Effects of short term increase of phenylalanine levels
on neuropsychological functions and well-being
in adults with phenylketonuria: the *diet for life* study

Phenylketonuria (PKU; MIM 261600) is an autosomal recessive disorder of
phenylalanine (Phe) metabolism caused by a deficiency of the enzyme
phenylalanine hydroxylase (PAH; EC 1.14.16.1). Untreated PKU results in
severely retarded mental development and neurological abnormalities. Patients
with PKU are treated with a Phe-restricted diet and supplementation of all
amino acids except Phe. With the introduction of newborn screening and the
early institution of the diet, mental retardation due to PKU has been nearly
eliminated. At this moment, the most important issue in the treatment of PKU is
whether the reduction of the Phe levels, by a strict and socially invalidating
diet, is still relevant in adults. Relaxation of the diet in adolescence is
common practice and dietary guidelines for adults vary greatly between the
different countries.

To evaluate the effects of short term supplementation of Phe to levels
comparable to levels observed in adult patients who fully discontinued their
diet on neuropsychological functions and wellbeing of adult patients with PKU.

We aim to perform a double blind study with crossover design with repeated
measures.

During two periods of four weeks each, an additional supplement of aminoacids
will be added to the diets of the subjects. During one of the 4 weeks periods
the supplement will not contain any Phe or its metabolite tyrosine, but
different aminoacids. The other 4 weeks period the supplement will contain the
amount of Phe that, added to the Phe intake from the patients* own diet,
increases the daily Phe intake to a normal Phe intake for a healthy person of
that age and sex. Between the two study periods there will be a washout period
of at least 4 weeks in which the patients take their own usual diet.

Patients will visit the AMC and/or the VUMC 4 times during the study. They will
undergo neuropsychological tests (4x), a MEG scan (2x), dietary evaluation (3x)
and send in bloodspots (20x) for Phe measurements. They will complete a
questionnaire to evaluate wellbeing 8 times. For 2 periods of 4 weeks each
they will add an extra aminoacid supplement to their own supplement that they
take 3 times per day every day.
During a total of 4 weeks patients will have elevated phenylalanine levels. In
the literature a reversible decrease of neuropsychological functions has been
reported with high phenylalanine levels. In other countries, where the diet is
discontinued in adulthood, no problems have been reported. Because in many
countries the diet is relaxed in adulthood without evaluation of the possible
consequences, it is very important for the safety of the patients to evaluate
the effect of high phenylalnine levels on the functioning and the well being of
the patients. If no effects are found, a relaxation of the diet in adulthood
may be considered. If effects are detected it will be clear to the patients why
a strict diet will be necessary.