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Allen W Miller - One of the best experts on this subject based on the ideXlab platform.
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Interaction of the Trans-Frame Potyvirus Protein P3N- PIPO with Host Protein PCaP1 Facilitates Potyvirus Movement
2016Co-Authors: Paramasivan Vijayapalani, Masayoshi Maeshima, Nahoko Nagasaki-takekuchi, Allen W MillerAbstract:A small open reading frame (ORF), pipo, overlaps with the P3 coding region of the potyviral polyprotein ORF. Previous evidence suggested a requirement for pipo for efficient viral cell-to-cell movement. Here, we provide immunoblotting evidence that the protein PIPO is expressed as a trans-frame protein consisting of the amino-terminal half of P3 fused to PIPO (P3N-PIPO). P3N-PIPO of Turnip mosaic virus (TuMV) fused to GFP facilitates its own cell-to-cell movement. Using a yeast two-hybrid screen, co-immunoprecipitation assays, and bimolecular fluorescence complementation (BiFC) assays, we found that P3N-PIPO interacts with host protein PCaP1, a cation-binding protein that attaches to the plasma membrane via myristoylation. BiFC revealed that it is the PIPO domain of P3N-PIPO that binds PCaP1 and that myristoylation of PCaP1 is unnecessary for interaction with P3N-PIPO. In PCaP1 knockout mutants (pcap1) of Arabidopsis, accumulation of TuMV harboring a GFP gene (TuMV-GFP) was drastically reduced relative to the virus level in wild-type plants, only small localized spots of GFP were visible, and the plants showed few symptoms. In contrast, TuMV-GFP infection in wild-type Arabidopsis yielded large green fluorescent patches, and caused severe stunting. However, viral RNA accumulated to high level in protoplasts from pcap1 plants indicating that PCaP1 is not required for TuMV RNA synthesis. In contrast to TuMV, the tobamovirus Oilseed rape mosaic virus did not require PCaP1 to infect Arabidopsis plants. We conclude that potyviral P3N-PIPO interacts specifically with the host plasma membrane protein PCaP1 to participate in cell-to-cell movement. W
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interaction of the trans frame potyvirus protein p3n pipo with host protein pcap1 facilitates potyvirus movement
2012Co-Authors: Paramasivan Vijayapalani, Masayoshi Maeshima, Nahoko Nagasakitakekuchi, Allen W MillerAbstract:A small open reading frame (ORF), pipo, overlaps with the P3 coding region of the potyviral polyprotein ORF. Previous evidence suggested a requirement for pipo for efficient viral cell-to-cell movement. Here, we provide immunoblotting evidence that the protein PIPO is expressed as a trans-frame protein consisting of the amino-terminal half of P3 fused to PIPO (P3N-PIPO). P3N-PIPO of Turnip mosaic virus (TuMV) fused to GFP facilitates its own cell-to-cell movement. Using a yeast two-hybrid screen, co-immunoprecipitation assays, and bimolecular fluorescence complementation (BiFC) assays, we found that P3N-PIPO interacts with host protein PCaP1, a cation-binding protein that attaches to the plasma membrane via myristoylation. BiFC revealed that it is the PIPO domain of P3N-PIPO that binds PCaP1 and that myristoylation of PCaP1 is unnecessary for interaction with P3N-PIPO. In PCaP1 knockout mutants (pcap1) of Arabidopsis, accumulation of TuMV harboring a GFP gene (TuMV-GFP) was drastically reduced relative to the virus level in wild-type plants, only small localized spots of GFP were visible, and the plants showed few symptoms. In contrast, TuMV-GFP infection in wild-type Arabidopsis yielded large green fluorescent patches, and caused severe stunting. However, viral RNA accumulated to high level in protoplasts from pcap1 plants indicating that PCaP1 is not required for TuMV RNA synthesis. In contrast to TuMV, the tobamovirus Oilseed rape mosaic virus did not require PCaP1 to infect Arabidopsis plants. We conclude that potyviral P3N-PIPO interacts specifically with the host plasma membrane protein PCaP1 to participate in cell-to-cell movement. We speculate that PCaP1 links a complex of viral proteins and genomic RNA to the plasma membrane by binding P3N-PIPO, enabling localization to the plasmodesmata and cell-to-cell movement. The PCaP1 knockout may contribute to a new strategy for recessive resistance to potyviruses.
