Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights. 3066 73

Introduction: Vitamin B6 dependent epilepsies are a group of treatable diseases (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinaemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects) responding to pyridoxine or pyridoxal-5I-phosphate. Areas covered: A critical review was conducted on the therapeutic management of all the reported patients with genetically confirmed diagnoses of diseases affecting vitamin B6 metabolism and presenting with pyridoxine or pyridoxal-5I-phosphate dependent-seizures. Data about safety and efficacy were analyzed as well as the management of supplementation with pyridoxine or pyridoxal-5I-phosphate both in the acute phases and in the maintenance therapies. The authors also analyzed alternative therapeutic strategies for ALDH7A1 deficiency (lysine-restricted diet, arginine supplementation, oligonucleotide antisense therapy, upstream inhibition of aminoadipic semialdehyde synthase). Expert opinion: The administration of pyridoxine or pyridoxal-5I-phosphate should be considered in all intractable seizures also beyond the first year of life. Lysine restricted diet and arginine supplementation should be introduced in all the confirmed ALDH7A1 deficient patients. Pre or post-natal supplementation with pyridoxine should be given in familial cases until an eventual molecular genetic disconfirmation. Minor data about alternative therapies are available for other disorders of vitamin B6 metabolism.
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PMID:Update on the treatment of vitamin B6 dependent epilepsies. 3134 Jun 80


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