The Brain and Neuropsychological Functioning in Adults With Sapropterin Dihydrochloride Treated Phenylketonuria



Status:Completed
Conditions:Endocrine
Therapuetic Areas:Endocrinology
Healthy:No
Age Range:18 - 55
Updated:2/7/2018
Start Date:April 2015
End Date:April 2017

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The Brain, Neurological Features and Neuropsychological Functioning in Adults With Sapropterin Dihydrochloride Treated Phenylketonuria

Newborn screening and early treatment prevent the most severe manifestations of
phenylketonuria (PKU). However, executive functioning deficits, attention deficit disorder,
slow processing speed, and visual-motor problems commonly occur. Many adults with this
disorder also suffer depression and anxiety. In this study the investigators will examine
adults with PKU on sapropterin dihydrochloride (Kuvan) treatment for PKU and compare their
results to those of subjects with PKU not on Kuvan. Using magnetic resonance imaging (MRI)
techniques, including novel MR spectroscopy (MRS) the investigators hope to discover why this
distinct constellation of deficits occurs in PKU. Adult subjects with PKU will undergo a
comprehensive MRI evaluations, including a novel method of MR spectroscopy to determine brain
phenylalanine levels. In addition, participants will receive neurological and
neuropsychological examinations and dietary evaluation.

Phenylketonuria (PKU, OMIM 261600), an autosomal recessive disorder, affects approximately
1:11,000 individuals in the United States. In PKU, mutations in the gene responsible for the
liver enzyme phenylalanine hydroxylase (PAH) result in reduced or absent conversion of
phenylalanine (Phe) to tyrosine (Tyr) and subsequently to elevated plasma concentrations of
Phe and reduced concentrations of Tyr (Scriver and Kaufman, 2001). Untreated PKU results in
progressive, neurological decline by 6-12 months of age (Koch et al, 1971). Even with early
detection and treatment with a Phe-restricted diet, patients experience neurocognitive
deficits (Waisbren et al, 1994) and psychiatric disturbances as they get older (Brumm et al,
2010; Bilder et al, 2013; Weglage et al, 2013) as well as white matter abnormalities detected
through magnetic resonance imaging (MRI) (Mastrangelo et al, 2015).

In treated PKU, neuropsychological functioning is associated with exposure to elevated blood
phenylalanine levels (Jahja et a;. 2017; and decreased blood tyrosine (Luciana, Sullivan,
Nelson, 2001). However, the extent to which these biomarkers confer risks to cognitive and
emotional well-being varies dramatically, with some individuals experiencing serious deficits
and others functioning normally despite equally high phenylalanine or depleted tyrosine
levels in blood (Rajabi, Waisbren and Levy, 2016; Manti et al, 2017 ). One explanation is
that blood Phe and Tyr do not represent exposure in the brain (Diamond et al, 1997; Surtees
and Blau, 2000).

Previously, we reported on an improved method for measuring brain Phe and brain Tyr in PKU
(Waisbren et al, 2016) using two dimensional shift correlated magnetic resonance spectroscopy
(COSY) (Thomas et al, 2001). This allows for the unambiguous identification of cerebral
metabolites that could not be detected using conventional MRS methods due to spectral
overlap. By obtaining multiple acquisitions at different echo times, a second chemical shift
domain allows for metabolites to be identified by two chemical shifts instead of just one
based on scalar coupling of different proton groups. The concentration of the metabolite is
therefore shown in the third dimension. By visualizing the COSY data in three dimensions,
smaller resonances that would have been obscured by larger resonances can be measured (Figure
1). Different brain regions, separating white and gray matter tissue, can be assessed with
this method as a smaller voxel can be used.

In our previous study, we demonstrated that COSY could be used to quantify brain Phe and
brain Tyr in two brain regions in adults with treated PKU without the need for a
phenylalanine load. We also examined the relationship between these biomarkers and
neuropsychological functioning and found that associations were in the expected direction,
with higher brain Phe and lower brain Tyr related to poorer functioning (Waisbren et al,
2016).

The aims of the study reported here were to examine the relationships between blood and brain
concentrations of Phe and Tyr in patients on sapropterin dihydrochloride (BH4 or Kuvan) and
to assess the relationships between these biomarkers and neuropsychological functioning.

Inclusion Criteria:

- Adult with classic PKU currently on Kuvan treatment for at least one month.

- Age 18-55 years

- Medical Records available that include blood phenylalanine levels during the first 6
years of life.

- Capable of providing informed consent

- Able to undergo MRI procedures without sedating medication

- Does not have metal implants, braces, or permanent retainers.

Exclusion Criteria:

- Mild PKU or mild hyperphenylalaninemia

- Less than 18 years old or greater than 55 years old

- No medical records available for the first 6 years of life

- Not capable of providing informed consent

- Not able to undergo MRI without sedating medication

- Has metal implants, braces or permanent retainers

- Currently involved in any clinical trial
We found this trial at
1
site
300 Longwood Ave
Boston, Massachusetts 02115
(617) 355-6000
Principal Investigator: Susan E Waisbren, PhD
Phone: 617-355-7346
Boston Children's Hospital Boston Children's Hospital is a 395-bed comprehensive center for pediatric health care....
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