLP (P = 0.003) and an 11% decrease in HK: XA (P = 0.1), whereas nonresponders (24%) experienced a 25% increase in HK: XA (P = 0.02). CONCLUSION: Two independent measures of vitamin B-6 status confirm an association with disease activity in RA patients. The association of HK: XA with disease activity may also imply perturbations in kynurenine metabolism in RA. This trial was registered at helseforskning.etikkom.no as 2011/490.

[A microcytic sideroblastic anemia successfully treated with B6 vitamin]. / Une anémie microcytaire sidéroblastique carentielle traitée efficacement par de la vitamine B6.

INTRODUCTION: Sideroblastic anemia is a rare cause of microcytic anemia, which is characterized by ring sideroblasts on bone marrow aspirate. This anemia can be congenital or acquired. CASE REPORT: We report the case of an alcoholic 49-year-old man who presented with a severe microcytic sideroblastic anemia related to pyridoxine (B6 vitamin) deficiency. Acid folic deficiency was associated. The blood count normalized within one month after vitamin supplementation. CONCLUSION: Pyridoxine deficiency must be sought in sideroblastic anemia in patients at risk.

Accumulation of Liver Lipids Induced by Vitamin B6 Deficiency Was Effectively Ameliorated by Choline and, to a Lesser Extent, Betaine.

Despite previous studies suggesting that choline and betaine ameliorate lipid accumulation in rat livers, the relative effectiveness of the two nutrients is unclear. We examined the efficacy of dietary supplementation with choline or betaine in ameliorating lipid accumulation induced by vitamin B6 (B6) deficiency in the rat liver. Male Wistar rats were fed control, B6-deficient, choline-supplemented B6-deficient, betaine-supplemented B6-deficient, or both choline and betaine-supplemented B6-deficient diets (all containing 9 g of l-methionine (Met)/kg) for 35 d. Two experiments were performed, i.e., one using 17 mmol/kg diet choline bitartrate, betaine anhydrous, and the combination and another using 8.5 mmol/kg diet. Rats fed a B6-deficient diet developed lipid accumulation in the liver with a reduction of plasma lipids induced by the disruption of Met metabolism. However, the addition of 17 mmol/kg diet choline or betaine was sufficient to ameliorate the disruptions of lipid and Met metabolism. Additionally, 8.5 mmol/kg diet choline ameliorated liver lipid deposition, while the same amount of betaine had no significant effects on liver or plasma lipid profiles. Supplementation with choline resulted in a higher liver betaine than that found using the same amount of betaine alone, although the overall liver betaine content was reduced in B6-deficient rats. Our findings indicate that choline is more effective than betaine in ameliorating B6 deficiency-related disruptions in Met metabolism and liver lipid accumulation by increasing liver betaine levels.

Disorders affecting vitamin B6 metabolism.

Vitamin B6 is present in our diet in many forms, however, only pyridoxal 5'-phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs nonphosphorylated B6 vitamers, which are converted by specific enzymes to the active PLP form. The role of PLP is enabled by its reactive aldehyde group. Pathways reliant on PLP include amino acid and neurotransmitter metabolism, folate and 1-carbon metabolism, protein and polyamine synthesis, carbohydrate and lipid metabolism, mitochondrial function and erythropoiesis. Besides the role of PLP as a cofactor B6 vitamers also play other cellular roles, for example, as antioxidants, modifying expression and action of steroid hormone receptors, affecting immune function, as chaperones and as an antagonist of Adenosine-5'-triphosphate (ATP) at P2 purinoceptors. Because of the vital role of PLP in neurotransmitter metabolism, particularly synthesis of the inhibitory transmitter γ-aminobutyric acid, it is not surprising that various inborn errors leading to PLP deficiency manifest as B6 -responsive epilepsy, usually of early onset. This includes pyridox(am)ine phosphate oxidase deficiency (a disorder affecting PLP synthesis and recycling), disorders affecting PLP import into the brain (hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects), a disorder of an intracellular PLP-binding protein (PLPBP, previously named PROSC) and disorders where metabolites accumulate that inactivate PLP, for example, ALDH7A1 deficiency and hyperprolinaemia type II. Patients with these disorders can show rapid control of seizures in response to either pyridoxine and/or PLP with a lifelong dependency on supraphysiological vitamin B6 supply. The clinical and biochemical features of disorders leading to B6 -responsive seizures and the treatment of these disorders are described in this review.

