Phenylketonurias
Conditions
Brief summary
The goal of the proposed study is to elucidate neurologic and neuropsychological improvements associated with Palynziq-related reduction in plasma Phe levels in individuals with PKU. To this end, investigators will utilize state-of-the-art neuropsychological and multi-modal neuroimaging methods to examine the effects of large Phe level reduction (levels \<360 μmol/L for at least 3 consecutive months) on GM and WM brain structures, brain concentrations of Phe, functionality of brain networks, and associated cognitive functioning in a sample of individuals with PKU who are being treated with Palyzniq.
Detailed description
Past studies have documented PKU-related disruptions in brain phenylalanine (Phe) levels, white matter (WM) and gray matter (GM) brain structures, functional connectivity, and neurocognitive functioning. Additional research suggests that the disruptive effects of excessive blood Phe levels likely contribute to these abnormalities, and treatment aimed at lower Phe levels may lead to significant improvements. Within this context, the primary aim is to test the hypotheses that Palynziq-related reductions in blood Phe levels will be associated with: 1. A decrease in brain Phe levels as measured by magnetic resonance spectroscopy (MRS). 2. A decrease in the extent and severity of WM abnormalities as evidenced by increased mean diffusivity values - a measure of microstructural WM integrity that is derived via diffusion-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). 3. Closer-to-normal volumetric measurements for GM structures. Nature of this effect will be dependent on structure. For example, PKU is associated with increased volume in basal ganglia but decreased volume in posterior cortex and cerebellum (Aldridge et al., 2020; Bodner et al., 2012; Christ et al., 2016). 4. An increase in functional connectivity within the brain's functional networks as measured by resting state functional MRI (fMRI). 5. Improved performance on neurocognitive tests of executive function, attention, processing speed, and motor control. To accomplish this aim, a total sample of up to 13 adults with PKU who have previously completed baseline (pre-Palnyziq) neurocognitive and neuroimaging evaluations will be recruited from the two sites (University of Missouri, Boston Children's Hospital). Participants will be reassessed following a significant and prolonged Phe response to Palynziq (as reflected by at least 3 consecutive months of Phe levels below 360 μmol/L).
Interventions
DRUGPegvaliase-Pqpz
Participants will have been prescribed pegvaliase-pqpz (Palynziq) by their primary metabolic care providers as part of their standard care. \[Note that prescription and standard care are independent of the present study.\]
Sponsors
BioMarin Pharmaceutical
University of Missouri-Columbia
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-55 years * Participants identified by newborn screening with PKU as evidenced by a blood Phe level ≥ 360μmol/L; received treatment within the first 30 days of life * Previously received a neuropsychological and neuroimaging evaluation (as part of previously described MU or BCH studies) prior to enrollment in the present study (while Palynziq-naïve). * Capable of providing informed consent * Presently being treated with Palynziq and has demonstrated a prolonged Phe response to Palynziq (as reflected by at least 3 consecutive months of Phe levels below 360 μmol/L)
Exclusion criteria
* History of major neurologic disorder unrelated to PKU * Contraindications for safe MRI participation such as (a) pregnancy or plans to become pregnant during period of study enrollment; or (b) metallic objects inside the body (e.g., surgical staples left in the body following surgery, middle ear prosthesis, metal foreign objects lodged inside the eye, heart pacemakers). * Current participation in an interventional clinical trial (not Palynziq-related).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurologic Integrity | Single timepoint for 1 hour | Brain phenylalanine (Phe) levels, white matter integrity, gray matter integrity, functional connectivity as measured using magnetic resonance imaging (MRI) |
| Neuropsychological Functioning | Single timepoint for 2 hours | Neuropsychological functioning as assessed using a comprehensive battery of standardized neuropsychological tests |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cookie Theft Picture Test | Single timepoint for 10 minutes | Verbal linguistics as assessed using the Cookie Theft Picture Test from the Boston Diagnostic Aphasia Exam |
| In-the-moment Psychoemotional Symptomatology | 30 minutes total per day for 7 consecutive days | Cell phone-based ecological momentary assessment (EMA) to measure in-the-moment psychoemotional symptomatology |
Countries
United States
Outcome results
None listed