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an overlapping essential gene in the potyviridae
2008Co-Authors: Betty Y W Chung, Allen W Miller, John F Atkins, Andrew E FirthAbstract:The family Potyviridae includes >30% of known plant virus species, many of which are of great agricultural significance. These viruses have a positive sense RNA genome that is ≈10 kb long and contains a single long ORF. The ORF is translated into a large polyprotein, which is cleaved into ≈10 mature proteins. We report the discovery of a short ORF embedded within the P3 cistron of the polyprotein but translated in the +2 reading-frame. The ORF, termed pipo, is conserved and has a strong bioinformatic coding signature throughout the large and diverse Potyviridae family. Mutations that knock out expression of the PIPO protein in Turnip mosaic potyvirus but leave the polyprotein amino acid sequence unaltered are lethal to the virus. Immunoblotting with antisera raised against two nonoverlapping 14-aa antigens, derived from the PIPO amino acid sequence, reveals the expression of an ≈25-kDa PIPO fusion product in planta. This is consistent with expression of PIPO as a P3-PIPO fusion product via ribosomal frameshifting or transcriptional slippage at a highly conserved G1-2A6-7 motif at the 5′ end of pipo. This discovery suggests that other short overlapping genes may remain hidden even in well studied virus genomes (as well as cellular organisms) and demonstrates the utility of the software package MLOGD as a tool for identifying such genes.
Naomi E. Rance - One of the best experts on this subject based on the ideXlab platform.
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Glutamatergic Neurokinin 3 Receptor Neurons in the Median Preoptic Nucleus Modulate Heat-Defense Pathways in Female Mice.
2019Co-Authors: Sally J. Krajewski-hall, Nathaniel T. Mcmullen, Filipa Miranda Dos Santos, Elise M. Blackmore, Naomi E. RanceAbstract:We have proposed that arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin (KNDy neurons) contribute to hot flushes via projections to neurokinin 3 receptor (NK3R)-expressing neurons in the median preoptic nucleus (MnPO). To characterize the thermoregulatory role of MnPO NK3R neurons in female mice, we ablated these neurons using injections of saporin toxin conjugated to a selective NK3R agonist. Loss of MnPO NK3R neurons increased the core temperature (TCORE) during the light phase, with the frequency distributions indicating a regulated shift in the balance point. The increase in TCORE in the ablated mice occurred despite changes in the ambient temperature and regardless of estrogen status. We next determined whether an acute increase in ambient temperature or higher TCORE would induce Fos in preoptic enhanced green fluorescent protein (EGFP)-immunoreactive neurons in Tacr3-EGFP mice. Fos activation was increased in the MnPO but no induction of Fos was found in NK3R (EGFP-immunoreactive) neurons. Thus, MnPO NK3R neurons are not activated by warm thermosensors in the skin or viscera and are not warm-sensitive neurons. Finally, RNAscope was used to determine whether Tacr3 (NK3R) mRNA was coexpressed with vesicular glutamate transporter 2 or vesicular γ-aminobutyric acid (GABA) transporter mRNA, markers of glutamatergic and GABAergic neurotransmission, respectively. In the MnPO, 94% of NK3R neurons were glutamatergic, but in the adjacent medial preoptic area, 97% of NK3R neurons were GABAergic. Thus, NK3R neurons in the MnPO are glutamatergic and play a role in reducing TCORE but are not activated by warm thermal stimuli (internal or external). These findings suggest that KNDy neurons modulate thermosensory pathways for heat defense indirectly via a subpopulation of glutamatergic MnPO neurons that express NK3R.
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Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat.
2015Co-Authors: Melinda A. Mittelman-smith, Sally J. Krajewski-hall, Nathaniel T. Mcmullen, Naomi E. RanceAbstract:KNDy neurons facilitate tail skin vasodilation and modulate the effects of estradiol on thermoregulation. We hypothesize that KNDy neurons influence cutaneous vasodilation via projections to neurons in the median preoptic nucleus (MnPO) that express the neurokinin 3 receptor (NK3R). In support of this hypothesis, focal microinjections of senktide, an NK3R agonist, into the MnPO lowers core temperature (TCORE) in the female rat. To further study the role of MnPO NK3R neurons in thermoregulation, these neurons were specifically ablated using a conjugate of a selective NK3R agonist and saporin (NK3-SAP). NK3-SAP or blank-SAP (control) was injected into the MnPO/medial septum. Tail skin temperature (TSKIN) and TCORE were measured in ovariectomized rats exposed to 3 ambient temperatures (TAMBIENT) before and after estradiol-17β (E2) treatment. Before killing, we injected senktide (sc), monitored TCORE for 70 minutes, and harvested brains for Fos immunohistochemistry. Ablation of MnPO NK3R neurons lowered TSKIN...
