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Background. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of a-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available. Methods. We combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening. Results. We identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2- OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system. Conclusion. This study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients. Funding. Society for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC)., Introduction Pyridoxine-dependent epilepsy due to biallelic ALDH7A1 variants (OMIM 266100, PDE-ALDH7A1) is an inborn error of metabolism (IEM) that presents with refractory seizures in early infancy. These seizures are typically [...]

BACKGROUND/OBJECTIVES: Folate, pyridoxine and cobalamin are coenzymatically essential in one-carbon methyl metabolism, and their deficiencies could explain some alterations during breast carcinogenesis. We aimed to evaluate the validity of folate, pyridoxine and cobalamin estimates from a food frequency questionnaire (FFQ) on the basis of their corresponding fasting plasma biomarkers, in breast cancer (BC) patients. SUBJECTS/METHODS: In a prospective, consecutive case series, 149 women with primary BC aged between 30 and 69 years as a representative sample of Iranian women with BC were recruited. The 136-item FFQ was used for the validity assay. Fasting plasma folate and cobalamin were tested by automated electrochemiluminescence. The high-pressure liquid chromatography with fluorescence detection was used to determine the plasma levels of pyridoxal-5'-phosphate (PLP) and total homocysteine (tHcy). RESULTS: Area under the curve (AUC) for assessing the diagnostic accuracy of folate-related data through an FFQ was 0.74 (P CONCLUSIONS: Dietary folate and cobalamin estimates from FFQ were significantly correlated with their fasting plasma concentrations. Our data supported the validity of new FFQ to rank individuals by dietary intake status of folate and cobalamin. European Journal of Clinical Nutrition (2014) 68, 316-323;doi:10.1038/ejcn.2013.209; published online 30 October 2013 Keywords: food frequency questionnaire; folate; cobalamin; validation study; total homocysteine; breast cancer, INTRODUCTION Several lines of epidemiologic evidence and preclinical investigations have shown that diminished folate status in longitude could increase predominantly the risk of breast cancer (BC) carcinogenesis. (1-4) In addition, [...]

Glycine is a precursor of purines, protein, glutathione, and 1-carbon units as 5,10-methylenetetrahydrofolate. Glycine decarboxylation through the glycine cleavage system (GCS) and glycine-serine transformation by serine hydroxymethyl- transferase (SHMT) require pyridoxal 5'-phosphate (PLP; active form of vitamin B-6) as a coenzyme. The intake of vitamin B-6 is frequently low in humans. Therefore, we determined the effects of vitamin B-6 restriction on whole-body glycine flux, the rate of glycine decarboxylation, glycine-to-serine conversion, use of glycine carbons in nucleoside synthesis, and other aspects of 1-carbon metabolism We used a primed, constant infusion of [1,2-[sup.13][C.sub.2]glycine and [5,5,5- [sup.2][H.sub.3]leucine to quantify in vivo kinetics in healthy adults (7 males, 6 females; 20-39 y) of normal vitamin B-6 status of marginal vitamin B-6 deficiency. Vitamin B-6 restriction lowered the plasma PLP concentration from 55 [+ or -] 4 nmol/L (mean [+ or -] SEM) to 23 [+ or -] 1 nmol/L (P < 0.0001), which is consistent with marginal deficiency, whereas the plasma glycine concentration increased (P< 0.01 ). SHMT-mediated conversion of glycine to serine increased from 182 [+ or -] 7 to 205 [+ or -] 9 [micro]mol x [kg.sup.-1] x [h.sup.-1] (P < 0.05), but serine production using a GCS-derived 1-carbon unit (93 [+ or -] 9 vs. 91 [+ or -] 6 [micro]mol x [kg.sup.-1] x [h.sup.-1]) and glycine cleavage (163 [+ or -] 11 vs. 151 [+ or -] 8 [micro]mol x [kg.sup.-1] x [h.sup.-1]) were not changed by vitamin B-6 restriction. The GCS produced 1- carbon units at a rate (~140-170 [micro]mol x [kg.sup.-1] x [h.sup.-1]) that greatly exceeds the demand for remethylation and transmethylation processes (~4-7 [micro]mol x [kg.sup.-1] x [h.sup.-1]). We conclude that the in vivo GCS and SHMT reactions are quite resilient to the effects of marginal vitamin B-6 deficiency, presumably through a compensatory effect of increasing substrate concentration.

