The value of plasma vitamin B<sub>6</sub> profiles in early onset epileptic encephalopathies

Mathis, Déborah; Abela, Lucia; Albersen, Monique; Bürer, Céline; Crowther, Lisa M.; Beese, Karin; Hartmann, Hans; Bok, Levinus A.; Struys, Eduard A.; Papuc, Sorina Mihaela; Rauch, Anita; Hersberger, Martin; Verhoeven‐Duif, Nanda M.; Plecko, Barbara

doi:10.1007/s10545-016-9955-8

Cited by 20 publications

(29 citation statements)

References 31 publications

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“…All four patients presented here had markedly elevated plasma PLP concentrations while on pyridoxine. Compared with a robust control group,5 only two of these patients had values above those seen in patients with ALDH7A1 or PNPO deficiency and in patients with TNSALP deficiency (congenital hypophosphatasia) on pyridoxine 5 6. Thus the vitamin B6 plasma profile is not suitable for a clear differentiation of patients with PROSC mutations while on treatment with vitamin B 6 .…”

Section: Discussionmentioning

confidence: 67%

“…Mutation modelling was performed by standard procedures4 using the structure of a homologous yeast protein (PDB code: 1CT5) as a template. Vitamin B 6 vitamers were analysed in plasma of all four patients as described5 and a kinetic 6 hours plasma profile was performed in P1 after the oral intake of 300 mg of pyridoxine as a single dose. P1, P2 and P3 had analysis of plasma amino acids and P2 also of amino acids, neurotransmitters and 5-methyltetrahydrofolate (5-MTHF) as well as total and free GABA in CSF.…”

Section: Methodsmentioning

confidence: 99%

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Confirmation of mutations inPROSCas a novel cause of vitamin B_₆-dependent epilepsy

et al. 2017

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Vitamin-B-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes ( or ). In neonatal seizures, defects in explain a major fraction of cases. Very recently biallelic mutations in were shown to be a novel cause in five families. We identified four further unrelated patients harbouring a total of six different mutations, including four novel disease mutations. Vitamin B plasma profiles on pyridoxine did not enable the differentiation of patients with mutations. All four patients were normocephalic and had normal cranial imaging. Pyridoxine monotherapy allowed complete seizure control in one, while two patients had occasional febrile or afebrile seizures and one needed additional valproate therapy for photosensitive seizures. Two patients underwent a controlled pyridoxine withdrawal with signs of encephalopathy within a couple of days. Three had favourable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years, respectively, while one child had marked developmental delay at age 27 months. The clinical and electroencephalographic phenotype in patients with mutations was indistinguishable from and deficiency. We therefore confirm as a novel gene for vitamin-B-dependent epilepsy and delineate a non-specific plasma vitamin B profile under pyridoxine treatment.

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Section: Discussionmentioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Confirmation of mutations inPROSCas a novel cause of vitamin B_₆-dependent epilepsy

et al. 2017

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“…A rapid LC‐MS/MS‐based dried blood spot assay, which measures PNPO enzyme activity, has been developed for diagnosis of PNPO‐deficiency . An elevated plasma pyridoxamine concentration can also be indicative of this disorder irrespective of vitamin B 6 treatment …”

Section: Pyridox(am)ine Phosphate Oxidase Deficiencymentioning

confidence: 99%

“…96 An elevated plasma pyridoxamine concentration can also be indicative of this disorder irrespective of vitamin B 6 treatment. [98][99][100] 12 | CONGENITAL HYPOPHOSPHATASIA DUE TO ALPL MUTATIONS There is a very wide spectrum of disease caused by ALPL (TNALP, TNAP, TNSALP) mutations (hypophosphatasia) from skeletal hypomineralization and deformity detected in utero to presentation with premature loss of deciduous and/or permanent teeth. Only patients with the most severe neonatal form present with seizures in the neonatal period that can precede the detection of bone disease.…”

Section: Deficiency Of Aldh7a1mentioning

confidence: 99%

Disorders affecting vitamin B₆ metabolism

Wilson¹,

Plecko²,

Mills³

et al. 2019

J of Inher Metab Disea

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172

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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.

