Treatment goals for adults with early treated PKU should be determined by evidence-based shared decision making between patients and their medical team

Abstract This opinion article focusses on treatment targets in adults with early treated PKU (etPKU), specifically the recommended phenylalanine (Phe) level. The current body of evidence on the relationship between Phe levels at different times in life and neurocognitive functioning and quality of life in adults with etPKU is summarized and discussed. Based on this, recommendations on metabolic control throughout adult life are made. Maintaining plasma Phe < 600 umol/L up to (at least) age 20 years may be advisable. There is however a lack of robust evidence to support a specific single phenylalanine target level that is applicable to all adults and, in later adulthood, a patient-centred approach to optimize nutritional status and achieve individualised treatment goals should be taken. The available evidence indicates reduced processing speed and attentional difficulties with higher Phe concentrations in only a proportion of adult patients. These are potentially reversible with lowering of Phe levels. Patients may wish to achieve lower phenylalanine levels because they experience better mood or cognitive functioning, and the levels where they perceive these benefits are variable (e.g. <600, < 800 or < 1000 umol/L). Equally, patients may wish to avoid potential, as yet undiscovered, long term negative consequences of higher levels. All patients wishing to lower their Phe levels should receive full support to reach their goals. In some cases, subjective symptoms are the reason patients want to reduce their Phe levels. In such cases, subjective symptoms should be clearly defined and quantified, and the relationship between their occurrence and phenylalanine level, as well as improvement with lower phenylalanine levels, should be clearly established before treatment is intensified. Patients who, after having received and understood all currently available evidence on outcomes, do not wish to lower their Phe levels, should not be pressed to do so. In order to further understand the correlation between Phe levels at the different stages of life and neurological and cognitive functioning of etPKU patients a large, independent, multicentre registry needs to be established. This is urgently needed to facilitate rational treatment of PKU in adulthood, preventing both over- and undertreatment and facilitating cost-effective use of new and currently available drugs.