VCU researchers study the molecular basis of neonatal epileptic encephalopathy caused by a genetic defect in pyridoxine 5’-phosphate oxidase

By Sathya Achia Abraham

A team of Virginia Commonwealth University researchers is studying a rare genetic condition that causes seizures in infants to determine the molecular players involved in the devastating disease.

Led by Martin K. Safo, Ph.D., assistant professor in the Department of Medicinal Chemistry at VCU, the team hopes its work will pave the way for researchers to develop drugs that can target neonatal epileptic encephalopathy – a condition that is often fatal and has no cure.

Infants born with neonatal epileptic encephalopathy have a genetic defect in a key enzyme known as pyridoxine 5’-phosphate oxidase, or PNPOx, and are not able to produce pyridoxal 5’-phosphate, or PLP, the active form of vitamin B6. PLP is needed by more than 140 PLP-dependent enzymes for their biological activities, including, but not limited to glucose, amino acid, homocysteine and lipid metabolism, heme and DNA/RNA synthesis, and neurotransmitter production.

PNPOx and PLK are the two key enzymes that metabolize the nutritional forms of vitamin B6 - including pyridoxine, pyridoxamine, and pyridoxal - into the active co-factor form, PLP. Several mutations in PNPOx and PLK are known to lead to vitamin B6 deficiency.

According to Safo, a deficiency of PLP due to pathogenic mutations in PNPOx and PLK is also suspected in several other disorders, including autism, Down syndrome, Alzheimer’s, Parkinson’s, heart diseases, schizophrenia, immune disorders, seizures, attention deficit hyperactive disorder, learning disability and anxiety disorders.

In a study published in the Nov. 6 issue of The Journal of Biological Chemistry, Safo and a VCU research team, together with investigators from the University of Rome in Italy, report that they have found that the mutation in PNPOx that causes the enzyme to lose riboflavin easily, which may explain the inability of the enzyme to make PLP. Riboflavin is better known as vitamin B2 and is needed by PNPOx for its catalytic activity.

“Our studies provide the first clear insight regarding how natural mutations in PNPOx and PLK affect vitamin B6 metabolism, and may also provide avenues for nutritional or pharmacologic intervention to combat mutational-related vitamin B6 deficiency diseases,” explained Safo.

“Additionally, our findings give an impetus to screen patients afflicted with the above diseases who also exhibit PLP deficiency for possible mutations in PLK or PNPOx,” he added.

Safo said that the team plans to continue to build on this research. They are investigating other mutations in PNPOx and PLK that also affect the enzymatic activities leading to PLP deficiency. In addition the investigators are looking at how PLP is regulated in the cell, as well as transferred to dozens of PLP-dependent enzymes.
This work was supported by grants from AD Williams Fund, the Jeffress Research Grant Award.