Neurocognitive Outcomes in Mild Hyperphenylalaninemia Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by The Hospital for Sick Children
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Komudi Siriwardena, The Hospital for Sick Children Identifier:
First received: May 15, 2013
Last updated: May 12, 2014
Last verified: May 2014

Phenylketonuria is a genetic disorder known to cause severe reduction in intelligence and deficits in cognitive function; it is associated with an elevated level of Phenylalanine (Phe) in blood. Newborn screening and early treatment with restricted protein diet supplemented by a formula of amino-acids will preserve intelligence. In those with the severe form treated from birth, some deficits that affect higher functions of the brain are seen. Given this, there is disagreement about how milder forms of this disease should be managed and what level of Phe is safe to be left untreated. We seek to assess whether higher levels, between 360 and 600µmol/L, are safe with respect to preservation of intelligence and higher cognitive functions.

Mild Hyperphenylalaninemia

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Neuropsychological and Quality of Life Outcomes in Untreated Adults With Mild Hyperphenylalaninemia With Phenylalanine Levels Between 360 and 600 µmol/L.

Resource links provided by NLM:

Further study details as provided by The Hospital for Sick Children:

Primary Outcome Measures:
  • Executive function [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    As measured by subtests in Weschler-IV test, and supplemented with assessments from BRIEF-A and CANTAB

Secondary Outcome Measures:
  • Quality of Life [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • Presence of anxiety and depression [ Time Frame: Day 1 ] [ Designated as safety issue: Yes ]
    As measured by Beck Anxiety and Depression Inventories

Other Outcome Measures:
  • IQ [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    As measured by Wechsler-IV

Estimated Enrollment: 25
Study Start Date: September 2013
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Affected MHP
With Phe between 360 and 600 micromoles/L
Unaffected Siblings
With normal Phe levels

Detailed Description:

The following personal/medical information will be collected and reviewed:

  • Evaluation of current and past medical history, including psychological treatment such as medication and counseling/therapy.
  • Mutational analysis for each MHP subject
  • Detailed history of educational, employment, relationship, and socioeconomic status/achievements as a measure of successful transition to adulthood
  • Diet history, including past treatment with medical food or Sapropterin (Kuvan) for pre-conceptual and pregnancy Phe management
  • All available untreated Phe levels, including newborn screening results (where possible) will be collated to calculate lifetime mean Phe level. Age at collections will be recorded separately for each MHP subjects to ensure inclusion of Phe levels beyond infancy

The following clinical investigations will be administered:

  • Measurement of Phe and Tyr after an overnight fast, via blood spot using tandem mass spectrometry analysis. Blood spot collection will be done at the same time of day for all subjects.
  • Physical exam, height and weight measurements
  • Food Frequency Questionnaire assessment to estimate typical daily intake of natural protein.
  • Self-Report Questionnaires:

    • Brief-A
    • Beck Anxiety Inventory
    • Beck Depression Inventory
    • Quality of Life questionnaire
  • Neuropsychological Tests assessed by a trained psychologist:

    • Wechsler-IV IQ test (Canadian Version)
    • CANTAB

      • Choice Reaction Time (CRT)
      • Rapid Visual Information Processing (RVP)
      • Spatial Span (SSP)
      • Spatial Working Memory (SWM)
      • Stockings of Cambridge (SOC)

An informant BRIEF-A report will be completed for each subject. To ensure consistency in rating, the same informant will be used where possible for the MHP subject and their sibling control (i.e. parents). These questionnaires will be mailed to the informants and returned to the study site via FedEx.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Those with mild form of PKU known as mild hyperphenylalaninemia (MHP) and their unaffected siblings who fulfill the inclusion and exclusion criteria.


Inclusion Criteria:

  • Male or Female, ≥ 18 years
  • Confirmed to have MHP with at least three Phe levels during lifetime of above 360µmol/L and below 600µmol/L, including newborn screening levels (available since 1968 by either bacterial inhibition, enzymatic or tandem mass spectrometry methodology) and via mutation analysis. Those with occasional levels above 600µmol/L will not be excluded provided the majority of available levels fall within the 360-600µmol/L range.
  • On an unrestricted diet and not taking medical food. Women who were on dietary or Kuvan® treatment for past pre-conception or pregnancy management will not be excluded
  • Willing and able to give consent and comply with study procedures.
  • Must have a healthy sibling (male or female) ≥ 18 years willing and able to fully participate in the study

Exclusion Criteria:

  • Subjects on dietary or Kuvan® treatment within the last 12 weeks will be excluded.
  • Co-morbidities that may interfere with study participation and/or put the subject at a higher risk of adverse effects.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01924026

Contact: Komudi Siriwardena, MD 416-813-7538
Contact: Ashley Wilson 416-813-7654 ext 202646

Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Principal Investigator: Komudi Siriwardena, MD         
Sponsors and Collaborators
The Hospital for Sick Children
BioMarin Pharmaceutical
Principal Investigator: Komudi Siriwardena, MD The Hospital for Sick Children
  More Information

No publications provided

Responsible Party: Komudi Siriwardena, Paediatrician and Clinical Geneticist, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children Identifier: NCT01924026     History of Changes
Other Study ID Numbers: 1000039726
Study First Received: May 15, 2013
Last Updated: May 12, 2014
Health Authority: Canada: Ethics Review Committee
Canada: Health Canada
Canada: Ministry of Health & Long Term Care, Ontario

Keywords provided by The Hospital for Sick Children:
Mild Hyperphenylalaninemia

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 processed this record on March 26, 2015