Epidemiology of Hyperphenylalaninemia: A Systematic Review and Meta-Analysis

Background/objectives: This systematic review and meta-analysis quantified global and regional birth prevalence of hyperphenylalaninemia (HPA) caused by phenylalanine (Phe) hydroxylase deficiency. Data sources and methods: Searches of PubMed, Embase, the Cochrane Library and PROSPERO yielded 4297 records; 210 met inclusion and 97 contributed to a rasyndom-effects model stratified by blood Phe cut-off values. Results: The regionally weighted global prevalence of HPA was 0.84 per 10 000 live births (95% CI 0.44-1.24), ranging from 0.60 in South America to 1.30 in the Middle East and North Africa (MENA). Classic PKU (Phe: 1200 ± 200 μmol/l) occurred in 0.29 per 10 000 births overall, reaching 0.58 (0.34-0.87) in North America and 0.67 (0.28-1.23) in Europe. Conclusion: Prevalence patterns mirrored consanguinity rates, explaining the high burden in MENA and the low figures in Southeast Asia. The meta-analysis, applying rare-disease-specific minimum sample-size threshold, confirmed HPA, incl. PKU as a rare disease and validated prevalence estimates.