Pharmacologic Doses Of Pyridoxine Research Articles

A case for newborn screening for pyridoxine-dependent epilepsy.

Pyridoxine-dependent epilepsy due to mutations in ALDH7A1 (PDH-ALDH7A1) is a highly treatable developmental and epileptic encephalopathy. Pharmacologic doses of pyridoxine are associated with dramatic clinical seizure improvement, and most patients achieve adequate seizure control with pyridoxine alone. Unfortunately, some patients with PDE-ALDH7A1 have died prior to when the diagnosis was made and subsequent treatment with pyridoxine could be implemented, highlighting the importance of a timely diagnosis. Although critical for seizure control, pyridoxine treatment alone is not sufficient for normal outcomes as most patients suffer intellectual and developmental delay. Adjunct lysine reduction therapies are associated with significant developmental improvements, although these treatments have limited efficacy if delayed after the first few months of life. Recently two biomarkers were identified that overcome previous technical hurdles for newborn screening. Herein we provide commentary that PDE-ALDH7A1 meets both current and historic criteria for newborn screening, and that a neonatal diagnosis and treatment can both reduce mortality from uncontrolled seizures and significantly improve the cognitive delay that is pervasive in this treatable disorder.

Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.

Biomarker Profiling for Pyridoxine Dependent Epilepsy in Dried Blood Spots by HILIC-ESI-MS.

Pyridoxine dependent epilepsy is a condition where the affected infant or child has prolonged seizures (status epilepticus), which are nonresponsive to anticonvulsant therapy but can be treated with pharmacological doses of pyridoxine. If identified earlier and treated prophylactically with pyridoxine, severe brain damage due to seizures can be prevented. Alpha-amino adipic semialdehyde (AASA), piperidine-6-carboxylic acid (P6C), and pipecolic acid (PA) are known biomarkers of pyridoxine dependent epilepsy. We report the development and validation of a hydrophilic interaction liquid chromatography (HILIC) hyphenated with mass spectroscopy for the quantification of the above analytes from dried blood spot samples. The samples were extracted using methanol and analysed on a iHILIC fusion plus column with formic acid buffer (pH 2.5): acetonitrile (20:80) at a flow rate of 0.5 mL/min within 3 minutes. The method demonstrated a LOD of 10 ng/mL, LOQ of 50 ng/mL, linearity of r2 ≥ 0.990, and recovery of 92-101.98% for all analytes. The intra- and interday precision CVs were < 8% and 6%, respectively. Extensive stability studies demonstrated that the analytes were stable in stock solution and in matrix when stored at -80°C. We performed method comparison studies of the developed method with the literature reported method using normal samples and matrix matched spiked samples at pathological concentrations to mimic clinical validity. The Bland-Altman analysis for comparison of the analytical suitability of the method for the biomarkers in healthy and spiked samples with the literature reported method revealed a bias which suggested that the method was comparable. The newly developed method involves no derivatisation and has a simple sample preparation and a low run time enabling it to be easily automated with a high sample throughput in a cost-effective manner.

Pyridoxal phosphate dependency, a newly recognized treatable catastrophic epileptic encephalopathy

