Abstract

This article reviews the recent literature to explore the potential benefits of rethinking dietary treatment in phenylketonuria, considering new and integrative strategies. The aim is to explore whether greater flexibility in treatment could improve clinical outcomes and overall patient well-being.

A comprehensive literature review was conducted using PubMed, Scopus, and the Cochrane Library, focusing on studies published between 2000 and 2024. Inclusion criteria comprised clinical trials, systematic reviews, and observational studies addressing dietary interventions, large neutral amino acids (LNAA), glycomacropeptide (GMP), sapropterin, pegvaliase, and emerging therapies. Studies were critically appraised for the risk of bias using established tools.

Traditional dietary management remains effective but presents challenges related to adherence, nutritional adequacy, and psychosocial burden. Large neutral amino acid (LNAA) and glycomacropeptide (GMP) supplementation improve metabolic control and dietary flexibility, while slow-release amino acid formulas stabilize blood phenylalanine levels. Pharmacological options, including sapropterin and pegvaliase, enhance phenylalanine metabolism and dietary tolerance in eligible patients. Emerging therapies, such as sepiapterin, gene therapy, and SLC6A19 inhibitors, show potential for reducing dietary restrictions.

The evolving landscape of PKU treatment supports a more personalized, patient-centered approach integrating both dietary and pharmacological strategies. Expanding therapeutic options may enhance metabolic control, reduce dietary burden, and improve long-term outcomes. Further research is needed to optimize treatment combinations and assess the long-term safety and efficacy of emerging therapies.