The Brain and Neuropsychological Functioning in Adults With Sapropterin Dihydrochloride Treated Phenylketonuria
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Adults with PKU on Kuvan treatment for at least one month prior to enrolling in the study.