The study aims to examine the effect of a combination of folic acid, Vitamin B6, and Vitamin B12 on cancer risk in women found to be at high risk of cardiovascular disease. The results indicate that combination of folic acid, Vitamin B6, and Vitamin B12 had no significant effect on the risk of cancer in women.

We investigated the association of dietary intakes of folate, vitamin B-6, vitamin B-12, and methionine with the risk of colorectal cancer in a large prospective cohort study of middle-aged Japanese men and women. A total of 81,184 subjects (38,107 men and 43,077 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995-1998 to the end of 2002, during which 526 cases of colorectal cancer (335 men, 191 women) were newly identified. Dietary intake of nutrients was calculated using a 138-item self-administered FFQ. We observed a significant inverse association between vitamin B-6 intake and colorectal cancer in men. Compared with the lowest quartile, the multivariate hazard ratio (95% [Cl]) in the highest quartile of intake was 0.69 (0.48-0.98) ([P.sub.trend] = 0.03). Men who consumed 150 g/wk alcohol or more had twice the risk of colorectal cancer of those who drank less in the lowest quartile of vitamin B-6 intake, but risk due to alcohol intake was not higher in the highest quartile of vitamin B-6 intake. Vitamin B-6 intake and colorectal cancer were not associated in women. Folate and methionine intakes were not associated with colorectal cancer risk in men or women, but colorectal cancer risk tended to increase ([P.sub.trend] = 0.05) with increasing intake of vitamin B-12 in men. Our results support previous evidence that low vitamin B-6 intake is associated with an increased risk of colorectal cancer. In particular, a higher intake of vitamin B-6 appears beneficial in men with higher alcohol intake.

The transsulfuration pathway, which aids in regulating homocysteine concentration and mediates cysteine synthesis, may be sensitive to vitamin B-6 status because cystathionine [beta]-synthase (CBS) and cystathionine [gamma]-lyase (CGL) require pyridoxal 5'-phosphate (PLP). To assess relations between vitamin B-6 and transsulfuration, we evaluated the effects of dietary pyridoxine (PN) on the hepatic concentration of relevant metabolites and in vitro activity of CBS and CGL. Growing rats were fed AIN-93G- or AIN-76A-based diets that ranged from adequate to deficient in vitamin B-6 (2, 1, 0.5, 0.1, or 0 mg of PN/kg diet, n = 5). This design allowed assessment of the effects of supplemental methionine (AIN-76A) vs. cysteine (AIN-93G) in common research diets over a range of vitamin B-6 levels. CBS activity, assayed in the presence or absence of added S-adenosylmethionine, was independent of diet type and PN level. CGL activity was independent of diet type but proportional to dietary PN. Rats fed deficient (0 and 0.1 mg PN/kg) diets exhibited only ~30% of the CGL activity of those fed the 2 mg PN/kg diets. Hepatic cystathionine increased from 20 to 30 nmol/g for the 1-2 mg PN/kg diets to ~85 nmol/g for the 0 mg PN/kg diet; however, cysteine was reduced only in B-6--deficient rats consuming the AIN-93G diet (means of 30-40 nmol/g for adequate to 11.6 nmol/g for 0 mg PN/kg AIN-76A diet). In spite of these effects, hepatic glutathione concentration increased in vitamin B-6 deficiency. These results suggest that vitamin B-6-dependent changes in transsulfuration do not limit hepatic glutathione production.

Vitamin B therapy may prevent the progression of coronary artery disease in patients who have had angioplasty to open up blocked coronary arteries. In many patients, the arteries become blocked again within months. In a study of 553 patients, those who took folic acid, and vitamins B6 and B12 were less likely to need a second angioplasty compared to those who took a placebo, or inactive substance.

