Phenylketonuria (PKU) is a prototypical model of a neurodevelopmental metabolic disease that follows a cascade of pathological events affecting brain maturation and functioning. Neonatal screening and early treatment have eradicated the classical PKU phenotype in patients with early and continuously treated phenylketonuria (ECTPKU). However, effort is required to optimise the treatment of the disease to minimise the risk of lifelong neurological, cognitive and behavioural impairment, and to solve issues on the variability in clinical outcome that are rather not understood and has yet hampered a more personalised approach to its treatment. The aim of the present review is to focus on the inconsistencies in the clinical outcome of adult patients with ECTPKU unexplained by the biochemical markers adopted for the monitoring of the disease to date. The interindividual variability of clinical outcome in late as well as in early treated patients under similar biochemical control suggests the existence of disease-independent determinants influencing the individual vulnerability to the neurotoxic effect of phenylalanine. This is further supported by the low predictive power of blood phenylalanine on the clinical outcome from the second decade of life onwards. In conclusion, individual vulnerability to the metabolic alterations of PKU contributes to the prognosis of PKU, also in patients with ECTPKU. The biological factors constitutive of this vulnerability are unknown (but have not been the object of many studies so far) and should be the target of further research as prerequisite for a personalised treatment aimed at avoiding burden and costs of overtreatment and clinical consequences and risks of undertreatment in patients with PKU.
- personalized treatment
- clinical outcome
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Contributors VL made substantial contribution to the conception and the design of the work; to the acquisition, analysis or interpretation of data; wrote the first draft of the work; and participated in the critical revision for important intellectual content. FC participated in the design of the work, the analysis and interpretation of data; participated in the drafting of the work and in the critical revision for important intellectual content. FN participated in the design of the work, the acquisition and interpretation of data, the drafting of the work and in the critical revision for important intellectual content. DvV participated in the acquisition and interpretation of data, and in the critical revision for important intellectual content. FJvS participated in the design of the work and the interpretation of data; participated in the drafting of the work and in the critical revision for important intellectual content.
Funding FJvS received funding from NPKUA and UMCG.
Competing interests VL declares consultancy for Biomarin and APR. FC and FN have no competing interests to declare. DvV has received speaker’s honoraria from Biomarin. FJvS declares the following: participation at Advisory Boards for SoBi, Biomarin, Nutricia, APR, Arla Food Int, Lucane, Vivet, Moderna TX, Rivium, Eurocept Int, Origin Biosciences; grants from SoBi, Biomarin, Nutricia, Alexion, NPKUA, ESPKU, Tyrosinemia Foundation, Metakids, Stofwisselkracht, St PKU Research; consultancy for Biomarin, APR; lectures for Biomarin, Nutricia, Vitaflo; MendeliKABS.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.