Evidence map›Paper›PMID 30668673›Full record

ArticleBrain : a journal of neurology2019

PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights.

Devon L Johnstone, Hilal H Al-Shekaili, Maja Tarailo-Graovac, Nicole I Wolf, Autumn S Ivy, Scott Demarest, Yann Roussel, Jolita Ciapaite, Carlo W T van Roermund, Kristin D Kernohan and 44 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.

0numbers the graph read from it
0cells of the map it votes in
50citing papers in PubMed
4.9field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

50 citing papers in PubMed, 87 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. The ubiquitous pyridoxal 5'-phosphate-binding protein is also an RNA-binding protein.Protein science : a publication of the Protein Society · 2024
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  7. Review
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  9. Review
  10. Article
  11. Review
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  13. Scientific opinion on the tolerable upper intake level for vitamin B6.EFSA journal. European Food Safety Authority · 2023
    Article
  14. Review
  15. 4'-Deoxypyridoxine disrupts vitamin BMicrobiology (Reading, England) · 2023
    Article
  16. Review
  17. Article
  18. Article
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

54 authors at 19 institutions in 5 countries.

Devon L JohnstoneChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Hilal H Al-ShekailiDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Maja Tarailo-GraovacDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Nicole I WolfDepartment of Child Neurology, Amsterdam University Medical Centres, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Autumn S IvyDivision of Child Neurology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, CA, USA.
Scott DemarestDepartments of Pediatrics and Neurology, University of Colorado School of Medicine, Children's Hospital Colorado, CO, USA.
Yann RousselDepartment of Biology, University of Ottawa, Ottawa, ON, Canada.
Jolita CiapaiteDepartment of Genetics, Center for Molecular Medicine, University Medical Center, Utrecht, The Netherlands.
Carlo W T van RoermundDepartment of Pediatrics and Clinical Chemistry, Laboratory Division, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
Kristin D KernohanChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Ceres KosutaChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Kevin BanChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Yoko ItoChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Skye McBrideChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Khalid Al-ThihliGenetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.
Rana A AbdelrahimDepartment of Child Health, Sultan Qaboos University Hospital, Muscat, Oman.
Roshan KoulPaediatric Neurology Unit, Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman.
Amna Al FutaisiPaediatric Neurology Unit, Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman.
Charlotte A HaaxmaDepartment of Pediatric Neurology, Amalia Children's Hospital and Donders Institute of Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Heather OlsonDepartment of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA, USA.
Laufey Yr SigurdardottirDepartment of Neurology, University of Central Florida, Nemours Children's Hospital, Orlando, FL, USA.
Georgianne L ArnoldDepartment of Pediatrics, University of Pittsburgh Medical Center, Pittsburg, PA, USA.
Erica H GerkesDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
M BoonDepartment of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
M Rebecca Heiner-FokkemaDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Sandra NobleDepartment of Biology, University of Ottawa, Ottawa, ON, Canada.
Marjolein BosmaDepartment of Genetics, Center for Molecular Medicine, University Medical Center, Utrecht, The Netherlands.
Judith JansDepartment of Genetics, Center for Molecular Medicine, University Medical Center, Utrecht, The Netherlands.
David A KoolenDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Erik-Jan KamsteegGenome Diagnostics Nijmegen, Nijmegen, The Netherlands.
Britt DrögemöllerBritish Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
Colin J RossBritish Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
Jacek MajewskiMcGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
Megan T ChoGeneDx Inc., Gaithersburg, MD, USA.
Amber BegtrupGeneDx Inc., Gaithersburg, MD, USA.
Wyeth W WassermanBritish Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
Tuan BuiDepartment of Biology, University of Ottawa, Ottawa, ON, Canada.
Elise BrimbleDepartment of Neurology and Neurological Sciences, Stanford Medicine, Stanford, CA, USA.
Sara ViolanteDepartment of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sander M HoutenDepartment of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ron A WeversUnited for Metabolic Diseases, The Netherlands.
Martijn van FaassenDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Ido P KemaDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Nathalie LepageChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Care4Rare Canada Consortium
Matthew A LinesChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
David A DymentChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Ronald J A WandersDepartment of Pediatrics and Clinical Chemistry, Laboratory Division, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
Nanda Verhoeven-DuifDepartment of Genetics, Center for Molecular Medicine, University Medical Center, Utrecht, The Netherlands.
Marc EkkerDepartment of Biology, University of Ottawa, Ottawa, ON, Canada.
Kym M BoycottChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Jan M FriedmanDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Izabella A PenaChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Clara D M van KarnebeekBritish Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
Children's Hospital of Eastern Ontario · CAUniversity of Ottawa · CABC Children's Hospital · CASultan Qaboos University Hospital · OMUniversity Medical Center Utrecht · NLUniversity Medical Center Groningen · NLUniversity of British Columbia · CAIcahn School of Medicine at Mount Sinai · USRadboud University Nijmegen · NLUniversity of Groningen · NLAmsterdam Neuroscience · NLBoston Children's Hospital · USMcGill University and Génome Québec Innovation Centre · CARadboud Institute for Molecular Life Sciences · NLStanford Medicine · USStanford University · USUniversity of Central Florida · USUniversity of Colorado Denver · USUniversity of Pittsburgh Medical Center · US

Funding

Diagnosis and Genotype-Phenotype Correlations in Early Life Epilepsy and CDKL5 DisorderK23NS107646 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI OLSON, HEATHER ELISA · 2018 to 2023
$1.2M
CIHR 301221CIHR FDN-154279NINDS NIH HHS K23 NS107646
6 · The paper itself

Abstract

Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.

Indexed as

AnimalsDisease Models, AnimalEpilepsyFemaleHEK293 CellsHumansMalePhenotypeProteinsPyridoxal PhosphatePyridoxineVitamin B 6Vitamin B 6 DeficiencyZebrafishPLPBP protein, humanProteinsPyridoxal PhosphatePyridoxineVitamin B 6epilepsyPLPBPPROSCpyridoxinevitamin B6-responsive epilepsy

Identifiers

PMID30668673
PMCPMC6391652
OpenAlexW2912876039

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.