Byline: M.-C. Fortin (1), S.-L. Amyot (1), D. Geadah (3), M. Leblanc (1) Keywords: Key words Hemofiltration; Hemodiafiltration; Folic acid; Vitamin B6; Clearances; Micronutrient Abstract: Objective: To determine to what extent hydrosoluble vitamins are removed by continuous renal replacement therapy (CRRT) to evaluate clearances, removal rates, and evolution of serum concentrations of folic acid and pyridoxal-5 -phosphate (P-5 -P), the active moiety of vitamin B6 during CRRT. Design: A prospective, non-interventional, descriptive study on vitamin losses induced by CRRT. Setting: Medical and surgical intensive care units in a tertiary university-affiliated hospital. Patients: A total of ten critically ill patients in oligoanuric acute renal failure (five treated by continuous venovenous hemofiltration and five by continuous venovenous hemodiafiltration) with a mean effluent rate of 1801 +- 468 ml/h. Nutritional support was not modified and additional vitamin supplements were not provided during study periods. Measurements and results: Concentrations of folic acid and P-5 -P were determined daily during CRRT. Samples for folic acid, P-5 -P, urea, and creatinine were taken simultaneously from the blood at the dialyzer inlet and from the effluent, at CRRT initiation, and daily thereafter over an average of 3.4 +- 1.2 days. Samples were processed by immunochemiluminescence for folic acid and by radioenzymatic assay for P-5 -P determinations with normal ranges above 6.8 nmol/l and from 11.5 to 179.3 nmol/l, respectively. Marked decreases in serum folic acid and P-5 -P concentrations were noticed over time with mean daily reductions of 12.6 and 13.7 %. Serum folic acid concentrations decreased from 42.7 to 16.0 nmol/l and serum P-5 -P decreased from 14.4 to 5.0 nmol/l in the blood coming in to the dialyzer over the study period. Clearances and removal rates were determined from the effluent side. During CRRT, mean (+- SEM) folic acid and P-5 -P clearances were 20.5 +- 6.3 ml/min (n = 34) and 13.2 +- 10.6 ml/min (n = 22), whereas mean urea clearance was 27.1 +- 5.1 ml/min (n = 26). Folic acid and P-5 -P removal rates were 27.0 +- 34.2 and 3.4 +- 2.0 nmol/h, corresponding to mean daily losses of nearly 650 and 80 nmol/day respectively. Conclusion: Significant losses of folic acid and P-5 -P (and most likely of other hydrosoluble vitamins) occur during CRRT. Considering that stores of most hydrosoluble vitamins are relatively low in critically ill patients, supplementation should be provided to patients treated similarly. Author Affiliation: (1) Department of Intensive Care, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada, CA (2) Department of Nephrology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada, CA (3) Department of Biochemistry, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada, CA (4) Guy-Bernier Research Center, University of Montreal, Montreal, Quebec, Canada, CA Article note: Received: 30 December 1998 Final revision received: 15 March 1999 Accepted: 15 March 1999

This research was conducted to investigate 1) the bioavailability of pyridoxine-5[prime]-[Beta]-D-glucoside (PN-glucoside) relative to that of pyridoxine (PN) in human subjects, and 2) the competitive effect of PN-glucoside on the metabolism of co-ingested PN. To evaluate PN-glucoside bioavailability, the subjects were administered a single oral dose of either deuterium-labeled ([2[H.sub.2]]) PN (Trial 1) or [2[H.sub.2]]PN-glucoside (Trial 2), and the urinary excretion rates of labeled 4-pyridoxic acid (4PA) were measured. The [2[H.sub.2]]4PA derived from [2[H.sub.2]]PN or [2[H.sub.2]]PN-glucoside was excreted mainly in the first 8 h after the dose. Excretion of [2[H.sub.2]]4PA during the 48-h postdose period indicated that the bioavailability of PN-glucoside was [approximately]50% relative to PN, which is consistent with our previous report of 58% bioavailability determined using a different protocol and fewer subjects. To assess the effects of PN-glucoside on PN utilization, the subjects were administered different ratios of nonlabeled PN-glucoside with [2[H.sub.2]]PN in Trials 3 and 4. Comparing Trial 1 with Trials 3 and 4, the quantity of nonlabeled PN-glucoside, as a fraction of total vitamin B-6 administered, ranged from 0 to 40% (on the basis of pyridoxine equivalents), with a constant dose of [2[H.sub.2]]PN in each. In these trials, the rate but not the total extent of the excretion of [2[H.sub.2]]4PA derived from [2[H.sub.2]]PN was inversely related to the proportion of co-ingested nonlabeled PN-glucoside. Thus, antagonistic effects of PN-glucoside on PN metabolism do occur in humans, although the effect is less pronounced than that seen previously in rats. Such interactive effects must be considered in evaluating the net bioavailability of dietary forms of vitamin B-6. KEY WORDS: vitamin B-6; pyridoxine-5[prime]-[Beta]-D-glucoside; bioavailability; stable isotope; humans

