A new fatal case of pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency

Ruiz, Amaia Campos; García‐Villoria, Judit; Ormazábal, Aída; Zschocke, Johannes; Fiol, Miquel; Navarro-Sastre, Aleix; Artuch, Rafael; Vilaseca, M. A.; Ribes, Antònia

doi:10.1016/j.ymgme.2007.10.003

Cited by 57 publications

(70 citation statements)

References 8 publications

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“…To date there have been <40 cases reported in the medical literature (Mills et al 2005Hoffmann et al 2007;Bagci et al 2008;Ruiz et al 2008;Schmitt et al 2010;Veerapandiyan et al 2011;Ware et al 2014;Plecko et al 2014;Porri et al 2014). The initial clinical reported phenotype of PNPO deficiency included prematurity, early-onset neonatal encephalopathy and seizures that are resistant to conventional anticonvulsants and pyridoxine.…”

Section: Pyridoxal-5mentioning

confidence: 99%

“…The initial clinical reported phenotype of PNPO deficiency included prematurity, early-onset neonatal encephalopathy and seizures that are resistant to conventional anticonvulsants and pyridoxine. Those who have survived the neonatal period have had significant neurodevelopmental disorders in the form of ongoing seizures, developmental delay and microcephaly (Mills et al 2005;Hoffmann et al 2007;Bagci et al 2008;Ruiz et al 2008). As is often the case with rare diseases, the clinical phenotype expands as more cases are diagnosed with time.…”

Section: Pyridoxal-5mentioning

confidence: 99%

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Normal Neurodevelopmental Outcomes in PNPO Deficiency: A Case Series and Literature Review

Hatch

Coman

Clayton³

et al. 2015

JIMD Reports

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Pyridox(am)ine 5 0 -phosphate oxidase deficiency results in an early-onset neonatal encephalopathy that can be fatal if not detected and treated early. The condition is rare, can result in preterm delivery, and can mimic hypoxic ischemic encephalopathy. Thus, suspicion of the diagnosis, appropriate investigations, and therapeutic trials with pyridoxal-5 0 -phosphate are often delayed. In this paper we report four cases of pyridox(am)ine 5 0 -phosphate oxidase deficiency, two of whom are siblings. Three were treated with pyridoxal-5 0 -phosphate in the first few days of life and the fourth within the first month. One of the siblings was electively treated from birth until a diagnosis was secured. Our cases demonstrate that early diagnosis and treatment can be associated with normal neurodevelopment in childhood. We suggest that a low threshold for investigating for pyridox(am)ine 5 0 -phosphate oxidase deficiency and electively treating with pyridoxal-5 0 -phosphate is considered in any neonate with encephalopathy, including those with presumed hypoxic ischemic encephalopathy in whom the degree of encephalopathy is not expected from perinatal history, cord gases and/or neuroimaging.

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Section: Pyridoxal-5mentioning

confidence: 99%

Section: Pyridoxal-5mentioning

confidence: 99%

Normal Neurodevelopmental Outcomes in PNPO Deficiency: A Case Series and Literature Review

Hatch

Coman

Clayton³

et al. 2015

JIMD Reports

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“…Nonetheless, pathogenic mutations in the PNPO gene encoding for PNPOx are known to cause a reduced or null activity of PNPOx, resulting in PLP deficiency. Disruption of the salvage pathway can also occur by pathogenic mutations in the PL kinase gene or by drug induced inhibition of PNPOx and PL kinase enzymatic activity [5,6,[62][63][64][65][66][67]. Metabolites that accumulate as a consequence of inherited defects in enzymes of other metabolic pathways and drugs are also known to form complexes with PLP and reduce its availability [1,[67][68][69][70].…”

Section: Plp Deficiency and Neementioning

confidence: 99%

“…This disorder is sometimes referred to as PLP-dependent NEE as individuals with PNPO deficiency respond only to PLP or PL therapy, and not to the other forms of vitamin B 6 , such as PN and PM. At least seven mutations in the PNPO gene, including homozygous missense, stop codon, nonsense, splice site and frameshift mutations have been identified to cause PLP-dependent NEE [5,6,[62][63][64][65][66][67]. Most patients with these mutations are born prematurely and the disease can be fatal.…”

Section: Pnpox Deficiency-related Neementioning

confidence: 99%

“…Other PNPOx, including two novel homozygous missense mutations (R95H and R95C, in which arginine residue 95 is substituted by either a histidine or a cysteine) and a nonsense mutation (A174X; a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product) have also been identified in several patients with classical symptoms of PLP-dependent NEE [5,6,[62][63][64][65][66][67]. As will be discussed later, the elucidation of the crystal structure of PNPOx and the mechanism of PNP or PMP oxidation [57] have now contributed to the precise mechanism governing how some of these mutations lead to partial or complete loss of enzymatic function.…”

Section: Pathogenic Mutations In Pnpoxmentioning

confidence: 99%

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Molecular Defects of Vitamin B6 Metabolism Associated with Neonatal Epileptic Encephalopathy

Ghatge¹,

Salvo²,

Contestabile³

et al. 2012

Miscellanea on Encephalopathies - A Second Look

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Inactive mutants of human pyridoxine 5′‐phosphate oxidase: a possible role for a noncatalytic pyridoxal 5′‐phosphate tight binding site

et al. 2016

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Pyridoxal 5′‐phosphate ( PLP ) is a cofactor for many vitamin B6‐requiring enzymes that are important for the synthesis of neurotransmitters. Pyridoxine 5′‐phosphate oxidase ( PNPO ) is one of two enzymes that produce PLP . Some 16 known mutations in human PNPO ( hPNPO ), including R95C and R229W, lead to deficiency of PLP in the cell and have been shown to cause neonatal epileptic encephalopathy ( NEE ). This disorder has no effective treatment, and is often fatal unless treated with PLP . In this study, we show that R95C hPNPO exhibits a 15‐fold reduction in affinity for the FMN cofactor, a 71‐fold decrease in affinity for the substrate PNP , a 4.9‐fold decrease in specific activity, and a 343‐fold reduction in catalytic activity, compared to the wild‐type enzyme. We have reported similar findings for R229W hPNPO . This report also shows that wild‐type, R95C and R229W hPNPO bind PLP tightly at a noncatalytic site and transfer it to activate an apo‐B6 enzyme into the catalytically active holo‐form. We also show for the first time that hPNPO forms specific interactions with several B6 enzymes with dissociation constants ranging from 0.3 to 12.3 μ m . Our results suggest a possible in vivo role for the tight binding of PLP in hPNPO , whether wild‐type or variant, by protecting the very reactive PLP , and transferring this PLP directly to activate apo‐B6 enzymes.

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A new fatal case of pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency

Cited by 57 publications

References 8 publications

Normal Neurodevelopmental Outcomes in PNPO Deficiency: A Case Series and Literature Review

Normal Neurodevelopmental Outcomes in PNPO Deficiency: A Case Series and Literature Review

Molecular Defects of Vitamin B6 Metabolism Associated with Neonatal Epileptic Encephalopathy

Inactive mutants of human pyridoxine 5′‐phosphate oxidase: a possible role for a noncatalytic pyridoxal 5′‐phosphate tight binding site

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