The Brain and Neuropsychological Functioning in Adults With Sapropterin Dihydrochloride Treated Phenylketonuria
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|ClinicalTrials.gov Identifier: NCT02297347|
Recruitment Status : Completed
First Posted : November 21, 2014
Last Update Posted : February 5, 2018
|Condition or disease|
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.
|Study Type :||Observational|
|Actual Enrollment :||10 participants|
|Official Title:||The Brain, Neurological Features and Neuropsychological Functioning in Adults With Sapropterin Dihydrochloride Treated Phenylketonuria|
|Study Start Date :||April 2015|
|Actual Primary Completion Date :||April 2017|
|Actual Study Completion Date :||April 2017|
- Phenylalanine (phe) level in the brain as determined by MR Spectroscopy [ Time Frame: one day ]Brain phe described as umol/L through MR Spectroscopy in both the , posterior cingulate gyrus (PCG) and parietal white matter (PWM)
- Full Scale IQ [ Time Frame: one day ]Full Scale IQ is obtained from the Wechsler Abbreviated Scale of Intelligence
- Brain tyrosine (tyr) level as determined by MR Spectroscopy [ Time Frame: one day ]Brain tyr described as umol/L through MR Spectroscopy in both the , posterior cingulate gyrus (PCG) and parietal white matter (PWM)
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02297347
|United States, Massachusetts|
|Boston Children's Hospital|
|Boston, Massachusetts, United States, 02115|
|Principal Investigator:||Susan E. Waisbren, PhD||Boston Children's Hospital|