Recruitment

Recruitment Status
Completed

Exclusion Criterias

Other specific PKU therapies, including enzyme replacement therapy or any amino acid supplement designed to block uptake or transport of phenylalanine (i.e. large neutral amino acid mixtures)
Significant cognitive impairment (IQ <70 or clinical judgment).
Pregnancy
...
Other specific PKU therapies, including enzyme replacement therapy or any amino acid supplement designed to block uptake or transport of phenylalanine (i.e. large neutral amino acid mixtures)
Significant cognitive impairment (IQ <70 or clinical judgment).
Pregnancy
Any intercurrent illness within the previous 5 days (any of fever, vomiting, diarrhea, decreased intake, upper respiratory tract infection).

Summary

Conditions
  • Hyperphenylalaninemia
  • Phenylketonuria
Type
Observational
Design
  • Observational Model: Case-Control
  • Time Perspective: Prospective

Participation Requirements

Age
Between 4 years and 125 years
Gender
Both males and females

Description

Phenylketonuria (OMIM 261600) results from the inherited deficiency of the enzyme phenylalanine hydroxylase, (PAH, Enzyme Classification 1.14.16.1). A deficiency of this enzyme leads to elevated blood and tissue levels of the amino acid phenylalanine upon exposure to normal amounts of dietary protei...

Phenylketonuria (OMIM 261600) results from the inherited deficiency of the enzyme phenylalanine hydroxylase, (PAH, Enzyme Classification 1.14.16.1). A deficiency of this enzyme leads to elevated blood and tissue levels of the amino acid phenylalanine upon exposure to normal amounts of dietary protein. The elevated phenylalanine in the brain is harmful to cognitive development, usually resulting in permanent severe mental retardation. Soon after the development of a special dietary treatment for PKU and of a simple screening test to detect elevated phenylalanine, newborn screening for PKU became widespread and early detection and treatment largely prevented the severe neurological effects of PKU. With population-based detection of hyperphenylalaninemia, it soon became apparent that there was significant biological variation of phenylalanine levels between patients (i.e. inter-individual biological variation) with phenylketonuria (PKU) and this now forms part of the classification system for hyperphenylalaninemia (i.e. benign hyperphenylalaninemia, mild, moderate or classical phenylketonuria). While variations of the classification system exist, most commonly "classical" PKU refers to individuals with plasma phenylalanine levels greater than 1200 µmol/L on an unrestricted diet. "Moderate" PKU refers to levels between 900 and 1200 µmol/L, while "mild" PKU refers to levels between 600 and 900 µmol/L. "Non-PKU" or "benign" hyperphenylalaninemia refers to phenylalanine levels less than 600 µmol/L on an unrestricted diet, that while greater than normal phenylalanine levels (< 100 µmol/L), historically have not been prescribed dietary restriction of phenylalanine. This inter-individual variation is generally due to variable residual enzyme activity and genotype in PKU patients. Intra-individual variation (the changes of phenylalanine levels in one individual) has been observed by all clinicians who treat PKU. While some of this variation is simply the expression of the underlying genotype when a patient's dietary phenylalanine level exceeds prescribed amounts (i.e. "cheating" on their diet), other variation represents shifts from anabolic to catabolic states in a diurnal pattern or during intercurrent illness. While overall exposure to high phenylalanine has long been known to adversely affect IQ scores, recently increased variability in phenylalanine levels has been reported to be linked to lower IQ, highlighting the importance of improving our understanding of intra-individual variation. New treatments for PKU, therefore, need to be assessed in terms of their effect on biological variation of phenylalanine. Sapropterin dihydrochloride (KuvanTM) is a small molecule drug that can lower phenylalanine levels in patients with phenylalanine hydroxylase deficiency by a direct interaction with the enzyme . The pharmacokinetics of KuvanTM have been evaluated in adults and are undergoing evaluation in pediatric patients, however, the biological effect of KuvanTM in terms of lowering of blood phenylalanine levels would be expected to have a longer profile than the blood levels of the drug itself because the half-life of the activated enzyme would be longer. This suggests that KuvanTM may have a modulating effect on variation of blood phenylalanine levels in PKU patients. In this observational study, the investigators will directly measure the short-term biological variation of blood phenylalanine in hyperphenylalaninemic patients by frequent measurements of phenylalanine levels over a 24 hour period. The investigators will enroll subjects already followed at one of the two study sites who are treated by diet alone or who are treated with KuvanTM therapy (+/- diet). During the 24 hour period subjects will be asked to maintain their typical diet/therapy. Hypothesis: Biological variation will be less in KuvanTM treated patients than in classical phenylketonuria treated by diet alone. OBJECTIVES: Determine short-term biologic variation in people with hyperphenylalaninemia, with and without KuvanTM therapy.

Exclusion Criterias

Other specific PKU therapies, including enzyme replacement therapy or any amino acid supplement designed to block uptake or transport of phenylalanine (i.e. large neutral amino acid mixtures)
Significant cognitive impairment (IQ <70 or clinical judgment).
Pregnancy
...
Other specific PKU therapies, including enzyme replacement therapy or any amino acid supplement designed to block uptake or transport of phenylalanine (i.e. large neutral amino acid mixtures)
Significant cognitive impairment (IQ <70 or clinical judgment).
Pregnancy
Any intercurrent illness within the previous 5 days (any of fever, vomiting, diarrhea, decreased intake, upper respiratory tract infection).

Locations

Hamilton, Ontario, L8S 4J9
Ottawa, Ontario, K1H 8L1
Hamilton, Ontario, L8S 4J9
Ottawa, Ontario, K1H 8L1

Tracking Information

NCT #
NCT01869972
Collaborators
  • McMaster Children's Hospital
  • Children's Hospital of Eastern Ontario
  • BioMarin Pharmaceutical
Investigators
  • Principal Investigator: Murray Potter, MD Hamilton Health Sciences Corporation
  • Murray Potter, MD Hamilton Health Sciences Corporation