Inborn errors in the vitamin B6 salvage enzymes associated with neonatal epileptic encephalopathy and other pathologies

Ghatge, Mohini S.; Mughram, Mohammed Al; Omar, Abdelsattar M.

doi:10.1016/j.biochi.2020.12.025

Cited by 17 publications

(12 citation statements)

References 111 publications

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“…The EPICURE Consortium identified the pyridoxamine 5'‐phosphate oxidase gene ( PNPO ) in ~230 kb distance to SKAP1 as the most promising candidate for GGE. PNPO mutations and the resulting impairment of pyridoxine 5'‐phosphate (PNP) or vitamin B6 metabolism and insufficient delivery of pyridoxal 5'‐phosphate (PLP) to PLP‐dependent enzymes have neuropathological consequences in neonates (Ghatge et al, 2021; Levtova et al, 2015; Lloreda‐Garcia et al, 2017). PNPO is required for the synthesis of pyridoxal 5'‐phosphate (PLP) whose role in neurotransmitter metabolism is thought to be the primary cause of PNPO‐dependent neonatal epileptic encephalopathy (Mills et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Benchmarking of univariate pleiotropy detection methods applied to epilepsy

et al. 2022

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Pleiotropy is a widespread phenomenon that may increase insight into the etiology of biological and disease traits. Since genome‐wide association studies frequently provide information on a single trait only, only univariate pleiotropy detection methods are applicable, with yet unknown comparative performance. Here, we compared five such methods with respect to their ability to detect pleiotropy, including meta‐analysis, ASSET, conditional false discovery rate (cFDR), cross‐phenotype Bayes (CPBayes), and pleiotropic analysis under the composite null hypothesis (PLACO), by performing extended computer simulations that varied the underlying etiological model for pleiotropy for a pair of traits, including the number of causal variants, degree of traits' overlap, effect sizes as well as trait prevalence, and varying sample sizes. Our results indicate that ASSET provides the best trade‐off between power and protection against false positives. We then applied ASSET to a previously published International League Against Epilepsy (ILAE) consortium data set on complex epilepsies, comprising genetic generalized epilepsy and focal epilepsy cases and corresponding controls. We identified a novel candidate locus at 17q21.32 and confirmed locus 2q24.3, previously identified to act pleiotropically on both epilepsy subtypes by a mega‐analysis. Functional annotation, tissue‐specific expression, and regulatory function analysis as well as Bayesian colocalization analysis corroborated this result, rendering 17q21.32 a worthwhile candidate for follow‐up studies on pleiotropy in epilepsies.

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Section: Discussionmentioning

confidence: 99%

Benchmarking of univariate pleiotropy detection methods applied to epilepsy

et al. 2022

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“…Among the six vitB6 compounds, PLP is the biologically active and most important vitamer since it is required as a cofactor for a multitude of enzymes in the body. Humans and other mammals obtain PLP directly from diet or through synthesis from other vitameric forms ingested with food or recycled from degraded PLP-dependent enzymes via the salvage pathway [1,4] (Figure 2). The central enzyme in this pathway is PNP oxidase (PNPO), a flavin mononucleotide (FMN)dependent enzyme that is capable of converting PNP or PMP to the active cofactor Chemical structures of the six vitamin B6 vitamers.…”

Section: Metabolism Of Vitb6mentioning

confidence: 99%

“…VitB6 vitamers are widely available in animal and plant food sources. PLP and in a lesser amount, PMP are present as such in animal-derived foods, mainly associated with muscle glycogen phosphorylase, while plant foods are more enriched in PN, PNP and PN glucosides [1,4,8].…”

Section: Metabolism Of Vitb6mentioning

confidence: 99%

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Vitamin B6 and Related Inborn Errors of Metabolism