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“…In normal humans, abundant B6 forms are PLP, PL, and PA. Sometimes PM or PMP are detectable, whereas PN or PNP usually are undetectable[49,50,51,52,53]. PNP: pyridoxine 5'-phosphate, PLP: pyridoxal 5'-phosphate, PMP: pyridoxamine 5'-phosphate, PNPO: pyridox(am)ine 5'-phosphate oxidase, P: phosphatase, K: pyridoxal kinase, A: aminotransferase.…”

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confidence: 99%

Pyridox(am)ine 5’-phosphate oxidase deficiency induces seizures inDrosophila melanogaster

Chi

Iyengar

Albersen

et al. 2019

Preprint

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Pyridox(am)ine 5'-phosphate oxidase (PNPO) is a rate-limiting enzyme in converting dietary vitamin B6 (VB6) to pyridoxal 5'-phosphate (PLP), the biologically active form of VB6, and involved in the synthesis of neurotransmitters including GABA, dopamine, and serotonin. In humans, PNPO mutations have been increasingly identified in neonatal epileptic encephalopathy and more recently also in early-onset epilepsy. Till now, little is known about the neurobiological mechanisms underlying PNPO-deficiency-induced seizures due to the lack of animal models. Previously we identified a c.95 C > A missense mutation in sgll -the Drosophila homolog of human PNPO (hPNPO) and found mutant (sgll 95 ) flies exhibiting a lethal phenotype on a diet devoid of VB6.Here we report the establishment of both sgll 95 and ubiquitous sgll knockdown (KD) flies as valid animal models of PNPO-deficiency-induced epilepsy. Both sgll 95 and sgll KD flies exhibit spontaneous seizures before they die. Electrophysiological recordings reveal that seizures caused by PNPO deficiency have characteristics similar to that in flies treated with GABA antagonist picrotoxin. Both seizures and lethality are associated with low PLP levels and can be rescued by ubiquitous expression of wild-type sgll or hPNPO , suggesting the functional conservation of the PNPO enzyme between humans and flies. Results from cell type-specific sgll KD further demonstrate that PNPO in the brain is necessary for seizure prevention and survival. Our establishment of the first animal model of PNPO deficiency will lead to better understanding of VB6 biology, the PNPO gene and its mutations discovered in patients, and can be a cost-effective system to test therapeutic strategies.

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The value of plasma vitamin B₆ profiles in early onset epileptic encephalopathies

Abstract: PM concentrations and the PM/PA ratio clearly separated PNPO-deficient patients from the other cohorts. The plasma PM/PA ratio thus represents a robust biomarker for the selective screening of PNPO deficiency.

Cited by 20 publications

References 31 publications

Confirmation of mutations inPROSCas a novel cause of vitamin B_₆-dependent epilepsy

Confirmation of mutations inPROSCas a novel cause of vitamin B_₆-dependent epilepsy

Disorders affecting vitamin B₆ metabolism

Pyridox(am)ine 5’-phosphate oxidase deficiency induces seizures inDrosophila melanogaster

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The value of plasma vitamin B6 profiles in early onset epileptic encephalopathies

Abstract: PM concentrations and the PM/PA ratio clearly separated PNPO-deficient patients from the other cohorts. The plasma PM/PA ratio thus represents a robust biomarker for the selective screening of PNPO deficiency.

Cited by 20 publications

References 31 publications

Confirmation of mutations inPROSCas a novel cause of vitamin B6-dependent epilepsy

Confirmation of mutations inPROSCas a novel cause of vitamin B6-dependent epilepsy

Disorders affecting vitamin B6 metabolism

Pyridox(am)ine 5’-phosphate oxidase deficiency induces seizures inDrosophila melanogaster

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Product

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The value of plasma vitamin B₆ profiles in early onset epileptic encephalopathies

Confirmation of mutations inPROSCas a novel cause of vitamin B_₆-dependent epilepsy

Confirmation of mutations inPROSCas a novel cause of vitamin B_₆-dependent epilepsy

Disorders affecting vitamin B₆ metabolism