Pyridoxal 5′‐phosphate may be curative in early‐onset epileptic encephalopathy

Hoffmann, Georg F.; Schmitt, Bernhard; Windfuhr, M.; Wagner, Nicola; Strehl, H.; Bağcı, Soyhan; Franz, Axel R.; Mills, Philippa; Clayton, Peter T.; Baumgartner, Matthias R.; Steinmann, Beat; Bast, Thomas; Wolf, Nicole I.; Zschocke, Johannes

doi:10.1007/s10545-006-0508-4

Cited by 125 publications

(146 citation statements)

References 10 publications

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“…Biochemical abnormalities are secondary to impaired activities of the many enzymes needing pyridoxal phosphate as a cofactor and include slight elevations of glycine and threonine in CSF and plasma, an increase in the CSF concentration of 3-methoxytyrosine and a decrease in the CSF concentrations of 5-hydroxyindolacetic acid and homovanillic acid, the latter findings reflecting impaired activity of the aromatic amino acid decarboxylase (Mills et al 2005). It must be emphasized, however, that these biochemical abnormalities are not obligatory in PNPO deficiency (Hoffmann et al 2007). Treatment with pyridoxine and pyridoxal phosphate should be initiated as quickly as possible, without awaiting results of biochemical or genetic investigations as prognosis is better the earlier treatment is initiated.…”

Section: Neonatal-onset Epilepsymentioning

confidence: 99%

Epilepsy and inborn errors of metabolism in children

Wolf

García‐Cazorla

Hoffmann

2009

J of Inher Metab Disea

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Summary Epilepsy is a frequent symptom in inborn errors of metabolism, with virtually no specific seizure types or EEG signatures. It is most important to look quickly for those few inborn errors of metabolism in which specific therapies such as supplementation of cofactors or diets can make all the difference. If these investigations remain negative, epilepsy has to be treated with conventional antiepileptic drugs. Still, epilepsy is a potentially treatable symptom of many inborn errors of metabolism, and optimal treatment is of great importance for patients and their families.

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Section: Neonatal-onset Epilepsymentioning

confidence: 99%

Epilepsy and inborn errors of metabolism in children

Wolf

García‐Cazorla

Hoffmann

2009

J of Inher Metab Disea

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“…The initial clinical details have been previously reported (Hoffmann et al 2007;Schmitt et al 2010). In summary, this boy was born at term and developed seizures at 24 h of age.…”

Section: Casementioning

confidence: 66%

“…Mills and colleagues subsequently described the genotype and phenotype of neonatal epileptic encephalopathy due to pyridoxamine 5 0 -phosphate oxidase (PNPO) deficiency (Mills et al 2005). The treatment dose of PLP has largely been empirical, guided by clinical response with reported doses varying from 30 to 60 mg/kg/day (Mills et al 2005;Hoffmann et al 2007;Bagci et al 2008). PLP is not licensed as a drug for the treatment of epilepsy outside of Asia.…”

Section: Introductionmentioning

confidence: 99%

Cirrhosis Associated with Pyridoxal 5′-Phosphate Treatment of Pyridoxamine 5′-Phosphate Oxidase Deficiency

et al. 2014

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We report the case of an 8-year-old boy with pyridoxamine 5 0 -phosphate oxidase (PNPO) deficiency. He developed seizures at 24 h of age that were refractory to standard anticonvulsant therapy and a trial of pyridoxine but responded to pyridoxal phosphate (PLP) at 28 days of life. Genetic testing identified compound heterozygous mutations in the PNPO gene. Management of encephalopathic episodes required escalation of PLP dose to 100 mg/kg/day by 2 years of age. Routine blood tests at this time showed significantly deranged liver function tests (LFTs). A wedge liver biopsy showed early cirrhosis with marked elevation of pyridoxal and pyridoxic acid levels in the liver sample. Despite extensive investigation, no cause other than PLP therapy could be identified for the cirrhosis. The PLP dose was weaned to 50 mg/kg/day before episodes of encephalopathy recurred. Concurrent with the reduction of his PLP dose, LFTs showed improvement. However, at 8 years of age, there is persistent evidence of hepatic fibrosis and early portal hypertension. We hypothesise that hepatic toxicity due to PLP or its degradation products is the cause of cirrhosis in this boy. Until further evidence becomes available, we would suggest that people with PNPO deficiency are treated with the minimum dose of PLP required to prevent episodes of encephalopathy.

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“…Elevation of CSF glycine has been reported to occur secondary to a deficiency of the activity of the glycine cleavage system, which is PLP-dependent. It should be noted however that this does not occur in all PNPO-deficient patients, with some only showing a transient increase of glycine in CSF (Hoffmann et al 2007). Glycine levels have also been reported to be slightly raised in the CSF of patients with mutations in PROSC prior to B6-supplementation (Darin et al 2016).…”

Section: Discussionmentioning

confidence: 98%

“…Glycine levels have also been reported to be slightly raised in the CSF of patients with mutations in PROSC prior to B6-supplementation (Darin et al 2016). In patients with mutations in ALDH7A1, however, CSF glycine levels have been reported to be normal (Hoffmann et al 2007) or just slightly elevated (Mills et al 2010). Interestingly few studies report on serine levels leading us to assume that serine is kept within normal values in the CSF of vitamin B6 deficient patients.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B6 is essential for serine de novo biosynthesis

Ramos

Pras‐Raves

Gerrits

et al. 2017

J of Inher Metab Disea

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Pyridoxal 5′-phosphate (PLP), the metabolically active form of vitamin B6, plays an essential role in brain metabolism as a cofactor in numerous enzyme reactions. PLP deficiency in brain, either genetic or acquired, results in severe drug-resistant seizures that respond to vitamin B6 supplementation. The pathogenesis of vitamin B6 deficiency is largely unknown. To shed more light on the metabolic consequences of vitamin B6 deficiency in brain, we performed untargeted metabolomics in vitamin B6-deprived Neuro-2a cells. Significant alterations were observed in a range of metabolites. The most surprising observation was a decrease of serine and glycine, two amino acids that are known to be elevated in the plasma of vitamin B6 deficient patients. To investigate the cause of the low concentrations of serine and glycine, a metabolic flux analysis on serine biosynthesis was performed. The metabolic flux results showed that the de novo synthesis of serine was significantly reduced in vitamin B6-deprived cells. In addition, formation of glycine and 5-methyltetrahydrofolate was decreased. Thus, vitamin B6 is essential for serine de novo biosynthesis in neuronal cells, and serine de novo synthesis is critical to maintain intracellular serine and glycine. These findings suggest that serine and glycine concentrations in brain may be deficient in patients with vitamin B6 responsive epilepsy. The low intracellular 5-mTHF concentrations observed in vitro may explain the favourable but so far unexplained response of some patients with pyridoxine-dependent epilepsy to folinic acid supplementation.

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Pyridoxal 5′‐phosphate may be curative in early‐onset epileptic encephalopathy

Cited by 125 publications

References 10 publications

Epilepsy and inborn errors of metabolism in children

Epilepsy and inborn errors of metabolism in children

Cirrhosis Associated with Pyridoxal 5′-Phosphate Treatment of Pyridoxamine 5′-Phosphate Oxidase Deficiency

Vitamin B6 is essential for serine de novo biosynthesis

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