Tetrahydrobiopterin in phenylketonuria:Who can benefit?

Abstract

Phenylketonuria, abbreviated PKU, is a rare inherited metabolic disease. In this disease, a building block of protein (an amino acid) called phenylalanine cannot be converted to tyrosine. This results in high phenylalanine concentrations in blood and brain. If left untreated, this especially results in severe developmental delay as well as epilepsy and behavioral problems. Lifelong treatment consists of a strict low protein diet, supplemented with an amino acid mixture not containing phenylalanine. Although the diet is very effective, it leads to a lot of social restrictions and is considered a great burden.Research looking at other treatment options has shown that several PKU patients benefit from treatment with BH4 (in full: tetrahydrobiopterin). In some patients, the medicine BH4 stimulates the conversion of phenylalanine to tyrosine. In this thesis I looked at methods to use to select those patients who benefit the most from treatment and also at the effects of BH4 on the brain.The results reported in this thesis show that using a BH4 loading test during at least 48 hours is preferential to only 24 hours (as was used a lot in the past), as otherwise some patients are falsely regarded as non-responders. Also, we concluded that patients with so called null-mutations (gene aberrations resulting in zero phenylalanine conversion) are no candidates for BH4 treatment. Finally, we conclude that BH4 possibly has an effect on the brain via influence on signal molecules (neurotransmitters). Although, a direct association is not yet shown