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; Ceres Kosuta; Kevin Ban; Yoko Ito; Skye McBride; Khalid Al-Thihli; Rana A. Abdelrahim; Roshan Koul; Amna Al Futaisi; Charlotte A. Haaxma; Heather Olson; Laufey Yr Sigurdardottir; Georgianne L. Arnold; Erica H. Gerkes; M. Boon; M. Rebecca Heiner-Fokkema; Sandra Noble; Marjolein Bosma; Judith Jans; David A. Koolen; Erik-jan Kamsteeg; Britt Drogemoller; Colin J. Ross; Jacek Majewski; Megan T. Cho; Amber Begtrup; Wyeth W. Wasserman; Tuan Bui; Elise Brimble; Sara Violante; Sander M. Houten; Ron A. Wevers; Martijn van Faassen; Ido P. Kema; Nathalie Lepage; Matthew A. Lines; David A. Dyment; Ronald J. A. Wanders; Nanda Verhoeven-Duif; Marc Ekker; Kym M. Boycott; Jan M. Friedman; Izabella A. Pena; Clara D. M. van Karnebeek; Care4Rare Canada Consortium

doi:10.1093/brain/awy346

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

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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, …

Brain (London, England : 1878), Vol.142(3), pp.542-559

01/03/2019

DOI: https://doi.org/10.1093/brain/awy346

PMID: 30668673

Résumé

Clinical Neurology

Life Sciences & Biomedicine

Neurosciences

Neurosciences & Neurology

Science & Technology

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.

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Détails

Titre: PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights
Créateurs - sans rôle: Devon L. Johnstone - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Hilal H. Al-Shekaili - Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada
Maja Tarailo-Graovac - Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada
Nicole I. Wolf - University of Amsterdam
Autumn S. Ivy - Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Div Child Neurol, Stanford, CA 94305 USA
Scott Demarest - Univ Colorado, Sch Med, Childrens Hosp Colorado, Dept Pediat, Boulder, CO 80309 USA
Yann Roussel - Univ Ottawa, Dept Biol, Ottawa, ON, Canada
Jolita Ciapaite - Univ Med Ctr, Ctr Mol Med, Dept Genet, Utrecht, Netherlands
Carlo W. T. van Roermund - Univ Amsterdam, Med Ctr, Lab Genet Metab Dis, Dept Pediat & Clin Chem,Lab Div, Amsterdam, Netherlands
Kristin D. Kernohan - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Ceres Kosuta - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Kevin Ban - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Yoko Ito - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Skye McBride - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Khalid Al-Thihli - Sultan Qaboos Univ Hosp, Genet & Dev Med Clin, Muscat, Oman
Rana A. Abdelrahim - Sultan Qaboos Univ Hosp, Dept Child Hlth, Muscat, Oman
Roshan Koul - Sultan Qaboos Univ Hosp, Dept Child Hlth, Paediat Neurol Unit, Muscat, Oman
Amna Al Futaisi - Sultan Qaboos Univ Hosp, Dept Child Hlth, Paediat Neurol Unit, Muscat, Oman
Charlotte A. Haaxma - Radboud Univ Nijmegen, Med Ctr, Amalia Childrens Hosp, Dept Pediat Neurol, Nijmegen, Netherlands
Heather Olson - Boston Childrens Hosp, Dept Neurol, Div Epilepsy & Clin Neurophysiol, Boston, MA USA
Laufey Yr Sigurdardottir - Univ Cent Florida, Dept Neurol, Nemours Childrens Hosp, Orlando, FL 32816 USA
Georgianne L. Arnold - Univ Pittsburgh, Dept Pediat, Med Ctr, Pittsburgh, PA 15260 USA
Erica H. Gerkes - University of Groningen
M. Boon - Univ Groningen, Univ Med Ctr Groningen, Dept Neurol, Groningen, Netherlands
M. Rebecca Heiner-Fokkema - Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands
Sandra Noble - Univ Ottawa, Dept Biol, Ottawa, ON, Canada
Marjolein Bosma - Univ Med Ctr, Ctr Mol Med, Dept Genet, Utrecht, Netherlands
Judith Jans - Univ Med Ctr, Ctr Mol Med, Dept Genet, Utrecht, Netherlands
David A. Koolen - Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, Nijmegen, Netherlands
Erik-jan Kamsteeg - Genome Diagnost Nijmegen, Nijmegen, Netherlands
Britt Drogemoller - British Columbia Childrens Hosp, Res Inst, Vancouver, BC, Canada
Colin J. Ross - British Columbia Childrens Hosp, Res Inst, Vancouver, BC, Canada
Jacek Majewski - McGill Univ, Montreal, PQ, Canada
Megan T. Cho - GeneDx Inc, Gaithersburg, MD USA
Amber Begtrup - GeneDx Inc, Gaithersburg, MD USA
Wyeth W. Wasserman - British Columbia Childrens Hosp, Res Inst, Vancouver, BC, Canada
Tuan Bui - Univ Ottawa, Dept Biol, Ottawa, ON, Canada
Elise Brimble - Stanford Med, Dept Neurol & Neurol Sci, Stanford, CA USA
Sara Violante - Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
Sander M. Houten - Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
Ron A. Wevers - United Metab Dis, Amsterdam, Netherlands
Martijn van Faassen - Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands
Ido P. Kema - Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands
Nathalie Lepage - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Matthew A. Lines - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
David A. Dyment - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Ronald J. A. Wanders - Univ Amsterdam, Med Ctr, Lab Genet Metab Dis, Dept Pediat & Clin Chem,Lab Div, Amsterdam, Netherlands
Nanda Verhoeven-Duif - Univ Med Ctr, Ctr Mol Med, Dept Genet, Utrecht, Netherlands
Marc Ekker - Univ Ottawa, Dept Biol, Ottawa, ON, Canada
Kym M. Boycott - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Jan M. Friedman - University of British Columbia
Izabella A. Pena - Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
Clara D. M. van Karnebeek - British Columbia Childrens Hosp, Res Inst, Vancouver, BC, Canada
Care4Rare Canada Consortium
Détails de publication: Brain (London, England : 1878), Vol.142(3), pp.542-559
Éditeur: Oxford Univ Press
Nombre de pages: 18
Note de subvention: Natural Sciences and Engineering Research Council RTI grant Genome Canada Care4Rare Canada Consortium Al Awael Overseas Company LLC, Oman 111S217 / TUBITAK from Turkey; Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) Metakids Foundation CIHR; Canadian Institutes of Health Research (CIHR) CHEO Foundation Canadian Rare Diseases Models and Mechanism Network Ontario Research Fund
Identifiants: 99160607409311
Unité académique: Institut des Sciences de l'Evolution - Montpellier - ISEM
Langue: English
Type de ressource: Journal article