Abstract
Tyrosinemia type 1 (TT1) treatment with 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) and a phenylalanine-tyrosine restricted diet is associated with low phenylalanine concentrations. Phenylalanine supplementation is prescribed without comprehensive consideration about its effect on metabolic control. We investigated the effect of phenylalanine supplementation on bloodspot phenylalanine, tyrosine, NTBC and succinylacetone. Eleven TT1 patients received 0, 20 and 40 mg/kg/day phenylalanine supplementation with the phenylalanine-tyrosine free L-amino acid supplements. Bloodspots were collected before breakfast, midday and evening meal. Differences between study periods, sample times and days within a study period were studied using (generalized) linear mixed model analyses. Twenty and 40 mg/kg/day phenylalanine supplementation prevented daytime phenylalanine decreases (p = 0.05) and most low phenylalanine concentrations, while tyrosine concentrations increased (p < 0.001). Furthermore, NTBC and succinylacetone concentrations did not differ between study periods. To conclude, 20 mg/kg/day phenylalanine supplementation can prevent most low phenylalanine concentrations without increasing tyrosine to concentrations above the target range or influencing NTBC and succinylacetone concentrations, while 40 mg/kg/day increased tyrosine concentrations to values above the targeted range. Additionally, this study showed that the effect of phenylalanine supplementation, and a possible phenylalanine deficiency, should be assessed using pre-midday meal blood samples that could be combined with an overnight fasted sample when in doubt.
Highlights
Tyrosinemia type 1 (TT1; McKusick 276700) is a rare, autosomal recessive disorder of tyrosine metabolism caused by a deficiency of fumarylacetoacetate hydrolase, the last enzyme of the tyrosine degradation pathway
Patients were asked to document possible symptoms associated with phenylalanine supplementation
To further study a possible association between the occurrence of SA > 0.1 μmol/L and both blood tyrosine and NTBC concentrations, generalized linear mixed model analyses were performed. These analyses showed that blood tyrosine concentrations were not significantly correlated to the occurrence of SA > 0.1 μmol/L (p = 0.134), while blood NTBC concentrations were negatively correlated to the occurrence of SA > 0.1 μmol/L (p < 0.001)
Summary
Tyrosinemia type 1 (TT1; McKusick 276700) is a rare, autosomal recessive disorder of tyrosine metabolism caused by a deficiency of fumarylacetoacetate hydrolase, the last enzyme of the tyrosine degradation pathway (incidence 1:100.000). Without treatment, this deficiency results in the accumulation of toxic metabolites prior to the enzyme defect, such as maleylacetoacetate, fumarylacetoacetate, succinylacetoacetate and succinylacetone (SA), causing acute liver failure, hepatocellular carcinoma (HCC), renal tubulopathy, and porphyria-like-syndrome with neuropathy [1]. Due to the metabolic block caused by NTBC, tyrosine levels increased, and so a phenylalanine-tyrosine restricted diet remained necessary [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
