Dataset Information

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

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.

SUBMITTER: Johnstone DL

PROVIDER: S-EPMC6391652 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Johnstone Devon L DL Al-Shekaili Hilal H HH Tarailo-Graovac Maja M Wolf Nicole I NI Ivy Autumn S AS Demarest Scott S Roussel Yann Y Ciapaite Jolita J van Roermund Carlo W T CWT Kernohan Kristin D KD Kosuta Ceres C Ban Kevin K Ito Yoko Y McBride Skye S Al-Thihli Khalid K Abdelrahim Rana A RA Koul Roshan R Al Futaisi Amna A Haaxma Charlotte A CA Olson Heather H Sigurdardottir Laufey Yr LY Arnold Georgianne L GL Gerkes Erica H EH Boon M M Heiner-Fokkema M Rebecca MR Noble Sandra S Bosma Marjolein M Jans Judith J Koolen David A DA Kamsteeg Erik-Jan EJ Drögemöller Britt B Ross Colin J CJ Majewski Jacek J Cho Megan T MT Begtrup Amber A Wasserman Wyeth W WW Bui Tuan T Brimble Elise E Violante Sara S Houten Sander M SM Wevers Ron A RA van Faassen Martijn M Kema Ido P IP Lepage Nathalie N Lines Matthew A MA Dyment David A DA Wanders Ronald J A RJA Verhoeven-Duif Nanda N Ekker Marc M Boycott Kym M KM Friedman Jan M JM Pena Izabella A IA van Karnebeek Clara D M CDM

Brain : a journal of neurology 20190301 3

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 (t ...[more]

PMID: 30668673

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

Publications

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

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