Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy (PKU)

This study has been completed.
Information provided by (Responsible Party):
Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
First received: September 28, 2009
Last updated: February 4, 2013
Last verified: February 2013

The aim of this pilot study is to determine if there are any changes in brain glucose metabolism in the gray matter of patients with Phenylketonuria (PKU) and whether administration of KUVAN (BH4) therapy can improve such deficits.

Condition Intervention
Drug: KUVAN (BH4)

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Pilot Study of FDG PET Findings in Patients With Phenylketonuria Before and After BH4 Supplementation

Resource links provided by NLM:

Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • Brain PET scan to evaluate brain glucose metabolism before and after BH4 (KUVAN) therapy [ Time Frame: 4 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Secondary endpoints will include the following: the change in blood Phe levels, the change in Phe tolerance, and the change in neurodevelopmental tests [ Time Frame: 4 months ] [ Designated as safety issue: No ]

Enrollment: 6
Study Start Date: March 2010
Study Completion Date: September 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BH4( KUVAN) Drug: KUVAN (BH4)

All subjects will receive 20 mg/kg/day KUVAN. Before and 4 months after KUVAN therapy

  • FDG-PET imaging,
  • Neuropsychological tests,
  • Blood phenylalanine levels and
  • Dietary phenylalanine tolerance will be evaluated
Other Names:
  • BH4

Detailed Description:

Phenylketonuria (PKU) is an autosomal recessive disorder resulting from a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Phenylalanine hydroxylase is one of the three aromatic amino acid hydroxylases that utilizes tetrahydrobiopterin (BH4) as cofactor. The published reports indicate that there is altered energy metabolism in the brain of patients with PKU. Phenylalanine and its metabolites appear to impair several aspects of brain energetics including: (1) Inhibition of glucose uptake; (2) diminished glycosylation of cytoskeletal proteins; (3) Inhibition of pyruvate kinase; and (4) reduced flux through the glycolysis. Studies in vivo with magnetic resonance spectroscopy have demonstrated phenylalanine-responsive abnormalities in cerebral energy metabolism.

PET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate with high resolution and absolute quantitation. To date this technology has been used only for single case reports or the investigation of white matter abnormalities in small numbers of patients with PKU.

The aim of this pilot study is to determine if there are any changes in brain glucose metabolism in the gray matter of patients with PKU and whether KUVAN (BH4) can improve such deficits. This study will also elucidate the relationship between hyperphenylalaninemia, phenylalanine intake in diet, altered brain glucose handling and the neurocognitive profile of the patients with PKU before and after KUVAN therapy.


Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Males or females over the age of 18 years
  2. Subject must be able to give independent informed consent
  3. Girls must have a negative urine pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.
  4. Subject must have a confirmed diagnosis of PKU
  5. Subjects with Phe levels over 10 mg/dL
  6. Subjects naïve to BH4 (KUVAN) therapy or has not received KUVAN in the 6 months before screening

Exclusion Criteria:

  1. Pregnancy
  2. Cognitive deficits resulting from physical trauma (e.g. subject with history of severe birth trauma).
  3. Neurologic comorbidities including a history of a stroke or a seizure disorder.
  4. Laboratory abnormalities that indicate clinically significant hepatic disease Aspartate aminotransferase (AST)> 2.0 times the upper limit of normal Alanine transaminase (ALT) > 2.0 times the upper limit of normal Prothrombin Time (PT) > 2.0 times the upper limit of normal Partial Thromboplastin Time(PTT)> 2.0 times the upper limit of normal
  5. Subjects using medications such as steroids, insulin and glucagons that may interfere with the results of PET scan.
  6. Subjects using medications that inhibit folate metabolism such as methotrexate
  7. Subjects using medications known to affect nitric oxide-mediated vasorelaxation.
  8. Subjects using Levodopa
  9. Treatment with KUVAN in the past 6 months before study entry.
  10. Treatment with any investigational product in the last 90 days before study entry
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00986973

United States, Pennsylvania
Children's Hospital of Philadelphia, Section of Metabolism,PKU program
Philadelphia, Pennsylvania, United States, 19106
Sponsors and Collaborators
Children's Hospital of Philadelphia
Principal Investigator: Can Ficicioglu, MD, PhD Children's Hospital of Philadelphia,University of Pennsylvania
  More Information

No publications provided

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT00986973     History of Changes
Other Study ID Numbers: IRB 09-007154
Study First Received: September 28, 2009
Last Updated: February 4, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Hospital of Philadelphia:
PET scan

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases

ClinicalTrials.gov processed this record on April 30, 2015