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Neurocognitive Outcomes in Mild Hyperphenylalaninemia (MHP)MHP Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01924026
Recruitment Status : Completed
First Posted : August 16, 2013
Last Update Posted : February 17, 2016
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Annette Feigenbaum, The Hospital for Sick Children

Brief Summary:

Phenylketonuria (PKU) 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 Phe levels, between 360 and 600µmol/L, are safe with respect to preservation of intelligence and higher cognitive functions.

Condition or disease
Phenylketonuria Mild Hyperphenylalaninemia

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 Tyrosine 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:

    • Behavior Rating Inventory of Executive Function (BRIEF)-A
    • Beck Anxiety Inventory
    • Beck Depression Inventory
    • Quality of Life questionnaire
  • Neuropsychological Tests assessed by a trained psychologist

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.

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Study Type : Observational
Actual Enrollment : 10 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Neuropsychological and Quality of Life Outcomes in Untreated Adults With Mild Hyperphenylalaninemia (MHP)/Phenylketonuria (PKU) With Phenylalanine Levels Between 360 and 600 µmol/L Caused by Phenylalanine Hydroxylase (PAH) Deficiency.
Study Start Date : September 2013
Actual Primary Completion Date : February 2016
Actual Study Completion Date : February 2016

Affected MHP
With Phe between 360 and 600 micromoles/L
Unaffected Siblings
With normal Phe levels

Primary Outcome Measures :
  1. Executive function [ Time Frame: Day 1 ]
    As measured by subtests in Weschler-IV test, and supplemented with assessments from BRIEF-A and CANTAB(computerised cognitive tests by Cambridge Cognition).

Secondary Outcome Measures :
  1. Quality of Life [ Time Frame: Day 1 ]
  2. Presence of anxiety and depression [ Time Frame: Day 1 ]
    As measured by Beck Anxiety and Depression Inventories

Other Outcome Measures:
  1. IQ [ Time Frame: Day 1 ]
    As measured by Wechsler-IV

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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 two 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.

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.

Subjects who do not have an unaffected sibling may still participate.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01924026

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Canada, Ontario
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
The Hospital for Sick Children
BioMarin Pharmaceutical
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Principal Investigator: Annette Feigenbaum, MD The Hospital for Sick Children
Principal Investigator: Komudi Siriwardena, MD Stollery Children's Hospital
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Responsible Party: Annette Feigenbaum, Staff Physician, Metabolic Program, Clinical and Metabolic Genetics, The Hospital for Sick Children Identifier: NCT01924026    
Other Study ID Numbers: 1000039726
First Posted: August 16, 2013    Key Record Dates
Last Update Posted: February 17, 2016
Last Verified: February 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: in progress- to be decided.
Keywords provided by Annette Feigenbaum, The Hospital for Sick Children:
Mild Hyperphenylalaninemia
Additional relevant MeSH terms:
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Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases