Grant: Project Grant

Pyridoxine-dependent epilepsy (PDE) is a rare genetic form of epilepsy or seizure disorder that is also associated with abnormal brain development. PDE is caused by alterations (or mutations) in the antiquitin gene. These mutations lead to accumulation of toxic chemical compounds in the brain. PDE is characterized by recurrent fits or seizures that begin around the time of birth and are resistant to conventional seizure medications (anticonvulsant treatments), but show remarkable response to the administration of vitamin B6 or pyridoxine. The seizures usually begin again when pyridoxine is stopped either incidentally or for diagnostic purposes. Most PDE patients suffer also from developmental delay and moderate to severe intellectual disability along with variety of structural brain abnormalities. Progress in the development of effective treatments for PDE has been hampered by a lack of understanding of how the genetic mutation causes the brain disease and also by the absence of an appropriate animal model. We created a mouse model for PDE to fill the knowledge gaps about disease biology, and to use as a disease model in which we can test new treatments that can eventually be brought to human patients. The research plan of this project will be divided to three parts. In the first part, we will study the PDE mouse model for the presence of various disease symptoms such as seizures and cognitive disturbances a well as testing the presence of disease-associated chemical compounds in blood and brain tissue. In the second part, we will examine the effects of selective loss of the antiquitin gene in specific types of brain cells or selective loss at a specific ages. The third part of the project will be dedicated to treatment trials to improve the disease symptoms in these PDE mice. These will include manipulation of diet and administration of drugs that will minimize the toxic chemical compounds.