Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2021 Jun 3;16(1):253.
doi: 10.1186/s13023-021-01874-6.

Birth prevalence of phenylalanine hydroxylase deficiency: a systematic literature review and meta-analysis

Pamela K Foreman  1 , Andrea V Margulis  2 , Kimberly Alexander  1 , Renee Shediac  1 , Brian Calingaert  3 , Abenah Harding  3 , Manel Pladevall-Vila  2 , Sarah Landis  4
Affiliations
Meta-Analysis

Birth prevalence of phenylalanine hydroxylase deficiency: a systematic literature review and meta-analysis

Pamela K Foreman et al. Orphanet J Rare Dis. .

Abstract

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. 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 estimate regional differences, overall and for various clinically relevant 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.

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 because of temporal and regional overlap, estimates from 45 publications were included in the meta-analysis. The global birth prevalence of PAH deficiency, estimated by weighting regional birth prevalences relative to their share of the population of all regions included in the study, was 0.64 (95% confidence interval [CI] 0.53-0.75) per 10,000 births and ranged from 0.03 (95% CI 0.02-0.05) per 10,000 births 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 prevalences 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 1200 ± 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.

Keywords: Hyperphenylalaninemia; Newborn screening; Phenylalanine hydroxylase deficiency; Phenylketonuria; Prevalence.

PubMed Disclaimer

Conflict of interest statement

RS, KA, and SL are employees of BioMarin Pharmaceutical Inc. PKF was a consultant for BioMarin Pharmaceutical Inc. when this research was conducted. Research team members AH, AVM, BC and MP are full-time employees of RTI Health Solutions. RTI Health Solutions is a unit of RTI International, an independent, nonprofit organization that conducts work for government, public, and private organizations, including pharmaceutical companies. RTI authors participate in this work in the course of employment as work for hire, pursuant to a contract to conduct an independent research study for a client (BioMarin Pharmaceutical Inc.).

Figures

Fig. 1
Fig. 1
Study selection process. PRISMA chart modeled after Moher et al. [21]. BH4 = tetrahydrobiopterin; PAH = phenylalanine hydroxylase deficiency; PKU = phenylketonuria
Fig. 2
Fig. 2
a–e Quality of evidence assessments of birth prevalence estimates
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. van Spronsen FJ, van Wegberg AM, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. 2017;5(9):743–756. doi: 10.1016/S2213-8587(16)30320-5. - DOI - PubMed
    1. van Wegberg AMJ, MacDonald A, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162. doi: 10.1186/s13023-017-0685-2. - DOI - PMC - PubMed
    1. Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188–200. doi: 10.1038/gim.2013.157. - DOI - PubMed
    1. Blau N. Genetics of phenylketonuria: then and now. Hum Mutat. 2016;37(6):508–515. doi: 10.1002/humu.22980. - DOI - PubMed
    1. PAHvdb: Phenylalanine Hydroxylase Gene Locus-Specific Database. 2020. http://www.biopku.org/home/pah.asp. Accessed 4 Sept 2020.

Publication types