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

Care4Rare Canada Consortium, 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 HaaxmaHeather 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 Drögemöller, 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

OnderzoeksoutputAcademicpeer review

41 Citaten (Scopus)


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.

Originele taal-2English
Pagina's (van-tot)542-559
Aantal pagina's18
StatusPublished - mrt.-2019

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