To determine the effect of varying levels of dietary protein with a constant intake of vitamin B-6 (B-6) on B-6 status, nine women were fed diets providing daily intakes of 1.25 mg B-6 and 0.5, 1.0 and 2.0 g protein/kg body weight. After an 8-d adjustment period, the women consumed each level of dietary protein for 14 d in a Latin-square design. Several direct and indirect B-6 status indicators were measured in blood and urine. Significant differences among protein levels were found for urinary 4-pyridoxic acid (4-PA) excretion (P < 0.01), plasma pyridoxal 5[prime]-phosphate (PLP) concentration (P < 0.05), and urinary excretion of volatile amines (VA, kynurenine plus acetylkynurenine) after a 2-g L-tryptophan load (P < 0.05). Nitrogen intake was significantly negatively correlated with urinary 4-PA excretion (r = -0.619, P < 0.001) and plasma PLP concentration (r = -0.549, P < 0.01), and positively correlated with erythrocyte alanine aminotransferase percentage stimulation (r = 0.418, P < 0.05) and urinary post-tryptophan load excretion of xanthurenic acid (r = 0.535, P < 0.05), kynurenic acid (r = 0.563, P < 0.05) and VA (r = 0.626, P < 0.01). Compared with men consuming diets with similar B-6 to protein ratios in a previous study, the women excreted a greater percentage of the B-6 intake as 4-PA, had lower plasma PLP concentrations and excreted greater amounts of postload urinary tryptophan metabolites at all three protein levels. If the Recommended Dietary Allowance (RDA) of vitamin B-6 is to be based on the dietary B-6 to protein ratio, gender differences in response to varying protein intakes should be considered. For the levels of protein intake used in this study and a B-6 intake of 1.25 mg/d, a B-6 to protein ratio of greater than 0.020 mg/g is required for adequate vitamin B-6 status in women. INDEXING KEY WORDS: vitamin B-6; protein intake; status; requirements; women

For nonruminants, stress and disease greatly increase requirements for vitamin [B.sub.6], folic acid, pantothenic acid, and ascorbate. The effects of feed restriction, virus infection, and vitamin injections on plasma concentrations of B vitamins critical to the immune response were evaluated. Twelve beef steer calves, 6 to 8 mo of age, were fed below maintenance for 17 d and deprived of food for 3 d during a 20-d period after weaning. They then were inoculated intranasally with live attenuated bovine herpesvirus-1 (BHV-1). Six calves received saline injections and six received injections of a B vitamin mixture and ascorbate every 48 h for 14 d before and 14 d after inoculation. A mild respiratory infection developed inall calves 4 to 5 d after inoculation. In control calves, restricted intake and food deprivation decreased plasma vitamin [B.sub.6] and pantothenate and increased vitamin [B.sub.12] but did not affect folic acid and ascorbate concentrations. Vitamin injections increased plasma concentrations of vitamin [B.sub.6], folic acid, vitamin [B.sub.12], pantothenic acid, and ascorbate (P < .002). Plasma concentrations of vitamin [B.sub.6], vitamin [B.sub.12], pantothenic acid, and ascorbate, but not folic acid, were markedly reduced in all calves during the BHV-1 infection (P = .001). The vitamin [B.sub.6], pantothenic acid, vitamin [B.sub.12], and ascorbate status of stressed calves may affect their immune response to vaccination or infection. Key Words: Immunity, Bovine Herpesvirus, Stress, Pyridoxal, Vitamins

Pyridoxine glucoside is a partially available form of vitamin B-6 present in plant-derived foods. in this set of three studies, rats were fed diets containing different concentrations of either pyridoxine or pyridoxine glucoside in the presence or absence of a fixed concentration of pyridoxine for 2 wk. The distribution of B-6 vitamers and [Beta]-glucosidase activity in tissues was examined to determine the metabolic effects of chronic consumption of pyridoxine glucoside. Rats fed pyridoxine glucoside either with or without pyridoxine exhibited a significant increase in the amount of hepatic pyridoxine 5[prime]-phosphate (not detected in rats fed pyridoxine alone), whereas hepatic pyridoxal 5[prime]-phosphate was decreased with increasing dietary pyridoxine glucoside. The activity of cytosolic [Beta]-glucosidases in small intestine and kidney was affected by the dietary concentration of both pyridoxine and pyridoxine glucoside. Enzymatic activity capable of hydrolyzing pyridoxine glucoside was found in mucosal and intraluminal fractions of small intestine and in the kidney. Other tissues examined, including liver, spleen and stomach, did not hydrolyze pyridoxine glucoside in detectable quantities. These findings indicate that microbial and mucosal enzymes can participate in the intestinal hydrolysis of pyridoxine glucoside and that the kidney may contribute to postabsorptive hydrolysis. These findings further support the observations that dietary pyridoxine glucoside influences vitamin B-6 metabolism. INDEXING KEY WORDS: * vitamin B-6 * pyridoxine-5[prime]-[Beta]-D-glucoside * [Beta]-glucosidase * rats

