Phenylketonuria as an Adherence Disease

Abstract: This narrative review explores a novel challenge to adherence in patients with phenylketonuria (PKU). Traditional barriers to maintaining the core of PKU therapy, which involves dietary restrictions, include limited palatability, high costs, difficult access to low-phenylalanine foods, time constraints, and social interference. We propose that adherence may also be hindered by elevated phenylalanine levels in nonadherent patients, leading to cognitive and executive function impairment that reduces their ability to adhere to the diet. Specifically, we hypothesize that the pathophysiological features of PKU create a vicious cycle that exacerbates adherence challenges to the phenylalanine-restricted diet. We therefore propose that PKU may be considered “an adherence disease”. The implications of this hypothesis are threefold: 1. Long-term dietary nonadherence is probable among individuals with PKU; 2. the disease itself contributes to the difficulty in adhering to dietary restrictions, potentially alleviating patient guilt; 3. while treatment options depend on individual factors such as disease severity, the most effective approach to mitigating the neurocognitive and psychosocial impacts of PKU is to replace or restore phenylalanine hydroxylase activity. Plain Language Summary: Phenylketonuria (PKU) is the most common genetic metabolic disorder. Its management requires adhering to a challenging diet that eliminates phenylalanine to prevent its accumulation in the brain, which can cause significant neurological deficits affecting the patient’s quality of life.This review focuses on long-term adherence to this diet, as part of a broader investigation into the mechanisms of nonadherence which represents a critical issue in medicine.In this article, we propose to consider PKU as an adherence disease—a unique case where the disease’s pathophysiology negatively impacts adherence through a vicious cycle, detailed in this review.This narrative review is the first to apply general adherence concepts from other diseases to PKU in an interdisciplinary manner.Finally, the concept of “adherence disease”—analogous to terms like heart disease— suggests that adherence is a beneficial function prone to failure that can be corrected by understanding its mechanisms.This investigation provides strong support for research in gene therapy for PKU. Keywords: executive functions, impulsivity, prospective memory, gene therapy