Tyrosinemia type 1: Remaining challenges after introduction of NTBC

Tyrosinemia type 1 is an inherited metabolic disorder of tyrosine metabolism. Due to an enzymatic defect, the amino acid tyrosine cannot be catabolized properly. As tyrosine is an amino acid - a building block of proteins - dietary intake of protein results in the accumulation of tyrosine associated metabolites in patients with Tyrosinemia type 1. Untreated, these metabolites cause severe liver, renal and neurological problems at a very young age. This changed after introduction of NTBC. This herbicide blocks the metabolic pathway upstream from the original enzymatic defect. Thus, by preventing the accumulation of toxic metabolites, NTBC diminishes the clinical problems that characterize the disease. However, several challenges still remain and some of these challenges are addressed in this thesis.
Firstly, despite treatment with NTBC, patients still have an increased risk for developing liver cancer. This risk can be reduced by early and continuous treatment with NTBC and diet, stressing the importance of neonatal screening and adequate treatment monitoring afterwards. The second challenge concerns the neuropsychological problems that have recently been reported. Our research showed a non-optimal neuropsychological and behavioural functioning, which was most likely associated with metabolic control (high tyrosine and low phenylalanine concentrations). Because of the possible association between metabolic control and cognitive-behavioural outcome, monitoring and improving metabolic control is of utmost importance and therefore the third investigated challenge. We showed that phenylalanine concentrations could be improved with supplementation and that metabolic control can be assessed at home as long as bloodsampling is done at the right hour.