Vitamin B-6 and depressive symptomatology, over time, in older Latino adults.

Background: Low vitamin B-6 status has been linked to depressive symptomatology. We examined the longitudinal association of vitamin B-6 status with depressive symptomatology across 3-time points over ∼5-7 years in a cohort of older Hispanic adults. Methods: We used two-level hierarchical linear regression models for continuous outcomes. Vitamin B-6 status was associated with depressive symptomatology across these time points. Results: Plasma pyridoxyl-5-phosphate (PLP) concentration, a time-varying predictor, was significantly associated with depressive symptomatology. Study participants with PLP deficiency, vs. optimal PLP, had higher baseline depressive symptoms (Center for Epidemiologic Studies-Depression Scale (CES-D) score of 22 ± 14, vs. 20 ± 13); this differential remained constant over time and persisted after controlling for age, sex, education, body mass index, smoking and alcohol use, other relevant nutritional factors, perceived stress, stressful life events, allostatic load, and use of antidepressant medication. However, PLP concentration was not associated with the rate of change in depressive symptomatology over time. Conclusions: Suboptimal plasma PLP is associated with higher depressive symptomatology in older Hispanic of Puerto Rican descent and this appears to persist over time. Our data suggest that identification and treatment of vitamin B-6 deficiency may be a useful preventive approach in this population.

Pseudotumor cerebral asociado a hipovitaminosis A, B6 y D: A propósito de dos casos / Pseudotumor cerebri associated with hypovitaminosis A, B6 and D: About two cases

La hipertensión endocraneana idiopàtica se asocia infrecuentemente con la hipovitaminosis A y D. Se presenta el caso de una paciente femenina de 8 años con visión borrosa de 24 horas y papiledema bilateral. Resonancia magnética nuclear normal. Presión de apertura de líquido cefalorraquídeo: 260 mm^O. Presentó déficit de vitamina A y D, e inició un tratamiento sustitutivo. El segundo caso corresponde a un paciente masculino de 12 años con fiebre y odinofagia de 3 días. Con antecedente de glomerulonefritis y sobrepeso. Presentaba edema bipalpebral y papiledema. Tomografia axial computada de la órbita: aumento de líquido en la vaina de ambos nervios ópticos. Resonancia magnética nuclear: aracnoidocele intraselar. Presión de apertura de líquido cefalorraquídeo: 400 mm^O. Presentó déficit de vitamina D y B6, e inició el tratamiento sustitutivo. La elevación de la presión intracraneal desencadena mecanismos de compensación que, al fallar, pueden comprometer la vida o provocar graves discapacidades neurológicas. Reconocer la causa para un enfoque terapéutico preciso es clave para disminuir la morbimortalidad asociada a esta patología.

Idiopathic endocranial hypertension is infrequently associated with hypovitaminosis A and D. The case of an 8-year-old female with 24-hour blurred vision and bilateral papilledema is presented. Nuclear magnetic resonance was normal. Opening pressure of cerebrospinal fluid: 260 mm^O. She presented vitamin A and D deficiency and started replacement therapy. The second case corresponds to a 12-year-old male with fever and odynophagia of 3 days. History of glomerulonephritis and overweight. He had bipalpebral edema and papilledema. Computed tomography scan of the orbit: increase of fluid in the sheath of both optic nerves. Nuclear magnetic resonance: intrasellar arachnoidocele. Opening pressure of cerebrospinal fluid: 400 mmH2O. He presented vitamin D and B6 deficiency and started replacement treatment. The elevation of intracranial pressure triggers compensation mechanisms that, when they fail, can compromise life or cause serious neurological disabilities. Recognizing the cause for an accurate therapeutic approach is key to reduce the morbidity and mortality associated with this pathology.

[Pseudotumor cerebri associated with hypovitaminosis A, B6 and D. About two cases]. / Pseudotumor cerebral asociado a hipovitaminosis A, B6 y D. A propósito de dos casos.