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Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat.
2015Co-Authors: Melinda A. Mittelman-smith, Sally J. Krajewski-hall, Nathaniel T. Mcmullen, Naomi E. RanceAbstract:KNDy neurons facilitate tail skin vasodilation and modulate the effects of estradiol on thermoregulation. We hypothesize that KNDy neurons influence cutaneous vasodilation via projections to neurons in the median preoptic nucleus (MnPO) that express the neurokinin 3 receptor (NK3R). In support of this hypothesis, focal microinjections of senktide, an NK3R agonist, into the MnPO lowers core temperature (TCORE) in the female rat. To further study the role of MnPO NK3R neurons in thermoregulation, these neurons were specifically ablated using a conjugate of a selective NK3R agonist and saporin (NK3-SAP). NK3-SAP or blank-SAP (control) was injected into the MnPO/medial septum. Tail skin temperature (TSKIN) and TCORE were measured in ovariectomized rats exposed to 3 ambient temperatures (TAMBIENT) before and after estradiol-17β (E2) treatment. Before killing, we injected senktide (sc), monitored TCORE for 70 minutes, and harvested brains for Fos immunohistochemistry. Ablation of MnPO NK3R neurons lowered TSKIN at neutral and subneutral TAMBIENT regardless of E2 treatment. However, ablation did not prevent the effects of E2 on TCORE and TSKIN. In control rats, senktide injections induced hypothermia with numerous Fos-immunoreactive cells in the MnPO. In contrast, in NK3-SAP rats, senktide did not alter TCORE and minimal Fos-immunoreactive neurons were identified in the MnPO. These data show that NK3R neurons in the MnPO are required for the hypothermic effects of senktide but not for the E2 modulation of thermoregulation. The lower TSKIN in NK3-SAP-injected rats suggests that MnPO NK3R neurons, like KNDy neurons, facilitate cutaneous vasodilation, an important heat-dissipation effector.
Peter E Clayton - One of the best experts on this subject based on the ideXlab platform.
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normal cerebrospinal fluid pyridoxal 5 phosphate level in a PNPO deficient patient with neonatal onset epileptic encephalopathy
2015Co-Authors: Alina Levtova, Peter E Clayton, Keith Hyland, Stephane Camuzeaux, Annemarie Laberge, Pierre Allard, Catherine Brunelguitton, Paola Diadori, Elsa Rossignol, Philippa B MillsAbstract:Deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO, OMIM 610090) is a treatable autosomal recessive inborn error of metabolism. Neonatal epileptic encephalopathy and a low cerebrospinal fluid (CSF) pyridoxal 5′-phosphate level are the reported hallmarks of PNPO deficiency, but its clinical and biochemical spectra are not fully known. Case presentation: A girl born at 33 3/7 weeks of gestation developed seizures in the first hours of life. Her seizures initially responded to GABAergic agonists, but she subsequently developed a severe epileptic encephalopathy. Brain MRI and infectious and metabolic evaluations at birth, including urinary alpha-aminoadipic semialdehyde (AASA), were normal. Lumbar puncture at age 3 months showed: pyridoxal 5′-phosphate, 52 nmol/L (normal, 23–64); homovanillic acid, 392 nmol/L (normal, 450–1,132); 5-hydroxyindoleacetic acid, 341 nmol/L (normal, 179–711); and 3-ortho-methyldopa, 30 nmol/L (normal, below 300). The patient was not being treated with pyridoxine nor with pyridoxal 5′-phosphate at the time of the lumbar puncture. She died at age 14 months. A sequencing panel targeting 53 epilepsy-related genes revealed a homozygous missense mutation in PNPO (c.674G>A, p.R225H). Homozygosity was confirmed by parental testing. Expression studies of mutant p.R225H PNPO revealed greatly reduced activity. In conclusion, a normal CSF level of pyridoxal 5′-phosphate does not rule out PNPO deficiency.
