Resources and expertise that help solve the unique challenges of rare disease research

Case Study: Phenylketonuria – Quality of Life Questionnaire (PKU-QOL) Psychometric Validation Claim

Phenylketonuria (PKU) is a rare genetic disorder with an incidence of 1 in 10,000 births in Europe. It is characterized by a deficiency of a hepatic enzyme (phenylalanine hydroxylase, or PAH) responsible for the conversion of the amino acid phenylalanine (Phe) into tyrosine. An absence of (or deficiency in) PAH results in increased blood concentrations of Phe and toxic accumulation in the brain. If PKU is left untreated, it may lead to deficit in cognitive functions, intellectual impairment, seizures, various behavioral problems, and psychiatric symptoms.

The aim of our study was to develop and validate the first set of PKU-specific Health-Related Quality of Life (HRQoL) questionnaires developed for patients with PKU and their parents, which cover the physical, emotional, and social impacts of PKU and its treatment on patient’s lives.


Phenylketonuria (PKU) is a rare disease area, and the management of PKU is complex. It requires strict adherence to diet therapy and Phe-free protein supplement intake, regular collection of blood samples, recording of food intake, and regular visits to the PKU clinic. Adherence to the diet is especially important during the early childhood years since cognitive outcomes are closely related to the control of blood phenylalanine levels, and should be maintained through adulthood to protect from neuropsychological dysfunction.

The strict low-Phe diet imposes a burden on both patients and their families and is associated with dietary non-compliance, especially in adolescents and young adults. Primary obstacles to adherence include time constraints and stress associated with food preparation and record keeping, as well as the restrictions imposed on social life.

There was no instrument currently available to comprehensively capture the perspective of the patients with PKU on their disease and treatment.


Development of a specific questionnaire would enable the measurement of PKU-impact on patients and caregiver’s daily lives simultaneously in seven different countries; with validation of the instrument in the largest HRQL study in PKU patients (250 patients; 250 parents).

For finalization and psychometric validation purposes, the pilot versions were included in a multi-center, prospective, non-interventional, and observational study. This study was conducted in 34 sites in France, Germany, Italy, the Netherlands, Spain, Turkey and the UK. Iterative and multi-trait analyses were conducted.

Outcome & Client Benefit

Mapi developed the first PKU-specific Quality of Life questionnaire available and validated in four age groups and seven languages.

They are very promising tools to explore how patients’ perceptions evolve with age, to increase knowledge of the impact of PKU on patients and parents in different countries, and to help monitor the effect of therapeutic strategies.

  • Regnault et al., Orphanet Journal of Rare Diseases 2015
  • Bettiol E et al., SSIEM, Turkey, 2010
  • Bettiol E et al., SSIEM, Switzerland, 2011
  • Bosch AM et al., SSIEM, Austria, 2014
  • Bosch AM et al., ISPOR, Netherlands, 2014