Pyridoxal phosphate (PLP) and epilepsy. (360G-Wellcome-080927_Z_06_Z)

The aim of the project is to develop and apply methods for:-i) determination of the six B6 vitamers and pyridoxic acid in body fluids; ii) determination of the activity of enzymes that affect pyridoxal phosphate homeostasis; iii) sequencing and expression of the corresponding genes; iv) determination of the activity of PLP-dependent enzymes involved in the metabolism of neurotransmitters and neuromodulators and analysis of the corresponding genes. These, and methods already developed, will be u sed to examine 5 hypotheses: a) atypical pyridoxine-dependent seizures can be caused by mutations in the ALDH7A1 gene; b) epilepsy with progressive spastic paraparesis and hyperlysinaemia can be caused by mutations in the U26 gene; c) infants with a CSF profile suggestive of PLP deficiency but no response to PLP therapy have mutations in the pyridoxal kinase gene; d) some patients with seizures and high CSF threonine (but no other signs of PLP deficiency) have mutations in the PLP-dependent seri ne racemase gene. Improved understanding of genetic factors involved in the control of the PLP concentration in brain cells should lead to more rational use of pyridoxine and PLP in epilepsy.