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pyridoxine responsiveness in novel mutations of the PNPO gene
2014Co-Authors: Barbara Plecko, Peter E Clayton, Philippa B Mills, Eduard Paschke, K Paul, Oliver Maier, Oswald Hasselmann, G Schmiedel, Simone Kanz, Mary B ConnollyAbstract:Objective: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. Methods: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. Results: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5′-phosphate (PLP). Conclusions: This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5′-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug–resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.
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cirrhosis associated with pyridoxal 5 phosphate treatment of pyridoxamine 5 phosphate oxidase deficiency
2014Co-Authors: Annapurna Sudarsanam, Harry Singh, Bridget Wilcken, Michael Stormon, Susan Arbuckle, Bernhard Schmitt, Peter E Clayton, John W Earl, Richard WebsterAbstract:We report the case of an 8-year-old boy with pyridoxamine 5′-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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Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency.
2010Co-Authors: Bernhard Schmitt, Peter E Clayton, Matthias R. Baumgartner, Cornelis Jakobs, Philippa B Mills, Elmar Keller, Gabriele WohlrabAbstract:AimWe report on seizures, paroxysmal events, and electroencephalogram (EEG) findings in four female infants with pyridoxine-dependent epilepsy (PDE) and in one female with pyridoxine phosphate oxidase deficiency (PNPO).MethodVideos and EEGs were analysed and compared with videos of seizures and paroxysmal events archived from 140 neonates. PDE and PNPO were proven by complete control of seizures once pyridoxine or pyridoxal 5'-phosphate was administered and by recurrence when withdrawn. Mutations in the antiquitin gene were found in three patients and in the PNPO gene in one child.ResultsSeizures began within 48 hours after birth in four newborns and at age 3 weeks in one. Frequent multifocal and generalized myoclonic jerks, often intermixed with tonic symptoms, abnormal eye movement, grimacing, or irritability, were observed in all infants with PDE and PNPO, but rarely in the other archived videos of neonates. EEGs were inconstant and frequently no discernable ictal changes were recorded during the seizures and the paroxysmal events. In addition, interictal EEGs were inconclusive, with normal and abnormal recordings. In older children tonic-clonic seizures, abnormal behaviour, inconsolable crying, frightened facial expression, sleep disturbance, loss of consciousness, paraesthesia, or intermittent visual symptoms were described during controlled and uncontrolled withdrawal or insufficient dosage.InterpretationPDE or PNPO should be considered in infants with prolonged episodes of mixed multifocal myoclonic tonic symptoms, notably when associated with grimacing and abnormal eye movements.
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pyridoxal 5 phosphate values in cerebrospinal fluid reference values and diagnosis of PNPO deficiency in paediatric patients
2008Co-Authors: Aida Ormazabal, Keith Hyland, Marcus Oppenheim, Mercedes Serrano, Angels Garciacazorla, Jaume Campistol, Antonia Ribes, Angeles Ruiz, Juan Antonio Moreno, Peter E ClaytonAbstract:Abstract Our aim was to establish reference values for cerebrospinal fluid (CSF) pyridoxal 5′-phosphate (PLP) in a paediatric population for the diagnosis of pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency. For reference values, CSF samples from 113 paediatric controls (age range: 1 day–18 years) from Barcelona and London were analysed. Cerebrospinal fluid PLP and biogenic amine concentrations were analysed by HPLC with fluorescence and electrochemical detection. Pyridoxal 5′-phosphate concentrations in 4 patients with PNPO deficiency were determined. A negative correlation between CSF PLP values and age of controls was observed in both populations ( r =−0.503; p r =−0.542; p =0.002). Reference values were stratified into 4 (Barcelona) and 3 age groups (London). For the newborn period, CSF PLP reference intervals were 32–78 and 44–89nmol/L for the Barcelona and London centers, respectively). No correlation was observed in the different age groups between PLP values and biogenic amines metabolites. PLP values in neonates with PNPO deficiency were clearly decreased (PLP=3.6, 12.0, 14.0 and 18.0nmol/L) compared with our reference ranges. In conclusion, reference values for CSF PLP should be stratified according to age. No association was observed between PLP values and biogenic amines metabolites. In our 4 cases with PNPO deficiency, CSF PLP values were clearly below the reference values.
Philippa B Mills - One of the best experts on this subject based on the ideXlab platform.
