MRI Spectroscopy and Neuropsychological Functioning in Phenylketonuria

Despite newborn screening and early initiation of treatment, many adolescents and adults with
PKU experience some degree of neuropsychological dysfunction or mood disturbances. Blood
phenylalanine (Phe) levels and low levels of tyrosine (Tyr) only partially explain why some
individuals with PKU have these difficulties and others do not. In this study, the
investigators will use a new approach involving magnetic resonance imaging (MRI) and magnetic
resonance spectroscopy (MRS) for measuring brain Phe (and other brain chemicals) in order to
determine relationships between brain biomarkers and neuropsychological functioning and mood.
Previously, brain Phe and Tyr could not be reliably measured by MRS methods, especially in
concentrations likely to be found in individuals with treated PKU. This project will use an
improved method for measuring brain Phe and Tyr. The investigators will use two-dimensional
shift correlated magnetic resonance spectroscopy (COSY). COSY is a non-invasive method that
allows for quantitative measurement of Phe, Tyr and other amino acids in the brain. This
project has the potential to close one of the most important gaps in the knowledge of PKU,
namely to define how PKU affects the brain. The aims of this study are to examine brain Phe
and Tyr in individuals with PKU and in an age-matched healthy comparison group, and 2)
determine the association of Phe and Tyr in distinct brain regions with measures of
neuropsychological functioning and mood. Participants with PKU will receive 2 MRI scans with
spectroscopy and the comparison group will receive 1 MRI scan with spectroscopy under fasting
conditions. All participants will provide a blood specimen for blood amino acid
determinations and will receive neuropsychological testing. The investigators will develop
statistical models that can be applied in future studies to enhance understanding of PKU.
This pilot study is important because it will provide evidence of the usefulness of COSY.
COSY has the potential to explain individual differences in PKU, identify specific cognitive
functions or mood disturbances related to high brain Phe or low brain Tyr, and offer an
additional marker or endpoint for evaluating new treatments in clinical trials.

Inclusion Criteria:

1. Age 12-25 years

2. Not currently participating in a clinical trial

3. Capable of providing informed assent/consent

4. Able to undergo MRI procedures without sedation

5. Does not have metal implants (braces or permanent retainers made of MRI-compatible
materials are permitted since we will not be doing procedures, such as DTI, affected
by non-ferrous metals).

6. PKU Group: identified by newborn screening; received treatment within the first 30
days of life

7. PKU Group: Pre-treatment/off-diet blood Phe concentration at or above 600 umol/L

Exclusion Criteria:

1. Older than 25 years or younger than 12 years of age.

2. Currently participating in a clinical trial

3. Incapable of providing informed assent/consent

4. Pregnant women will be excluded

5. Not able to tolerate MRI procedures without sedation

6. Has metal implants or braces on teeth not compatible with MRI

7. Has any known contraindication for MRI

8. PKU Group: Pre-treatment/off-diet blood Phe concentration below 600 umol/L)

9. PKU Group: Not identified through newborn screening or treatment was initiated after
30 days of life