In contrast to recent reports among patients with PKU are willing to accept the risks of hypersensitivity reactions to optimize their treatment [[i]] we could clearly show the patients reservation against the invasive treatment of their disorder. One aspect is certainly the different management of PKU in Europe for the last decade, which permitted the loose permissive value of plasma Phe levels of 1200µmol/l.
Another aspect is the low burden of disease in most adult patients, most of which would not consider themselves as patients with an inborn error of metabolism. This is based on the low predictive power of blood phenylalanine on the clinical outcome from the second decade of life onwards [[ii]]. There is clear evidence for improved quality of life in patients with relaxation of their Phe-restricted diet [[iii], [iv], [v]]. This argument is often used as an argument for expected tolerance of PKU patients to harmful side effects of treatment with Pegvaliase [[vi]], but misses the point, that most patients that probably benefit from a treatment with Pegvaliase did not stick to their diet for years. Additionally, individual vulnerability to the metabolic alterations of PKU contributes to the prognosis of PKU. That means, that the long-term benefit for the individual patient is not predictable [16]. Therefore, it is still not easy to determine the indications for recommending a treatment with Pegvaliase resulting in severe adverse events in 10% of the treated patients [[vii]] compared to Saproterine [8, [viii], [ix]].
Even in subsets with clear indications (adult patient, blood Phe level >600µmol/l and fail at dietary adherence) we could clearly show that the patient’s will is remarkably different to the marketing attempts of the manufacturer, mainly based on the invasive application and the unfavorable side effects. The burden for quality of life of daily injections with regular side effects might be more harmful than elevated Phe levels alone. The presented cognitive data for admission of the treatment [10, [x], [xi], [xii]], based on depression and activity rating scalers, are far away from clinical reality, showing clear evidence for a persisting central executive impairment even in patients with well treated PKU and low blood Phe-levels [[xiii]]. Detailed cognitive testing and an assessment of quality of life in long-term follow-ups are needed to answer the question if life-long blood Phe control is able to prevent or improve cognitive impairment, and if daily injections with side-effects are more harmful to well-being than uncontrolled Phe-levels.
Another clear result of this study is the apparent untapped potential for reducing plasma Phe-levels in patients with PKU without any special intervention or additional medication. The patients in our cohort who refused a treatment with Pegvaliase showed significantly reduced Phe-levels within four weeks. This effect could be explained by recreation of disease consciousness only by being focused on their diet by preparing a nutrition protocol over three days. Another fact could be, that the imminence of the beginning of an invasive treatment activates recourses for therapy and diet-adherence. This clearly shows that individual patient care and regular professional focus on the diet improves therapy adherence and should be part of every regular visit in patients with PKU, even in patients with pretended non-adherence rather than imprudent invasive therapeutic interventions.
Patients who accepted the treatment with Pegvaliase tend to elevation of Phe-levels compared to controls after four weeks. This might be explained by the expectations in a life without Phe-restricted diet causing a looser adherence to therapy.