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normal cerebrospinal fluid pyridoxal 5 phosphate level in a PNPO deficient patient with neonatal onset epileptic encephalopathy
2015Co-Authors: Alina Levtova, Peter E Clayton, Keith Hyland, Stephane Camuzeaux, Annemarie Laberge, Pierre Allard, Catherine Brunelguitton, Paola Diadori, Elsa Rossignol, Philippa B MillsAbstract:Deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO, OMIM 610090) is a treatable autosomal recessive inborn error of metabolism. Neonatal epileptic encephalopathy and a low cerebrospinal fluid (CSF) pyridoxal 5′-phosphate level are the reported hallmarks of PNPO deficiency, but its clinical and biochemical spectra are not fully known. Case presentation: A girl born at 33 3/7 weeks of gestation developed seizures in the first hours of life. Her seizures initially responded to GABAergic agonists, but she subsequently developed a severe epileptic encephalopathy. Brain MRI and infectious and metabolic evaluations at birth, including urinary alpha-aminoadipic semialdehyde (AASA), were normal. Lumbar puncture at age 3 months showed: pyridoxal 5′-phosphate, 52 nmol/L (normal, 23–64); homovanillic acid, 392 nmol/L (normal, 450–1,132); 5-hydroxyindoleacetic acid, 341 nmol/L (normal, 179–711); and 3-ortho-methyldopa, 30 nmol/L (normal, below 300). The patient was not being treated with pyridoxine nor with pyridoxal 5′-phosphate at the time of the lumbar puncture. She died at age 14 months. A sequencing panel targeting 53 epilepsy-related genes revealed a homozygous missense mutation in PNPO (c.674G>A, p.R225H). Homozygosity was confirmed by parental testing. Expression studies of mutant p.R225H PNPO revealed greatly reduced activity. In conclusion, a normal CSF level of pyridoxal 5′-phosphate does not rule out PNPO deficiency.
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pyridoxine responsiveness in novel mutations of the PNPO gene
2014Co-Authors: Barbara Plecko, Peter E Clayton, Philippa B Mills, Eduard Paschke, K Paul, Oliver Maier, Oswald Hasselmann, G Schmiedel, Simone Kanz, Mary B ConnollyAbstract:Objective: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. Methods: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. Results: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5′-phosphate (PLP). Conclusions: This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5′-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug–resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.
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Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency.
2010Co-Authors: Bernhard Schmitt, Peter E Clayton, Matthias R. Baumgartner, Cornelis Jakobs, Philippa B Mills, Elmar Keller, Gabriele WohlrabAbstract:AimWe report on seizures, paroxysmal events, and electroencephalogram (EEG) findings in four female infants with pyridoxine-dependent epilepsy (PDE) and in one female with pyridoxine phosphate oxidase deficiency (PNPO).MethodVideos and EEGs were analysed and compared with videos of seizures and paroxysmal events archived from 140 neonates. PDE and PNPO were proven by complete control of seizures once pyridoxine or pyridoxal 5'-phosphate was administered and by recurrence when withdrawn. Mutations in the antiquitin gene were found in three patients and in the PNPO gene in one child.ResultsSeizures began within 48 hours after birth in four newborns and at age 3 weeks in one. Frequent multifocal and generalized myoclonic jerks, often intermixed with tonic symptoms, abnormal eye movement, grimacing, or irritability, were observed in all infants with PDE and PNPO, but rarely in the other archived videos of neonates. EEGs were inconstant and frequently no discernable ictal changes were recorded during the seizures and the paroxysmal events. In addition, interictal EEGs were inconclusive, with normal and abnormal recordings. In older children tonic-clonic seizures, abnormal behaviour, inconsolable crying, frightened facial expression, sleep disturbance, loss of consciousness, paraesthesia, or intermittent visual symptoms were described during controlled and uncontrolled withdrawal or insufficient dosage.InterpretationPDE or PNPO should be considered in infants with prolonged episodes of mixed multifocal myoclonic tonic symptoms, notably when associated with grimacing and abnormal eye movements.
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pyridoxal 5 phosphate may be curative in early onset epileptic encephalopathy
2007Co-Authors: Georg F Hoffmann, Bernhard Schmitt, Peter E Clayton, Philippa B Mills, M Windfuhr, N Wagner, H Strehl, Soyhan Bagci, Axel R Franz, Matthias R. BaumgartnerAbstract:Neonatal epileptic encephalopathy can be caused by inborn errors of metabolism. These conditions are often unresponsive to treatment with conventional antiepileptic drugs. Six children with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency presented with neonatal epileptic encephalopathy. Two were treated with pyridoxal 5'-phosphate (PLP) within the first month of life and showed normal development or moderate psychomotor retardation thereafter. Four children with late or no treatment died or showed severe mental handicap. All of the children showed atypical biochemical findings. Prompt treatment with PLP in all neonates and infants with epileptic encephalopathy should become mandatory, permitting normal development in at least some of those affected with PNPO deficiency.