Weanling male rats were fed diets that varied in protein quality (casein or wheat gluten) and vitamin B-6 (0.0, 0.5, 1.0 and 1.5 mg pyridoxine HCl/kg diet) to test the hypotheses that low protein quality would depress vitamin B-6 nutritional status and that activity of ornithine decarboxylase (ODC) would be a sensitive functional indicator of vitamin B-6 nutritional status. The wheat gluten diet depressed body weight gain [approximately]17% at higher vitamin B-6 levels, as expected. However, vitamin B-6 nutritional status was not worse in gluten-fed compared with casein-fed groups, as evidenced by static measures (B-6 vitamer concentrations in plasma and tissues) and a functional indicator (tryptophan load test). The activity of ODC (holo- and total) in liver, kidney and small intestine did not vary significantly at the three higher levels of vitamin B-6 intake. in groups fed casein, total ODC activity in these tissues was two- to fivefold higher in rats fed diets containing 0.0 mg vitamin B-6/kg compared with higher B-6 levels, without corresponding differences in ODC mRNA abundance in liver and kidney. Concentrations of B-6 vitamers (except pyridoxal phosphate in plasma) increased linearly with dietary vitamin B-6 in plasma, liver, kidney and intestine. These data suggest that low quality protein fed as wheat gluten suppresses growth but not vitamin B-6 nutritional status, and that ODC activity is not a sensitive functional indicator of marginal vitamin B-6 status. INDEXING KEY WORDS: vitamin B-6; ornithine decarboxylase; nutritional status; protein quality; rats

A number of children may develop seizures due to isoniazid (INH) neurotoxicity or poisoning. INH is an effective drug in the treatment and prevention of tuberculosis but also causes massive seizures. Seven children with acute INH neurotoxicity were treated. All patients had been taking INH prescriptions to prevent tuberculosis. One 5-day-old infant boy had received high doses of preventive INH due to a prescription error. Therapy with pyridoxine or vitamin B resolved his seizures and tremors. The remaining 6 adolescents had taken large amounts of INH either accidentally or intentionally to end their lives. In addition to seizures, patients may experience nausea, vomiting, dizziness, and low blood pressure. Delays in starting pyridoxine therapy due to unavailability may result in late treatment. A recent rise in tuberculosis infection may be related to the increase of INH poisoning among children., Objectives. To describe the presentation and treatment of acute isoniazid (INH) neurotoxicity appearing at an inner-city municipal hospital. Design. Case series. Participants. Seven patients (eight patient visits) with an age range of 5 days to 14.9 years. Results. At our institution, no children appeared with acute INH neurotoxicity in the period 1985 through 1990, whereas seven patients were treated from 1991 through 1993. This paralleled the rise in the number of children with tuberculous infection and disease seen at our institution, from an average 96 per year to 213 per year during these two time periods. AR seven patients were receiving INH daily for tuberculosis (TB) prophylaxis. Accidental ingestion (five episodes) and suicidal attempts (three episodes) accounted for these visits. The total amount ingested range from 14.3 to 99.3 mg/kg (mean, 54 mg/kg). All but one patient presented with afebrile seizures. One patient presented twice with seizures. Acute INH neurotoxicity was not suspected on the first admission; however, when readmitted 4 weeks later with another seizure, the diagnosis of acute INH neurotoxicity was made. Intervention. Intravenous pyridoxine was used in five episodes. Because it was not a stocked item in our pediatric emergency cart (as well as at another hospital, necessitating a transfer of a patient with refractory seizures to our hospital), the average delay was 5.8 hours (range, 1.3 to 13 hours) before it was given. Two patients with refractory seizures failed to respond to anticonvulsants, and their seizures were controlled only after parenteral pyridoxine. Conclusions. We have seen an increased incidence of acute INH neurotoxicity because of the resurgence of TB in New York City. Others as well may see a similar rise based on local trends in TB infection and disease. Acute INH toxicity should be suspected in children presenting with seizures with or without fever. In patients with a known access to INH, seizures should be considered to be caused by INH toxicity unless proved otherwise. Parenteral pyridoxine, the specific antidote for INH-induced refractory seizures, should be readily available in every emergency department in the areas similarly experiencing increasing trends of TB. Pediatrics 1995,95:700-704; acute isoniazid neurotoxicity., The incidence of tuberculosis (TB) in Brooklyn, NY, increased from 30.7 new cases per 100 000 population in 1985 to 51.8 new cases per 100 000 population in 1992. In [...]

