Sapropterin in Individuals With Phenylketonuria
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Study type: Observational

Summary: 
      Investigators at Washington University will examine the effects of sapropterin (Kuvan) on
      brain and cognition in individuals with phenylketonuria (PKU) using neuropsychological and
      neuroimaging procedures. Sapropterin is a medication developed by BioMarin Pharmaceutical
      Inc. that is approved by the FDA for treatment of patients with PKU to reduce phenylalanine
      (Phe) levels. Patients beginning treatment with sapropterin as standard clinical care will be
      enrolled in the study. As a first step, patients with PKU will receive baseline
      neuropsychological and neuroimaging evaluations 1 day prior to beginning treatment with
      sapropterin. Screening for response to sapropterin will occur over 4 weeks. At the end of 4
      weeks, response to sapropterin will be reviewed. Patients with a reduction of ≥ 20% in blood
      Phe (i.e., responders) will receive follow-up neuropsychological and neuroimaging evaluations
      after 6 months of treatment with sapropterin. Patients (both responders and nonresponders)
      will receive long-term follow-up neuropsychological and neuroimaging evaluations 3 to 5 years
      after initial enrollment in the study.

      The focus of neuropsychological testing will be executive abilities, as these abilities are
      particularly susceptible to disruption in individuals with PKU. We hypothesize that
      improvements in these abilities will occur following treatment with sapropterin. For
      neuroimaging assessments, structural magnetic resonance imaging (MRI) will permit evaluation
      of changes in the structure and volume of the gray and white matter of the brain, whereas
      diffusion tensor imaging (DTI) will permit evaluation of microstructural white matter
      integrity.
    

Detailed description: 
      Investigators at Washington University will examine the effects of sapropterin (Kuvan) on
      brain and cognition in individuals with phenylketonuria (PKU) using neuropsychological and
      neuroimaging procedures. Sapropterin is a medication developed by BioMarin Pharmaceutical
      Inc. that is approved by the FDA for treatment of patients with PKU to reduce phenylalanine
      (Phe) levels. Patients beginning treatment with sapropterin as standard clinical care will be
      enrolled. As a first step, patients with PKU who are ≥ 6 years of age will receive baseline
      neuropsychological and neuroimaging evaluations 1 day prior to beginning their treatment with
      sapropterin. Screening for response to sapropterin (20mg/kg/day) will then occur over 4 weeks
      as standard care for enrolled patients. At the end of 4 weeks, response to sapropterin will
      be reviewed. Patients with a reduction of ≥ 20% in blood Phe (i.e., responders) will receive
      follow-up neuropsychological and neuroimaging evaluations after 6 months of treatment with
      sapropterin. Patients (both responders and nonresponders) will receive long-term follow-up
      neuropsychological and neuroimaging evaluations 3 to 5 years after initial enrollment in the
      study.

      A matched control group of healthy individuals without PKU will receive baseline and
      follow-up neuropsychological and neuroimaging evaluations for comparison purposes and to
      control for possible practice effects in repeated neuropsychological testing.

      The focus of neuropsychological testing will be executive abilities, as these abilities are
      particularly susceptible to disruption in individuals with PKU. Specifically, the focus of
      neuropsychological assessment will be working memory, strategic processing, and inhibitory
      control, as our research group has shown that each of these executive abilities is impaired
      in individuals with PKU. (White, D. 2001 Neuropsychol.)(White, D. 2002 J. Int. Neuropsychol.
      Soc.)(Christ, S. 2006 Dev. Neuropsychol.) We hypothesize that improvements in these abilities
      will occur following treatment with sapropterin.

      For neuroimaging assessments, both structural magnetic resonance imaging (MRI) and diffusion
      tensor imaging (DTI; mean diffusivity and fractional anisotropy) will be used. Structural MRI
      will permit evaluation of changes in the structure and volume of the gray and white matter of
      the brain. DTI will permit evaluation of microstructural white matter integrity. Brain
      abnormalities have been noted in individuals with PKU, and using DTI our research group
      recently identified abnormalities in the integrity of white matter in early and continuously
      treated individuals with PKU.

      The primary objectives of the proposed study are two-fold. First, we will determine whether
      cognition (particularly executive abilities) improves in patients with PKU who have been
      treated with sapropterin. Second, we will determine whether the integrity of the brain
      improves in patients with PKU who have been treated with sapropterin. In addition, the
      interrelationships between changes in cognition and brain will be examined.
    

Intervention name(s): Sapropterin (Kuvan)
Intervention type(s): Drug
Intervention description(s): 20mg/kg/day taken once daily or as otherwise prescribed by physician as standard care.
Other intervention name(s): Kuvan
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Primary care clinic for phenylketonuria. St. Louis community for control.
      
Keywords: phenylketonuria; sapropterin; Kuvan; cognition; executive abilities; brain