A Pilot Study on Diurnal Variation

Phenylketonuria (PKU) is a rare genetic metabolic disease caused by a mutation that codes
for an enzyme that converts the essential amino acid phenylalanine (Phe) into tyrosine. An
absence or deficiency of this enzyme activity results in a Phe elevation, where higher Phe
levels result in neurological damage. Diurnal variations of Phe levels have been observed in
PKU patients in a 24-hour period.

As Kuvan has shown to stabilize Phe levels in PKU patients over time, our hypothesis is that
this can be demonstrated within a 24-hour period of observation and indicate therefore that
Kuvan may correlate with a lower plasma Phe variability. This study on PKU patients' diurnal
variation will also provide important information as to the current method of blood Phe
monitoring in a clinical setting to learn more about the optimal way to measure Phe
concentration.

The study will last about 4 weeks (6 study visits) for the PKU participants and about 1 week
(2 study visits) for the control group.

Participants will be required to follow a recommended diet, complete a dietary log, and
undergo several blood draws, including a 24-Hour Blood Assessment in which blood will be
obtained 8 times throughout the day.

Inclusion Criteria:

PKU PARTICIPANTS (ARM 1):

- Subject has a confirmed diagnosis of PKU with hyperphenylalaninemia documented by a
fasting Phenylalanine level of at least 360 umol/L (6 mg/dL)

- Patient is at least 4 years old (there is no upper age limit for this study)

- Willing and able to provide written authorization or, if under the age of 18 years,
provide written assent (if required) and written patient authorization by a parent or
legal guardian

- Willing to undergo study related procedures including commencing Kuvan treatment for
patient not currently on treatment; temporary discontinuation of Kuvan for patient on
treatment; and completing the 24-Hour Blood Assessment

- Authorized to provide personal health information

- Subjects should not be pregnant and willing to use appropriate birth control during
the study

CONTROL GROUP (ARM 2):

- Healthy, non-PKU individuals. They will be age-sex matched to the PKU group. They may
be a relative (ex: sibling) of a PKU participant, but they don't have to be a blood
relation.

- Individual is at least 4 years old (there is no upper age limit)

- Willing and able to provide written consent or, if under the age of 18 years, provide
written assent and written participant authorization by a parent or legal guardian

- Authorized to provide personal health information

Exclusion Criteria (BOTH ARMS):

- Subjects who do not meet all the inclusion criteria

- Age < 4 years

- Concomitant medical problems or medications which at the discretion of the principal
investigator would put participant at health risk or prevent them from completing
study.

- If female, unwillingness to use birth control during the period of the study drug
administration (this doesn't apply to Arm 2)