Pyridoxine-Dependent Epilepsy (PDE)
Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder characterized by vitamin B6-responsive seizures caused by ALDH7A1 mutations. At Protheragen, we are committed to advancing the understanding and management of PDE through cutting-edge therapeutic development and disease modeling services. Our goal is to provide end-to-end solutions for the entire process from PDE therapeutic research to commercialization.
Overview of Pyridoxine-Dependent Epilepsy (PDE)
Pyridoxine-dependent epilepsy (PDE) is an extraordinary genetic illness heralded by persistent seizures which only respond to pharmacological doses of pyridoxine, also known as vitamin B6. Originally described in 1954, PDE generally presents in neonates (hours to days post-partum) or, in a less common form, as an infantile variant. In the absence of immediate intervention, individuals suffer from intractable seizures, encephalopathy, and profound neurodevelopmental impairment.
Fig.1 Lysine is metabolized through two distinct pathways usually referred to as the pipecolate and saccharopine pathways, respectively, as these are the prominent metabolites. (Coughlin C R, Gospe Jr S M., 2023)
Pathogenesis of Pyridoxine-Dependent Epilepsy (PDE)
Pyridoxine-dependent epilepsy (PDE) is primarily linked to recessive changes in the ALDH7A1 gene due to deficient antiquitin and the subsequent build-up of neurotoxic metabolites during the breakdown of lysine. These neurotoxic metabolites bind to pyridoxal phosphate (PLP, the active cofactor of vitamin B6) irreversibly and deplete it, resulting in PLP deficiency. This deficiency, in turn, impairs synthesis of GABA and glutamate. The resulting neurotransmitter imbalance causes the hyperexcitable neurons and uncontrollable seizures. In addition, the accumulation of metabolites continues to damage the developing nervous system.
Therapeutic Development for Pyridoxine-Dependent Epilepsy (PDE)
| Drug Names | Mechanism of Action | Targets | Research Phase |
| Pyridoxine | Precursor conversion to pyridoxal phosphate (PLP); restores PLP-dependent enzymatic activity in neurotransmitter synthesis | Glutamic acid decarboxylase (GAD), GABA transaminase, and other PLP-dependent enzymes | Approved |
| Pyridoxal-5'-Phosphate (PLP) | Direct administration of active cofactor bypasses metabolic conversion defects | Same PLP-dependent enzymes as pyridoxine | Approved |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers advanced diagnostic and therapeutic development services for rare epileptic syndromes such as pyridoxine-dependent epilepsy (PDE). We concentrate on designing sophisticated models for diseases to improve understanding of the PDE's pathogenesis while applying novel blood-brain barrier (BBB) models to improve the delivery and efficacy of therapeutic compounds. We strive to accelerate devising precise diagnostic kits and effective therapies tailored to PDE through our holistic methodologies.
Therapeutic Development Services
By Mechanism of Action
Disease Model Development Services
In Vitro Model Development
- Aldh7a1-knockout (KO) mouse model recapitulates key features of PDE, including α-AASA/pipecolic acid accumulation, seizure susceptibility, and pyridoxine-responsive neurological deficits, providing a validated system for investigating disease mechanisms and testing novel therapies.
- Other Models
At Protheragen, we are committed to supporting the development of innovative therapeutics through comprehensive preclinical research services, including pharmacodynamics (PD), pharmacokinetic (PK) and toxicology studies. Our customized approach addresses the unique challenges of your studies and helps you optimize your drug candidates for commercial success. If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
Reference
- Coughlin C R, Gospe Jr S M. Pyridoxine‐dependent epilepsy: Current perspectives and questions for future research[J]. Annals of the Child Neurology Society, 2023, 1(1): 24-37.