BACKGROUND: Phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disorder that results in elevated concentrations of phenylalanine (Phe) in the blood. If left untreated, the accumulation of Phe can result in profound neurocognitive disability.
OBJECTIVES: The objective of this systematic literature review and meta-analysis was to estimate the global birth prevalence of PAH deficiency from newborn screening studies and to evaluate regional differences, overall and by Phe cutoff values used in confirmatory testing.
METHODS: The protocol for this literature review was registered with PROSPERO (International prospective register of systematic reviews). Pubmed and Embase database searches were used to identify studies that reported the birth prevalence of PAH deficiency. Only studies including numeric birth prevalence reports of confirmed PAH deficiency were included. A quality assessment tool was used to score each estimate as strong, moderate, or weak in five domains. Only estimates derived from confirmatory diagnostic assays that were assessed as strong were eligible for meta-analysis. Meta-analyses were performed to determine aggregated regional and global birth prevalence. A regionally-weighted global prevalence was calculated by weighting results from each region by the region’s relative contribution to the total population of all the regions included.
RESULTS: From the 85 publications included in the review, 238 birth prevalence estimates were extracted. After excluding prevalence estimates that did not meet quality assessment criteria or due to temporal and regional overlap, estimates from 45 publications were included. The regionally-weighted global birth prevalence of PAH deficiency was 0.64 (95% CI, 0.53-0.75) per 10,000 births and ranged from 0.03 per 10,000 births (95% CI, 0.02-0.05) in Southeast Asia to 1.18 (95% CI, 0.64-1.87) per 10,000 births in the Middle East/North Africa. Regionally-weighted global birth prevalence estimates per 10,000 births by confirmatory test Phe cutoff values were 0.96 (95% CI, 0.50-1.42) for the Phe cutoff value of 360 ± 100 µmol/L; 0.50 (95% CI, 0.37-0.64) for the Phe cutoff value of 600 ± 100 µmol/L; and 0.30 (95% CI, 0.20-0.40) for the Phe cutoff value of 1,200 ± 200 µmol/L.
CONCLUSIONS: Substantial regional variation in the birth prevalence of PAH deficiency was observed in this systematic literature review and meta-analysis of published evidence from newborn screening. The precision of the prevalence estimates is limited by relatively small sample sizes, despite widespread and longstanding newborn screening in much of the world.