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neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox am ine 5 phosphate oxidase
2005Co-Authors: Philippa B Mills, Robert Surtees, Michael Champion, Clare E Beesley, Neil Dalton, Peter J Scambler, Simon J R Heales, Anthony Briddon, Irene Scheimberg, Georg F HoffmannAbstract:In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate and failure to maintain pyridoxal phosphate (PLP) levels results in epilepsy. This study of five patients with neonatal epileptic encephalopathy suggests that the same is true in man. Cerebrospinal fluid and urine analyses indicated reduced activity of aromatic L-amino acid decarboxylase and other PLP-dependent enzymes. Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5'-phosphate oxidase (PNPO). Sequencing of the PNPO gene identified homozygous missense, splice site and stop codon mutations. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1g>a) and stop codon (X262Q) mutations were null activity mutations and that the missense mutation (R229W) markedly reduced pyridox(am)ine phosphate oxidase activity. Maintenance of optimal PLP levels in the brain may be important in many neurological disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).
Georg F Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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pyridoxal 5 phosphate may be curative in early onset epileptic encephalopathy
2007Co-Authors: Georg F Hoffmann, Bernhard Schmitt, Peter E Clayton, Philippa B Mills, M Windfuhr, N Wagner, H Strehl, Soyhan Bagci, Axel R Franz, Matthias R. BaumgartnerAbstract:Neonatal epileptic encephalopathy can be caused by inborn errors of metabolism. These conditions are often unresponsive to treatment with conventional antiepileptic drugs. Six children with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency presented with neonatal epileptic encephalopathy. Two were treated with pyridoxal 5'-phosphate (PLP) within the first month of life and showed normal development or moderate psychomotor retardation thereafter. Four children with late or no treatment died or showed severe mental handicap. All of the children showed atypical biochemical findings. Prompt treatment with PLP in all neonates and infants with epileptic encephalopathy should become mandatory, permitting normal development in at least some of those affected with PNPO deficiency.
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Pyridoxal 5′-phosphate may be curative in early-onset epileptic encephalopathy
2007Co-Authors: Georg F Hoffmann, M Windfuhr, N Wagner, H Strehl, Soyhan Bagci, Axel R Franz, B. Schmitt, P. B. Mills, P. T. Clayton, M. R. BaumgartnerAbstract:Neonatal epileptic encephalopathy can be caused by inborn errors of metabolism. These conditions are often unresponsive to treatment with conventional antiepileptic drugs. Six children with pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency presented with neonatal epileptic encephalopathy. Two were treated with pyridoxal 5′-phosphate (PLP) within the first month of life and showed normal development or moderate psychomotor retardation thereafter. Four children with late or no treatment died or showed severe mental handicap. All of the children showed atypical biochemical findings. Prompt treatment with PLP in all neonates and infants with epileptic encephalopathy should become mandatory, permitting normal development in at least some of those affected with PNPO deficiency.
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neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox am ine 5 phosphate oxidase
2005Co-Authors: Philippa B Mills, Robert Surtees, Michael Champion, Clare E Beesley, Neil Dalton, Peter J Scambler, Simon J R Heales, Anthony Briddon, Irene Scheimberg, Georg F HoffmannAbstract:In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate and failure to maintain pyridoxal phosphate (PLP) levels results in epilepsy. This study of five patients with neonatal epileptic encephalopathy suggests that the same is true in man. Cerebrospinal fluid and urine analyses indicated reduced activity of aromatic L-amino acid decarboxylase and other PLP-dependent enzymes. Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5'-phosphate oxidase (PNPO). Sequencing of the PNPO gene identified homozygous missense, splice site and stop codon mutations. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1g>a) and stop codon (X262Q) mutations were null activity mutations and that the missense mutation (R229W) markedly reduced pyridox(am)ine phosphate oxidase activity. Maintenance of optimal PLP levels in the brain may be important in many neurological disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).