Few conditions are as riveting to physicians as devastating encephalopathies that are treatable. In this issue of the Journal, Georg F. Hoffmann and colleagues describe the clinical syndrome of pyridoxal-phosphate dependent seizures with its inherent, and compelling, responsiveness to specific therapy. This story begins over fifty years ago, when Hunt and colleagues reported the successful treatment of infantile seizures with pyridoxine (vitamin B6) (Hunt et al 1954). Hence, pyridoxine-dependent seizures became the prototype of the severe but eminently treatable conditions that no clinician wants to miss. The cardinal diagnostic feature is the presence of refractory seizures, classically during the neonatorum, which cease only when pharmacological doses of pyridoxine are administered. While the condition is rare, with an estimated birth incidence between 1:400 000 and 1:750 000, the importance of early recognition is emphasized by an improved prognosis with early treatment (Baxter 2003). Patients will present with multiple seizure types in the neonatal period or even prenatally, with fetal seizures perceived by mothers as fluttering or hammering sensations beginning at 5 months_ gestation or later. Patients have an associated newborn encephalopathy which may include jitteriness, hypothermia, dystonia, and a prodrome of restlessness, irritability and emesis preceding seizures. The classic diagnostic procedure is intravenous administration of 100 mg of pyridoxine during EEG monitoring, aiming for resolution of a generalized or multifocal spike, or burstsuppression, pattern and cessation of clinical seizures. In an infant with pyridoxine dependency, the seizures and epileptiform EEG abnormalities will typically subside within 2–6 minutes after injection. However, some patients with pyridoxine dependency require up to 500 mg before clinical and electrographic responses are demonstrated. After receiving this initial treatment with pyridoxine, some neonates with pyridoxine dependency may become sleepy and hypotonic for a period of 24 hours. An alternative approach to diagnosis is to treat the patient with daily enteral doses of pyridoxine, 15 mg/kg. In pyridoxine-dependent patients, clinical seizures will resolve within a week of the initiation of this therapy. After a patient is clinically diagnosed by either the acute parenteral administration of pyridoxine or the daily enteral treatment with the vitamin, continued daily supplementation with pharmacological doses of pyridoxine is necessary, as the seizures tend to recur after a median delay of 9 days. Therefore, lifelong maintenance therapy is necessary (Gospe 2002). The classic neonatal phenotype may represent the tip of the iceberg. There are several atypical phenotypes J Inherit Metab Dis (2008) 30:2–4 DOI 10.1007/s10545-008-9974-1

Treatment of the primary hyperoxalurias: A new chapter

Despite advances in the enzymology, molecular genetics, and clinical knowledge of the primary hyperoxalurias, few treatments are available. Oxalobacter formigenes is a promising new therapy with potential to induce secretion of oxalate into the intestinal lumen, where it can be degraded by the bacteria.

High prevalence ofCBS p.T191M mutation in homocystinuric patients from Colombia

Homocystinuria is an autosomal recessive disease most commonly caused by mutations in cystathionine beta-synthase (CBS). In this study we present the mutation analysis of 36 Colombian individuals from 10 unrelated kindred, with 11 individuals clinically classified as homocystinuric. Mutation analysis of the CBS gene revealed p.T191M, a prevalent mutation in Spain and Portugal, in the homozygous state in seven of the unrelated patients. Genotype-phenotype assessment of the p.T191M homozygous patients showed a high level of variability, including different severity in one pair of affected siblings. None of the patients responded biochemically to treatment with pharmacological doses of pyridoxine and folic acid as revealed by essentially unchanged homocysteine levels. This study offered a unique opportunity to study 18 heterozygous (p.T191M/wt) relatives of the homocystinuric patients. One atypical finding was that many of them presented with above average total homocysteine levels, putting them at an increased risk for vascular disease. Cryptorchidism was present in three of the cases, one of which presented also with Klinefelter syndrome. In addition to the previously described p.T191M mutation, a new mutation, p.A288T, was identified in a single individual. In this paper we present the first characterization, at a molecular level, of patients with homocystinuria from Colombia.

Pyridoxine‐dependent seizures responding to extremely low‐dose pyridoxine

We report on a male infant with pyridoxine dependency and seizures from birth, controlled with pharmacological doses of pyridoxine at 4 months of age. Seizures stopped between 30 and 80 days of age when very‐low doses of pyridoxine were given in a multivitamin supplement. Daily dose was 0.5 mg that corresponded to 0.08 to 0.16 mg/kg/day when weight gain is considered. In previous reports doses have ranged from 0.2 to 30 mg/kg/day. Another distinctive feature was that this infant went into a coma and developed hypotonia and irregular breathing when pyridoxine was given by enteral tube which has usually been reported when the vitamin is given intravenously. Use of low doses of pyridoxine in multivitamin supplements could be a confounding factor for early diagnosis and appropriate treatment of pyridoxine‐dependent seizures.

