Nutritional and metabolic management of phenylketonuria: Integrating dietary strategies, medical nutrition therapy, and emerging treatments.

BACKGROUND

Phenylketonuria (PKU) is an inherited metabolic disorder characterized by impaired phenylalanine metabolism, leading to neurotoxicity if untreated. Lifelong dietary restriction remains the cornerstone of management; however, adherence challenges and evolving therapeutic options necessitate an integrated approach to treatment.

METHODS

A comprehensive literature review was conducted using PubMed, Scopus, and Web of Science databases, including clinical studies, systematic reviews, and preclinical investigations published between 2007 and 2025. Current dietary strategies, medical nutrition therapies, and emerging pharmacological and gene-based treatments were evaluated.

RESULTS

Nutritional management, particularly phenylalanine-restricted diets supported by medical foods such as amino acid mixtures and glycomacropeptide, remains essential for metabolic control. Adjunctive strategies, including large neutral amino acid supplementation and tetrahydrobiopterin therapy, may enhance dietary flexibility in selected patients. Enzyme substitution therapy with pegvaliase provides substantial reductions in blood phenylalanine levels and improves dietary liberalization. Emerging gene-editing approaches, including CRISPR-based technologies, offer potential long-term therapeutic benefits, although they remain in early developmental stages.

CONCLUSION

Effective management of PKU requires a multidisciplinary and personalized approach integrating nutritional, pharmacological, and emerging molecular therapies. While dietary management continues to be fundamental, novel therapeutic strategies may significantly improve long-term outcomes and quality of life in individuals with PKU.