Hyperhomocysteinemia and low concentrations of folate and vitamin B6 appear to be associated with an increased risk of carotid artery stenosis in the elderly. Hyperhomocysteinemia is a condition in which plasma levels of homocysteine are higher than normal. Inadequate folate and vitamin B6 concentrations in the blood are associated with the condition. A group of 1,041 people over the age of 66 were divided into two groups based upon the severity of stenosis in two carotid vessels. People with high levels of homocysteine were found to be twice as likely to be in the group with more severe stenosis than those with normal homocysteine concentrations. Higher concentrations of folate and B6 in the plasma were related to less stenosis, while lower concentrations of folate and B6 were found in patients with more severe sclerosis.

Orthophosphate and pyridoxine therapy may provide better kidney function, fewer kidney stones, and an improved prognosis for persons with primary hyperoxaluria. Primary hyperoxaluria is an inherited metabolic disorder that results in increased production of oxalates that are excreted in the urine. Kidney stones are common. Oxalates may build up in the blood and in organs as the disease progresses, leading to end-stage kidney disease and death. A study of 25 patients with primary hyperoxaluria who received orthophosphate and pyridoxine therapy over a range of 0.3 to 26 years found that the therapy reduced calcium oxalate production and crystal formation. An actuarial rate of end-stage kidney disease was calculated for these patients as being 26% after 20 years, in contrast to the usual poor prognosis for primary hyperoxaluria. Even those patients whose symptoms began before the age of five were able to maintain normal kidney function with therapy. The therapy was well tolerated by the patients.

Successful treatment of pyridoxine-dependent epilepsy appears to require doses of vitamin B6 that not only control epilepsy but also normalize blood levels of glutamate. Pyridoxine is vitamin B6. Pyridoxine-dependent epilepsy is a rare genetic disorder that can cause structural or functional abnormalities of the brain, mental retardation, epilepsy, and neurologic problems. Glutamate is a neurotransmitter that induces physiological changes that ultimately destroy nerve cells. Researchers examined samples of cerebrospinal fluid (CSF) from a patient with pyridoxine-dependent epilepsy. B6 doses of five mg/kg of body weight/day controlled the patient's seizures and normalized brain-wave EEG measurements. CSF glutamate levels, however, were 10 times higher than normal. Each time physicians discontinued B6 treatment, the patient experienced seizures and CSF glutamate levels climbed to 200 times higher than normal. B6 doses of 10 mg/kg of body weight/day controlled the seizures and normalized the CSF glutamate levels., Background. Pyridoxine-dependent epilepsy is a rare autosomal recessive disorder. Untreated patients suffer from a progressive encephalopathy with mental retardation, intractable epilepsy, and progressive neurological signs and symptoms. Lifelong supplementation with vitamin [B.SUB.6] is the treatment of choice. However, despite early treatment, many patients develop mental retardation. Objectives. To assess the role of glutamate as an excitatory neurotransmitter and neurotoxin in pyridoxine-dependent epilepsy. Methods. We examined cerebrospinal fluid (CSF) levels of glutamate, [gamma]-aminobutyric acid, and pyridoxal-5&apos;-phosphate in a patient with pyridoxine dependency while on and off vitamin [B.sub.6] treatment. Results. Off vitamin [B.sub.6] the glutamate level was two hundred times normal. An intermediate dose of vitamin [B.sub.6] (5 mg/kg BW/day) caused normalization of the EEG and remission of the seizures, but the CSF glutamate concentration was still ten times normal. With a higher dose of pyridoxine (10 mg/kg BW/day) the CSF glutamic acid normalized. Conclusions. The results indicate that control of epilepsy might not suffice as the therapeutic aim in treating of pyridoxine dependency. In view of the evidence for the role of excitatory amino acids in destruction of CNS nerve cells, the optimal treatment must counteract the raised levels of CSF glutamate and the dosage of vitamin [B.sub.6] must be adjusted accordingly. The development of mental retardation might theoretically be prevented by adjusting the dose of vitamin [B.sub.6] to achieve not only remission of epilepsy but also normalization of CSF glutamate. Pediatrics 1994;94:318-321; epilepsy, GABA, glutamate, pyridoxine, pyridoxine dependency, vitamin [B.sub.6].

