Journal
BRAIN
Volume 142, Issue -, Pages 542-559Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awy346
Keywords
PLPBP; PROSC; epilepsy; pyridoxine; vitamin B6-responsive epilepsy
Categories
Funding
- B.C. Children's Hospital Foundation
- Genome British Columbia [SOF-195]
- BC Clinical Genomics Network (Michael Smith Foundation for Health Research) [00032]
- Canadian Institutes of Health Research (CIHR) [301221]
- Rare Diseases Foundation
- Canadian Rare Diseases Models and Mechanism Network
- Care4Rare Canada Consortium
- Genome Canada
- CIHR
- Ontario Genomics
- Ontario Research Fund
- CHEO Foundation
- National Ataxia Foundation
- Physicians' Services Inc. (PSI) Foundation
- Genome British Columbia
- Genome Canada (ABC4DE Project)
- Natural Sciences and Engineering Research Council RTI grant
- Vanier Canada Graduate Scholarship
- CIHR postdoctoral fellowship award
- CIHR Foundation grant [FDN-154279]
- Ministry of Higher Education, Oman
- Al Awael Overseas Company LLC, Oman
- TUBITAK from Turkey [111S217]
- Michael Smith Foundation for Health Foundation Research Scholar Award
- Metakids Foundation
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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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