PHENYLKETONURIA: A NARRATIVE REVIEW OF GLOBAL PREVALENCE, DIETARY MANAGEMENT, EMERGING THERAPIES, AND THE ROLE OF NUTRITIONAL SUPPLEMENTATION

Abstract

Background: Phenylketonuria (PKU) is an inborn error of metabolism that is an autosomal recessive, caused by the deficiency of phenylalanine hydroxylase (PAH), resulting in toxic phenylalanine buildup and avoidable intellectual disability without treatment. Although six decades of newborn screening and dietary management have been made, adherence, global access disparities, and new therapeutic options are considered a challenge that requires updated evidence synthesis.

Purpose: This narrative review critically analyzes PKU through the lenses of its prevalence trends on the global spectrum, dietary management approaches, novel pharmacological and biological interventions, and nutritional supplementation.

Methods: A systematic literature search was carried out on PubMed, Scopus, Web of Science, Cochrane Library and Google Scholar to identify articles published in the period between January 2015 and March 2026. Following screening, 32 articles comprising peer-reviewed articles, systematic reviews, meta-analyses, and clinical guidelines were identified and thematically synthesised.

Findings: The prevalence of global classic PKU is about 6 per 100,000 neonates with significant regional differences due to consanguinity (Turkey highest, 38.13 per 100,000; Thailand lowest, 0.3 per 100,000). Most low- and middle-income nations do not have universal newborn screening, and under-ascertainment is a result. Dietary management is still the cornerstone therapy, but early-treated patients do an average of 0.46 standard deviations worse than healthy controls on cognitive measures, and adherence in adults reduces to 40-60%. New treatments are sapropterin (working in 2050% of patients) and pegvaliase (reaching blood phenylalanine 360 000 mol/L in 60.7% of adults) but access and safety issues restrict their use. Gene therapy and mRNA-based approaches show preclinical promise. Nutritional supplementation using glycomacropeptide-based formula enhances palatability and bone parameters, though micronutrient deficiencies (vitamin D, B12, iron, zinc) and decreased bone mineral density are still prevalent in non-adherent patients.

Conclusions: PKU is an avoidable etiology of intellectual disability, but inequities in newborn screening and access to treatment exist globally. Dietary management is good but not enough to achieve the best long-term results. New treatments have revolutionary possibilities but demand equal opportunity. Nutritional supplement is necessary and should be given priority. The next decade of PKU care is characterized by addressing the global disparities