The cause of reduced plasma pyridoxal-5 prime-phosphate (PLP) concentration and the validity of plasma PLP concentration as a vitamin B-6 status indicator during pregnancy are not well understood. In this study, pregnant and nonpregnant women consumed a controlled diet for 5 d to exclude dietary intake as a factor in altered vitamin B-6 metabolic utilization. Plasma PLP and pyridoxal (PL) concentrations were significantly lower and higher, respectively, and plasma PL+PLP concentration was significantly lower during pregnancy. When plasma PLP and PL concentrations were normalized based on plasma albumin concentration, the differences were less marked but were still significant. The erythrocyte aspartate aminotransferase activity coefficient was significantly greater in pregnant women which is a further indication of reduced vitamin B-6 concentrations in the blood. No difference was observed in the urinary excretion of 4-pyridoxic acid between the pregnant and nonpregnant women. Results of this study demonstrate that vitamin B-6 status indices are lower during pregnancy without differences in the urinary excretion of 4-pyridoxic acid.

The cause for reduced plasma pyridoxal phosphate PLP) concentration during pregnancy is not well understood. in this study, nonplegnant (control) and pregnant rats were gavaged with [[H.sup.3]]pyridoxine for assessment of the intestinal absorption, tissue distribution, metabolic utilization and urinary excretion of the vitamin. In addition, plasma PLP and pyridoxal levels and erythrocyte aspartate aminotransferase (EAST) activity were measured. There was 50% lower plasma PLP concentration and 50% greater EAST activity in the pregnant rats and no difference in the stimulation of EAST with exogenous PLP. There was no difference in the intestinal absorption, hepatic uptake and retention or urinary excretion of the radioisotope. Less than 3% of the oral dose was detected in fetal/uterine tissue of the pregnant rats. Results of this study indicate that reduced plasma PLP concentration during pregnancy is not a result of diminished total vitamin B-6 body pools or fetal sequestration of vitamin B-6. Low plasma PLP during pregnancy may be a result of altered distribution of PLP between the plasma and erythrocytes. J. Nutr. 122: 1892-1897, 1992. INDEXIMG KEY WORDS: * pregnancy * vitamin B-6 * rats * bioavailability, The influence of pregnancy on the bioavailability of vitamin B-6 was analyzed by oral administration of pyridoxine to pregnant and non-pregnant rats. Plasma pyridoxal 5 phosphate levels (PLP) were found to be less in pregnant than in non-pregnant rats despite increased intake. Oral pyridoxine was almost totally absorbed in the gut and hepatic uptake was constant. Alkaline phosphatase activity does not affect PLP levels. PLP levels are decreased in pregnancy because of associated increase in erythrocyte levels available for binding and fetal consumption.

An abnormality of the key X chromosome-linked enzyme (ALAS2) in heme synthesis may be the cause of familial sideroblastic anemia. Sideroblastic anemia is a diverse group of anemias associated with reduced enzyme activity and characterized by abnormalities in heme synthesis and increased iron stores in bone marrow cells. Heme is the iron component of red blood cells. Protoporphyrin IX joins with iron to form heme. The enzyme and amino acid that bind to form protoporphyrin are controlled by the X chromosome-linked, blood cell-specific enzyme ALAS2. ALAS2 is an enzyme dependent on pyridoxal phosphate, or vitamin B6. A study of a family with sideroblastic anemia demonstrated a mutation in the gene that changed an amino acid near the ALAS2 receptor for the vitamin, resulting in reduced enzyme activity. Enzyme activity was enhanced by treatment with vitamin B6.