International Survey on Phenylketonuria Newborn Screening

Abstract

Newborn screening for Phenylketonuria enables early detection and timely treatment with a phenylalanine-restricted diet to prevent severe neurological impairment. Although effective and in use for 60 years, screening, diagnostic, and treatment practices still vary widely across countries and centers. To evaluate the Phenylketonuria newborn screening practices internationally, we designed a survey with questions focusing on the laboratory aspect of the screening system. We analyzed 24 completed surveys from 23 countries. Most participants used the same sampling age range of 48-72 h; they used tandem mass spectrometry and commercial non-derivatized kits to measure phenylalanine (Phe), and had non-negative cut-off values (COV) set mostly at 120 µmol/L of Phe. Participants mostly used genetic analysis of blood and detailed amino acid analysis from blood plasma as their confirmatory methods and set the COV for the initiation of dietary therapy at 360 µmol/L of Phe. There were striking differences in practice as well. While most participants reported a 48-72 h range for age at sampling, that range was overall quite diverse Screening COV varied as well. Additional screening parameters, e.g., the phenylalanine/tyrosine ratio were used by some participants to determine the screening result. Some participants included testing for tetrahydrobiopterin deficiency, or galactosemia in their diagnostic process. Results together showed that there is room to select a best practice from the many practices applied. Such a best practice of PKU-NBS parameters and post-screening parameters could then serve as a generally applicable guideline.

Keywords: cut-off; international; laboratory; methods; neonatal; newborn; phenylketonuria; screening; survey.

Figure 1

(a) Sampling age ranges of participating countries/centers. The vertical dashed lines represent the range 48–72 h; (b) Phe COVs, at which the screening result is no longer negative, by the method. The vertical dashed line represents the value 120 µmol/L. Participants with ranges utilized a borderline result, where the range produced a borderline result. T–TMS; F–Fluorometric; R–Radioimmuno assay * France planned to update their COV by the end of 2024 to 150 µmol/L. ** Sweden used another criterion: if both Phe is above 180 µmol/L and Phe/Tyr ratio is above 2, the screening result is positive.

Figure 2

Confirmatory methods used by centers. Genetic EDTA: genetic testing from EDTA blood; AA profile: detailed amino acid profile analysis; Pterins: biopterin and neopterin measurement/analysis from urine; Phe-plasma: Phe from blood plasma; Genetic DBS: genetic testing from DBS.

Figure 3

Phe COVs, at which therapy is indicated. (a) COVs of centers that measure Phe in DBS. (b) COV of centers that measure Phe in blood plasma. This information is used to help the designated physician determine whether the therapy should be initiated.