Phenylketonuria (PKU) is a rare metabolic disorder caused by a deficiency of the PAH enzyme, leading to the accumulation of phenylalanine (Phe) and, without treatment, can result in severe neurological damage. In 2017, the first European guidelines for the diagnosis and treatment of PKU were published. During the development of these guidelines, it became clear that limited evidence was available on several topics, which formed the basis of this manuscript. This manuscript of Annemiek van Wegberg addresses five topics: BH4 treatment, late-diagnosed patients, atypical patients, the preferences and values of healthcare professionals, and alternative biomarkers.
Research on BH4 treatment showed that the 48-hour test misses only a few slow responders, but lowering the threshold led to more false positives. Additionally, there is little consensus among healthcare professionals on the definition of BH4 responsiveness. Benefits, such as improved quality of life due to dietary liberalization, were not demonstrated in studies.
Late-diagnosed PKU still occurs, particularly among individuals from regions without neonatal screening or immigrants from those areas. The literature showed a considerable number of patients who, despite elevated phenylalanine levels, seem to avoid severe neurocognitive damage (atypical patients).
Expert opinion plays a significant role in the absence of evidence. A survey revealed differences within the guidelines panel, such as preferences for over-treatment over under-treatment.
New biomarkers, such as N-lactoyl-Phe, were identified, which may provide better insights into neurocognitive functioning. The overall discussion highlights the importance of consistent BH4 responsiveness definitions, appropriate questionnaires, and the potential of metabolomics to improve understanding of PKU.