Photosensitive dermatitis caused by pyridoxine hydrochloride

Few photosensitive reactions caused by pyridoxine hydrochloride have been reported. There have been no reports of detailed photosensitivity studies on patients who have developed photosensitivity from pharmacologic doses of pyridoxine. Two patients with pyridoxine photosensitivity are described. Photopatch tests were positive for pyridoxine hydrochloride. The minimal erythematous dose (MED) for UVA decreased after the intravenous injection of pyridoxine hydrochloride in both patients. Normal controls gave negative results in photopatch tests for pyridoxine hydrochloride and phototest for vitamin B complex containing pyridoxine hydrochloride. On the basis of these results, we believe both patients had a photoallergic reaction to pyridoxine hydrochloride.(J Am Acad Dermatol 1998;39:314-7.)

A far advanced case of gyrate atrophy in a 12‐year‐old girl

Gyrate atrophy (GA; McKusick 25887) is a progressive chorioretinal dystrophy with an autosomal recessive mode of inheritance. In this disorder there is a deficiency of the mitochondrial matrix enzyme ornithine-f-aminotransferase (OAT). Ocular symptoms usually present late in the first decade of life. Ophthalmological findings include myopia, constricted visual fields, elevated dark adaptation thresholds (night blindness), very small or absent electroretinographic responses, and characteristic patchy chorioretinal atrophy distributed circumferentially around the peripheral fundus. Gradually the round patches of atrophy coalesce to form widespread chorioretinal atrophy extending to the posterior pole. Cataracts develop requiring surgical intervention, and eventually blindness occurs due to progressive loss of functional retina at the age of 40 to 50 (Valle and Simell, 1989). Plasma ornithine levels range from 400 to 1400/~mol/L, and 0.5 to 10mmol of ornithine is excreted daily. Glutamate, glutamine, lysine, creatine and creatinine concentrations in plasma are modestly reduced. The pathophysiological mechanism responsible for the chorioretinal dystrophy in GA is not known. Hyperornithinaemia or associated secondary metabolic abnormalities may play an important role, but until the pathophysiology is understood, there is no assurance that correction of biochemical abnormalities in plasma will actually be beneficial (Berson et al., 1981). Four general therapeutic approaches have been used: pharmacological doses of pyridoxine, reducing the intake of arginine and administration of creatine or proline. In this paper we described a 12-year-old patient with night blindness and myopia as the first symptoms of gyrate atrophy with ornithinaemia.

Vitamin B6 metabolism in human red cells. I. Variations in normal subjects.

Physiologic and pharmacologic factors affecting intracellular red cell vitamin B6 metabolism in normal human subjects were studied using a new assay for pyridoxine kinase (PnK) together with saturated and total aspartate aminotransferase (AST) activities as indirect indices of intracellular pyridoxal 5-phosphate (PLP) availability. The presence of reduced PnK activity in Blacks was confirmed but this could not be explained on the basis of increased enzyme inactivation during red cell aging in vivo. Racial differences were also noted in the metabolism of AST and, in Caucasians, net dissociation of PLP from the apoprotein was demonstrated to occur in vivo. Despite the wide variation in Pn5 activity, AST levels were maintained within relatively narrow limits. However, when pharmacologic doses of pyridoxine were administered, PnK and AST activities increased proportionately. These findings suggest that when the supply of B6 vitamers is not limiting, PnK may play a role in regulating red cell PLP levels.

Effect of Pharmacological Doses of Pyridoxine on the Oxidative Catabolism of Tryptophan ‘In Vivo’

Effect of Pharmacological Doses of Pyridoxine on the Oxidative Catabolism of Tryptophan ‘In Vivo’