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. 2021 Mar 18;7(1):17.
doi: 10.3390/ijns7010017.

Clinical and Genetic Characteristics of Patients with Mild Hyperphenylalaninemia Identified by Newborn Screening Program in Japan

Shino Odagiri  1 , Daijiro Kabata  2 , Shogo Tomita  2 , Satoshi Kudo  1 , Tomoko Sakaguchi  1 , Noriko Nakano  1 , Kouji Yamamoto  3 , Haruo Shintaku  4 , Takashi Hamazaki  1
Affiliations

Clinical and Genetic Characteristics of Patients with Mild Hyperphenylalaninemia Identified by Newborn Screening Program in Japan

Shino Odagiri et al. Int J Neonatal Screen. .

Abstract

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA), both identified in newborn screening, are attributable to variants in PAH. Reportedly, the p.R53H(c.158G>A) variant is common in patients with HPA in East Asia. Here, we aimed to define the association between p.R53H and HPA phenotype, and study the long-term outcome of patients with HPA carrying p.R53H. We retrospectively reviewed the genotype in 370 patients detected by newborn screening, and identified the phenotype in 280 (117, HPA; 163, PKU). p.R413P(c.1238G>C) was the most frequently found (n = 117, 31.6%) variant, followed by p.R53H (n = 89, 24.1%). The odds ratio for heterozygous p.R53H to cause HPA was 48.3 (95% CI 19.410-120.004). Furthermore, we assessed the non-linear association between the phenylalanine (Phe) value and elapsed time using the follow-up data of the blood Phe levels of 73 patients with HPA carrying p.R53H. The predicted levels peaked at 161.9 μmol (95% CI 152.088-172.343) at 50-60 months of age and did not exceed 360 μmol/L during the 210-month long observation period. The findings suggest that patients with HPA, carrying p.R53H, do not need frequent Phe monitoring as against those with PKU. Our study provides convincing evidence to determine clinical management of patients detected through newborn screening in Japan.

Keywords: genetic analysis; genotype–phenotype correlation; hyperphenylalaninemia; neonatal screening; phenylalanine hydroxylase; phenylketonuria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Frequency of PAH variants in 370 patients with elevated Phe levels detected by mass screening. Percentage of patients with mutations in PAH was detected by direct sequencing or multiplex ligation-dependent probe amplification (MLPA) in all the participants enrolled in this study. Numbers at the top of the vertical bars represent the actual number of patients with each mutation. Infrequent mutations have been omitted. Phe; phenylalanine, PAH; gene encoding phenylalanine hydroxylase, * stop codon.
Figure 2
Figure 2
p.R53H variant is observed at a higher frequency in patients with HPA phenotype than in patients with PKU phenotype. (A) Number of patients with R53H variant in PAH (p.R53H) in each of the 280 patients with a known phenotype of either HPA or PKU. (B) Odds ratios for patients with no, heterozygous, and homozygous p.R53H variant to develop HPA phenotype. HPA, hyperphenylalaninemia; PKU, Phenylketonuria.
Figure 3
Figure 3
Predicted Phe levels until 200-month-olds are less than 360 μmol/L in patients with HPA carrying p.R53H.
See this image and copyright information in PMC

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