JMIR Publications

ABSTRACT

Background:

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism, and if untreated, leads to severe neurocognitive impairment. Over the past two decades, treatment strategies have evolved from strict dietary phenylalanine restriction to include pharmacological therapies such as tetrahydrobiopterin (BH4) and, more recently, enzyme substitution with pegvaliase. Despite these advances, significant heterogeneity exists in global research priorities, collaboration patterns, and the translation of emerging therapies into clinical practice. A systematic overview of the field’s development, thematic shifts, and remaining knowledge gaps is currently lacking.

Objective:

This study presented a systematic bibliometric analysis of global treatment research on phenylketonuria (PKU) from 2000 to 2025. The aim is to qualify publication trends, collaboration patterns, thematic evolution, and research gaps, thereby informing future scientific and clinical directions.

Methods:

This study used the Web of Science Core Collection and searched on September 13, 2025, yielding 1,877 English-language articles and reviews published between 2000 and 2025. Publication trends were analyzed using Microsoft Excel (version 16.101), while VOSviewer 1.6.20 and CiteSpace 6.4 R1 were used to visualize country- and institutional-level collaborations, journal networks, keyword co-occurrence, citation bursts, and thematic clusters. Statistical charts were generated with GraphPad Prism 10.2.1.

Results:

Annual publication output demonstrated an overall upward trend, peaking in 2022 with 111 publications. The United States led in both publication volume (375 studies) and total citations (11,142 citations), maintaining strong collaborative ties with several European countries, particularly the Netherlands and the United Kingdom. China ranked seventh globally in publication volume, although its citation impact remains comparatively limited. Key institutions, including the University of Birmingham and the University of Copenhagen, as well as prominent scholars such as Francjan J. van Spronsen and Anita MacDonald occupied central positions in global collaboration networks. High-frequency and high-centrality keywords, such as "phenylalanine," "dietary treatment," and "tetrahydrobiopterin," highlighted continued emphasis on metabolic control and targeted therapies. Keyword burst analysis revealed a gradual shift from conventional dietary management toward enzyme replacement therapies, investigations of neurocognitive outcomes, and precision medicine-oriented approaches.

Conclusions:

Over the past 25 years, PKU treatment research has progressed from foundational dietary interventions to molecular mechanistic studies and individualized therapeutic strategies. Future research should prioritize longitudinal multi-omics investigations, targeted metabolic correction technologies, and enhanced international collaboration, particularly to strengthen diagnosis and management capacities in low- and middle-income regions. Such efforts will be critical to advancing global standards of PKU care.