The phenylalanine eat or diet study: direct effects of high or low phenylalanine values on cognitive functioning in adults with PKU.

Children with phenylketonuria (PKU) adhere to a strict protein-restricted diet
from birth. This diet results in acceptable phenylalanine (Phe) levels (<360
µmol/l) and prevents brain damage and overt cognitive impairment. However in
adults the necessity of dietary adherence is a topic of debate. Guidelines on
dietary adherence in adulthood differ immensely. This is due to a lack of
evidence about the effect of dietary adherence on cognitive function in adults
with PKU. This lack of evidence is present because there is a lack of objective
practical methods to investigate cognitive function.
Recently, the department of neuroscience of the Erasmus MC validated a method
for the objective and quantitative assessment of visuomotor functioning using
eye-hand coordination tasks. These tests are accurate, take only 30 minutes to
perform and, in healthy subjects, show a high test*retest reliability. As
visuomotor skills are good predictor of motor development and cognitive
functioning the eye-hand coordination tasks are the ideal tests to investigate
cognitive function in phenylketonuria. We hypothesise that adult patients with
PKU will perform worse on eye-hand coordination tasks if Phe levels are high,
and that the effect of high Phe is transient.

Primary objective: To accurately assess the direct functional consequences of
high versus low phenylalanine levels in adult patients with PKU, using eye-hand
coordination testing in tasks of different cognitive complexity.
Secondary objective: To asses quality of life with the disease specific PKU-QoL
questionnaire, the generic 36-item Short Form Survey (SF-36) questionnaire and
the Hospital Anxiety and Depression Scale (HADS) during high versus low
phenylalanine levels in adult patients with PKU.

A randomized double-blinded placebo controlled cross-over trail.

All included patients will be asked to follow a strict protein restricted diet,
aiming at Phe levels of < 360 µmol/l (with supplementation of essential amino
acids) during the whole study period of 14 weeks, starting 2 weeks before the
first intervention period. Patients will be randomly assigned to one of two
groups. During the first intervention period of 4 weeks group 1 will start
taking Phe-containing capsules (0,8 times their bodyweight in kilograms times
49 mg of Phe. Rounded to multiples of 500 mg.) which they will take daily.
Group 2 will take a placebo capsules. Thereafter there will be a wash-out
period of 4 weeks, followed by a second intervention period. During the second
periods the patients that took the Phe-capsules will take placebo and visa
versa.

Patients will visit our outpatient clinic 7 times and we estimate each visit
will take approximately 90 minutes. The first visit will take 1 hour extra for
dietary advise. During each visit they will perform the eye-hand movement
tasks, complete the QoL questionnaires and plasma will be drawn to determine
Phe levels and urine will be collected. Furthermore, during the total study
period of 14 weeks Phe levels will be measured twice a week in dried blood
spots (resulting in a total number of 24 bloodspots). Patients can draw blood
for the bloodspots at home, from the finger with a small lancet. The blood is
blotted on filter paper can this paper can be given to the investigators during
the next visit. The patients know how to do this as they did this regularly
throughout childhood.
During 14 weeks the patients will have to follow a stricter protein restricted
diet than they usually do, aiming at a Phe level of <360 µmol/L. This is the
level that is aimed at during childhood, so patients have experience with the
strict diet. A dietician with experience in treating patients with PKU will
make a personalised diet plan for each patient and the patients will be able to
contact the dietician for advice throughout the study. Patients will be asked
to fill in a diet diary.
Previous studies with Phe loading have shown there was a slight effect on mood
and concentration in some patients, but that using Phe in large amounts for a
short period of time did not have major side effects in adulthood.
The benefits of participating in this study for the patient are that they get a
good insight in if and how Phe levels effect their functioning. They can
implement this knowledge into their daily life. Furthermore the results of this
study will help to create clear guidelines about dietary adherence in adult
patients with ET-PKU.