The effect of phenylalanine supplementation on metabolic control in Tyrosinemia Type 1 patients.

Hereditary Tyrosinemia Type 1 (HT1) patients usually present with liver
dysfunction and or renal tubular dysfunction with rickets early in life. After
the introduction of 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione
(NTBC), problems resolved and life expectancy greatly increased. However, due
to NTBC, which blocks the conversion of tyrosine at an earlier step, tyrosine
concentrations increase, making dietary restrictment of tyrosine and its
precursor phenylalanine necessary. Recently, some articles report low
phenylalanine concentrations in HT1, making phenylalanine supplementation
necessary despite possible conversion to tyrosine and resulting increase in
tyrosine. Next to that, previous research of us showed a strong diurnal
variation of phenylalanine, with extremely low phenylalanine concentrations
early in the afternoon. These strong diurnal variation and increase in tyrosine
concentrations make more studies on the optimal dose of phenylalanine
supplementation necessary.

The primary objective of this study is to investigate the effect of different
levels of oral phenylalanine supplementation on the blood concentration and
diurnal variation of phenylalanine and tyrosine in HT1 patients treated with
NTBC. This in order to find a particular dose of phenylalanine in which low
phenylalanine as well as high tyrosine concentrations are prevented. In
addition to this, NTBC and succinylacetone concentrations are measured in the
bloodspots to ensure complete blockade of the tyrosine degradation pathway.
Therefore, as secondary objective, blood concentrations and diurnal variation
of NTBC and succinylacetone will be investigated.

This longitudinal study will include two rounds of nutritional supplementation
of phenylalanine and has a total length of 24 days. The duration of both
rounds of phenylalanine supplementation will be five days and during these days
most bloodspot measurements will be done.
The study is open, not placebo controlled and is completely done at home. The
study is the follow-up of the study with reference number 2010/061 that
measured the day to day and daily fluctuation of the same variables without
supplementation of phenylalanine.

Patients will be treated with 2 different amounts of phenylalanine
supplementation. Phenylalanine supplementation is used in HT1 patients before,
without any side effects. Due to possible conversion of phenylalanine into
tyrosine, tyrosine concentrations can increase. However, only small amounts of
phenylalanine are given. The participating HT1 patients will perform 2 rounds
of 13 bloodspots (taken by finger prick). The total duration of the study is 24
days. No extra site visits are necessary. These patients are used to do
bloodspots at home. Therefore, no physical and physiological discomfort is
expected.