Idiopathic endocranial hypertension is infrequently associated with hypovitaminosis A and D. The case of an 8-year-old female with 24-hour blurred vision and bilateral papilledema is presented. Nuclear magnetic resonance was normal. Opening pressure of cerebrospinal fluid: 260 mmH2O. She presented vitamin A and D deficiency and started replacement therapy. The second case corresponds to a 12-year-old male with fever and odynophagia of 3 days. History of glomerulonephritis and overweight. He had bipalpebral edema and papilledema. Computed tomography scan of the orbit: increase of fluid in the sheath of both optic nerves. Nuclear magnetic resonance: intrasellar arachnoidocele. Opening pressure of cerebrospinal fluid: 400 mmH2O. He presented vitamin D and B6 deficiency and started replacement treatment. The elevation of intracranial pressure triggers compensation mechanisms that, when they fail, can compromise life or cause serious neurological disabilities. Recognizing the cause for an accurate therapeutic approach is key to reduce the morbidity and mortality associated with this pathology.

La hipertensión endocraneana idiopática se asocia infrecuentemente con la hipovitaminosis A y D. Se presenta el caso de una paciente femenina de 8 años con visión borrosa de 24 horas y papiledema bilateral. Resonancia magnética nuclear normal. Presión de apertura de líquido cefalorraquídeo: 260 mmH2O. Presentó déficit de vitamina A y D, e inició un tratamiento sustitutivo. El segundo caso corresponde a un paciente masculino de 12 años con fiebre y odinofagia de 3 días. Con antecedente de glomerulonefritis y sobrepeso. Presentaba edema bipalpebral y papiledema. Tomografía axial computada de la órbita: aumento de líquido en la vaina de ambos nervios ópticos. Resonancia magnética nuclear: aracnoidocele intraselar. Presión de apertura de líquido cefalorraquídeo: 400 mmH2O. Presentó déficit de vitamina D y B6, e inició el tratamiento sustitutivo. La elevación de la presión intracraneal desencadena mecanismos de compensación que, al fallar, pueden comprometer la vida o provocar graves discapacidades neurológicas. Reconocer la causa para un enfoque terapéutico preciso es clave para disminuir la morbimortalidad asociada a esta patología.

B6 and Bleeding: A Case Report of a Novel Vitamin Toxicity.

Pyridox(am)ine-5-phosphate oxidase deficiency is an inborn error of vitamin B6 metabolism that is characterized by neonatal seizures, requiring lifelong therapy with pyridoxal-5-phosphate. We present the first case of a patient with pyridox(am)ine-5-phosphate oxidase deficiency and mild hemophilia A, whose bleeding symptoms were exacerbated by the vitamin B6 therapy essential for his epileptic disorder. This report expands the spectrum of known vitamin B6 toxicity and demonstrates a need for vigilance in monitoring for bleeding symptoms in patients requiring pyridoxine or pyridoxal-5-phosphate supplementation.

Insight into vitamin B6 -dependent epilepsy due to PLPBP (previously PROSC) missense mutations.

Vitamin B6 -dependent genetic epilepsy was recently associated to mutations in PLPBP (previously PROSC), the human version of the widespread COG0325 gene that encodes TIM-barrel-like pyridoxal phosphate (PLP)-containing proteins of unclear function. We produced recombinantly, purified and characterized human PROSC (called now PLPHP) and its six missense mutants reported in epileptic patients. Normal PLPHP is largely a monomer with PLP bound through a Schiff-base linkage. The PLP-targeting antibiotic d-cycloserine decreased the PLP-bound peak as expected for pseudo-first-order reaction. The p.Leu175Pro mutation grossly misfolded PLPHP. Mutations p.Arg241Gln and p.Pro87Leu decreased protein solubility and yield of pure PLPHP, but their pure forms were well folded, similarly to pure p.Pro40Leu, p.Tyr69Cys, and p.Arg205Gln mutants (judged from CD spectra). PLPHP stability was decreased in p.Arg241Gln, p.Pro40Leu, and p.Arg205Gln mutants (thermofluor assays). The p.Arg241Gln and p.Tyr69Cys mutants respectively lacked PLP or had a decreased amount of this cofactor. With p.Tyr69Cys there was extensive protein dimerization due to disulfide bridge formation, and PLP accessibility was decreased (judged from d-cycloserine reaction). A 3-D model of human PLPHP allowed rationalizing the effects of most mutations. Overall, the six missense mutations caused ill effects and five of them impaired folding or decreased stability, suggesting the potential of pharmacochaperone-based therapeutic approaches.