Phenylketonuria: dopamine transmission and relationship with phenylalanine levels and cognitive performance in adults * a pilot study

Phenylketonuria (PKU; OMIM 261600), a relatively rare genetic metabolic
disorder characterized by the inability to convert the essential amino acid
phenylalanine (Phe) to tyrosine (Tyr), leads to severe intellectual disability
and neurological complications if untreated. Since 1974, PKU is most commonly
diagnosed on routine screening of newborns. Restriction of dietary Phe intake
very soon after birth until adulthood prevents most of the neuropsychological
complications, but early-treated subjects still experience significant
neurocognitive sequelae. The outcome of treatment is generally evaluated with
assessments of blood Phe and Tyr levels. Nevertheless, the target levels in
adulthood are unclear and these measurements may not be the best predictors for
optimal cognitive outcome. It may be hypothesized that individual variations in
the kinetics of amino acid uptake and distribution at the blood-brain barrier
are relevant for cognitive variations.
It is believed that as a result of low cerebral availability of Tyr, decreased
biosynthesis and subsequently hypofunction of the neurotransmitter dopamine
(DA) is responsible for cognitive deficits in early-treated adults with PKU.
However, the exact role of DA (hypo)function in cognitive performance and the
effects of treatment have yet to be elucidated. New therapies, including
supplementation of an essential cofactor or alternative amino acid formulas to
the conventional diet, and enzyme substitution are under investigation. To
investigate long-term outcome and clinical variability and to evaluate new
therapies there is a need for a method to study effects in brain, like DA
function.
In this pilot study, we will investigate whether postsynaptic DA receptor
binding (D2R BPND, reflecting synaptic DA concentrations) measured with single
photon emission computed tomography (SPECT) and the radioligand [123I]IBZM and
brain Phe levels, assessed with proton magnetic resonance spectroscopy (1H
MRS), prove a complementary predictor of outcome in addition to blood Phe and
Tyr levels. Therefore, in the pilot study we will assess whether adults with
lower Phe levels have lower D2R BPND in comparison with adults with higher Phe
levels. We will also assess the relationship with cognitive performance and
with neurophysiological task perfomance (eye movement assessments).

The main purpose of the proposed naturalistic pilot study is to compare
postsynaptic DA receptor binding (reflecting synaptic DA concentrations) and
brain Phe levels in PKU adults with lower blood Phe levels with PKU adults with
higher blood Phe levels. Our study results will contribute to the knowledge on
the underlying mechanisms of cognitive deficits in PKU, specifically the
involvement of central DA (dys-)regulation. Hopefully, our methods will also
prove useful to evaluate dietary treatment and novel promising therapies, like
supplementation of an essential cofactor to the conventional diet and enzyme
substitution.

Adult PKU patients will be informed about the study and will be asked if they
are willing to participate by treating physicians. They will receive the
enclosed information letter. All consenting and eligible subjects will visit
the AMC only one day. At arrival, the full study procedure will be explained
and subjects that agree to participate will be asked to give written informed
consent.
Study subjects will be asked to provide a capillary bloodspot on the two days
prior to the study day. On the study day, a blood spot will be collected twice
and all study subjects will be cannulated in a forearm vein for blood sample
collection and infusion of the used radioligand. The postsynaptic DA receptor
binding will be measured with single photon emission computed tomography
(SPECT) and the radioligand [123I]IBZM and brain Phe levels will be assessed
with proton magnetic resonance spectroscopy (1H MRS). Neuropsychological
performance will be assessed using a shortened version of Wechsler Adult
Intelligence Scale-III and The Amsterdam Neuropsychological Tasks. Eye movement
assessments will be recorded using the double magnetic induction method
(DMI-method). Impulsivity and motor function will be assessed with the Barratt
Impulsiveness Scale-11 and a finger tapping task, respectively.

* Study protocol (time): 1 day in the AMC + time to travel. Study subjects will
be asked to provide a capillary bloodspot on the two days prior to the study
day. Daily consumption of natural protein and amino acid supplements, in
particular with regard to the intake of LNAAs, will be evaluated in a 3-day
dietary record by a dietician prior to the start of the study.
* IBZM SPECT. The proposed total dose of IBZM is within the ranges that are
allowed for medical scientific research by the World Health Organisation. In
case of an unexpected, but clinically relevant, finding the study subject will
be referred to the general physician or a medical specialist.
* MRS-/ MRI scan: In case of an unexpected, but clinically relevant, finding
the study subject will be referred to the general physician or a medical
specialist.
* Eye movement assessments: golden metallic ring attached to the subject*s eye
may be inconvenient/ unpleasant