Phenylketonuria Clinical Trial
Official title:
Biological Variation of Phenylalanine in Patients With Hyperphenylalaninemia
Phenylketonuria (PKU) is a rare disease where the level of phenylalanine (one of the amino
acids) in the body is greatly increased. High levels can cause brain damage, especially in
babies and children. This brain damage can be prevented if a special low phenylalanine diet
is started soon after birth. A new drug, sapropterin, can also lower phenylalanine levels in
some patients. PKU therapy is monitored by measuring the blood phenylalanine every week,
with the goal to keep the level within a target range. Recently, studies have suggested that
the variation in the blood phenylalanine may be just as important as the absolute blood
phenylalanine level for brain outcome.
The investigators will look at the variation in blood phenylalanine level over 24 hours to
see how much the level changes. The investigators will measure this in patients with typical
PKU who are compliant with the diet and in patients who are not compliant with the diet. The
investigators will also measure this in patients with "mild" PKU who do not usually have as
high levels of phenylalanine. Finally, the investigators will see if patients on sapropterin
have lower variation.
Phenylketonuria (OMIM 261600) results from the inherited deficiency of the enzyme
phenylalanine hydroxylase, (PAH, Enzyme Classification 1.14.16.1). A deficiency of this
enzyme leads to elevated blood and tissue levels of the amino acid phenylalanine upon
exposure to normal amounts of dietary protein. The elevated phenylalanine in the brain is
harmful to cognitive development, usually resulting in permanent severe mental retardation.
Soon after the development of a special dietary treatment for PKU and of a simple screening
test to detect elevated phenylalanine, newborn screening for PKU became widespread and early
detection and treatment largely prevented the severe neurological effects of PKU.
With population-based detection of hyperphenylalaninemia, it soon became apparent that there
was significant biological variation of phenylalanine levels between patients (i.e.
inter-individual biological variation) with phenylketonuria (PKU) and this now forms part of
the classification system for hyperphenylalaninemia (i.e. benign hyperphenylalaninemia,
mild, moderate or classical phenylketonuria). While variations of the classification system
exist, most commonly "classical" PKU refers to individuals with plasma phenylalanine levels
greater than 1200 µmol/L on an unrestricted diet. "Moderate" PKU refers to levels between
900 and 1200 µmol/L, while "mild" PKU refers to levels between 600 and 900 µmol/L. "Non-PKU"
or "benign" hyperphenylalaninemia refers to phenylalanine levels less than 600 µmol/L on an
unrestricted diet, that while greater than normal phenylalanine levels (< 100 µmol/L),
historically have not been prescribed dietary restriction of phenylalanine. This
inter-individual variation is generally due to variable residual enzyme activity and
genotype in PKU patients.
Intra-individual variation (the changes of phenylalanine levels in one individual) has been
observed by all clinicians who treat PKU. While some of this variation is simply the
expression of the underlying genotype when a patient's dietary phenylalanine level exceeds
prescribed amounts (i.e. "cheating" on their diet), other variation represents shifts from
anabolic to catabolic states in a diurnal pattern or during intercurrent illness. While
overall exposure to high phenylalanine has long been known to adversely affect IQ scores,
recently increased variability in phenylalanine levels has been reported to be linked to
lower IQ, highlighting the importance of improving our understanding of intra-individual
variation.
New treatments for PKU, therefore, need to be assessed in terms of their effect on
biological variation of phenylalanine. Sapropterin dihydrochloride (KuvanTM) is a small
molecule drug that can lower phenylalanine levels in patients with phenylalanine hydroxylase
deficiency by a direct interaction with the enzyme . The pharmacokinetics of KuvanTM have
been evaluated in adults and are undergoing evaluation in pediatric patients, however, the
biological effect of KuvanTM in terms of lowering of blood phenylalanine levels would be
expected to have a longer profile than the blood levels of the drug itself because the
half-life of the activated enzyme would be longer. This suggests that KuvanTM may have a
modulating effect on variation of blood phenylalanine levels in PKU patients.
In this observational study, the investigators will directly measure the short-term
biological variation of blood phenylalanine in hyperphenylalaninemic patients by frequent
measurements of phenylalanine levels over a 24 hour period. The investigators will enroll
subjects already followed at one of the two study sites who are treated by diet alone or who
are treated with KuvanTM therapy (+/- diet). During the 24 hour period subjects will be
asked to maintain their typical diet/therapy.
Hypothesis: Biological variation will be less in KuvanTM treated patients than in classical
phenylketonuria treated by diet alone.
OBJECTIVES:
Determine short-term biologic variation in people with hyperphenylalaninemia, with and
without KuvanTM therapy.
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Observational Model: Case Control, Time Perspective: Prospective
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