Al-Shekaili¹,

Leavitt²

2022

B-Complex Vitamins - Sources, Intakes and Novel Applications

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Vitamin B6 (vitB6) is a generic term that comprises six interconvertible pyridine compounds. These vitB6 compounds (also called vitamers) are pyridoxine (PN), pyridoxamine (PM), pyridoxal (PL) and their 5′-phosphorylated forms pyridoxine 5′-phosphate (PNP), pyridoxamine 5′-phosphate (PMP) and pyridoxal 5′-phosphate (PLP). VitB6 is an essential nutrient for all living organisms, but only microorganisms and plants can carry out de novo synthesis of this vitamin. Other organisms obtain vitB6 from dietary sources and interconvert its different forms according to their needs via a biochemical pathway known as the salvage pathway. PLP is the biologically active form of vitB6 which is important for maintaining the biochemical homeostasis of the body. In the human body, PLP serves as a cofactor for more than 140 enzymatic reactions, mainly associated with synthesis, degradation and interconversion of amino acids and neurotransmitter metabolism. PLP-dependent enzymes are also involved in various physiological processes, including biologically active amine biosynthesis, lipid metabolism, heme synthesis, nucleic acid synthesis, protein and polyamine synthesis and several other metabolic pathways. PLP is an important vitamer for normal brain function since it is required as a coenzyme for the synthesis of several neurotransmitters including D-serine, D-aspartate, L-glutamate, glycine, γ-aminobutyric acid (GABA), serotonin, epinephrine, norepinephrine, histamine and dopamine. Intracellular levels of PLP are tightly regulated and conditions that disrupt this homeostatic regulation can cause disease. In humans, genetic and dietary (intake of high doses of vitB6) conditions leading to increase in PLP levels is known to cause motor and sensory neuropathies. Deficiency of PLP in the cell is also implicated in several diseases, the most notable example of which are the vitB6-dependent epileptic encephalopathies. VitB6-dependent epileptic encephalopathies (B6EEs) are a clinically and genetically heterogeneous group of rare inherited metabolic disorders. These debilitating conditions are characterized by recurrent seizures in the prenatal, neonatal, or postnatal period, which are typically resistant to conventional anticonvulsant treatment but are well-controlled by the administration of PN or PLP. In addition to seizures, children affected with B6EEs may also suffer from developmental and/or intellectual disabilities, along with structural brain abnormalities. Five main types of B6EEs are known to date, these are: PN-dependent epilepsy due to ALDH7A1 (antiquitin) deficiency (PDE-ALDH7A1) (MIM: 266100), hyperprolinemia type 2 (MIM: 239500), PLP-dependent epilepsy due to PNPO deficiency (MIM: 610090), hypophosphatasia (MIM: 241500) and PLPBP deficiency (MIM: 617290). This chapter provides a review of vitB6 and its different vitamers, their absorption and metabolic pathways in the human body, the diverse physiological roles of vitB6, PLP homeostasis and its importance for human health. Finally, the chapter reviews the inherited neurological disorders affecting PLP homeostasis with a special focus on vitB6-dependent epileptic encephalopathies (B6EEs), their different subtypes, the pathophysiological mechanism underlying each type, clinical and biochemical features and current treatment strategies.

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“…Biochemical studies show that different variants reduce the PNPO enzymatic activity to different levels, ranging from 0 to 83% ( 2 , 3 , 18 , 19 ). Such a wide range of variation can be attributed to the differential effects of different mutations on the catalytic site, FMN binding, and/or protein folding and thermostability ( 17 , 20 , 21 ). While these in vitro studies show clear evidence that different PNPO mutations affect enzymatic activity to varying degrees, they do not explain the variation in seizure types, seizure onsets, and comorbidities manifested by PNPO-deficient patients carrying the same mutation ( 3 , 17 ).…”

mentioning

confidence: 99%

Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes

Chi

Iyengar

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Pyridox(am)ine 5′-phosphate oxidase (PNPO) catalyzes the rate-limiting step in the synthesis of pyridoxal 5′-phosphate (PLP), the active form of vitamin B6 required for the synthesis of neurotransmitters gamma-aminobutyric acid (GABA) and the monoamines. Pathogenic variants in PNPO have been increasingly identified in patients with neonatal epileptic encephalopathy and early-onset epilepsy. These patients often exhibit different types of seizures and variable comorbidities. Recently, the PNPO gene has also been implicated in epilepsy in adults. It is unclear how these phenotypic variations are linked to specific PNPO alleles and to what degree diet can modify their expression. Using CRISPR-Cas9, we generated four knock-in Drosophila alleles, hWT, hR116Q, hD33V , and hR95H, in which the endogenous Drosophila PNPO was replaced by wild-type human PNPO complementary DNA (cDNA) and three epilepsy-associated variants. We found that these knock-in flies exhibited a wide range of phenotypes, including developmental impairments, abnormal locomotor activities, spontaneous seizures, and shortened life span. These phenotypes are allele dependent, varying with the known biochemical severity of these mutations and our characterized molecular defects. We also showed that diet treatments further diversified the phenotypes among alleles, and PLP supplementation at larval and adult stages prevented developmental impairments and seizures in adult flies, respectively. Furthermore, we found that hR95H had a significant dominant-negative effect, rendering heterozygous flies susceptible to seizures and premature death. Together, these results provide biological bases for the various phenotypes resulting from multifunction of PNPO, specific molecular and/or genetic properties of each PNPO variant, and differential allele–diet interactions.

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Inborn errors in the vitamin B6 salvage enzymes associated with neonatal epileptic encephalopathy and other pathologies

Cited by 17 publications

References 111 publications

Benchmarking of univariate pleiotropy detection methods applied to epilepsy

Benchmarking of univariate pleiotropy detection methods applied to epilepsy

Vitamin B6 and Related Inborn Errors of Metabolism

Drosophila carrying epilepsy-associated variants in the vitamin B6 metabolism gene PNPO display allele- and diet-dependent phenotypes

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