Mutational and phenotypic spectrum of phenylalanine hydroxylase deficiency in Zhejiang Province, China

Chen, Ting; Xu, Weize; Wu, Dingwen; Han, Jiamin; Zhu, Ling; Tong, Fan; Yang, Rong; Zhao, Zhengyan; Jiang, Pingping; Shu, Qiang

doi:10.1038/s41598-018-35373-9

Cited by 17 publications

(23 citation statements)

References 25 publications

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“…Patients with BH 4 deficiency were not identified during the study period, which may further confirm the regional differences in PKU typing 12 . Genetic analysis showed that the most common mutation was c.728G>A in the PAH gene, which is in consistent with previous reports 22 , 23 .…”

Section: Discussionsupporting

confidence: 92%

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Zhang

Qiang

Song

et al. 2021

Sci Rep

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Expanded newborn screening facilitates early identification and intervention of patients with inborn errors of metabolism (IEMs), There is a lack of disease spectrum data for many areas in China. To determine the disease spectrum and genetic characteristics of IEMs in Xi'an city of Shaanxi province in northwest China, 146152 newborns were screening by MSMS from January 2014 to December 2019 and 61 patients were referred to genetic analysis by next generation sequencing (NGS) and validated by Sanger sequencing. Seventy-five newborns and two mothers were diagnosed with IEMs, with an overall incidence of 1:1898 (1:1949 without mothers). There were 35 newborns with amino acidemias (45.45%, 1:4176), 28 newborns with organic acidurias (36.36%, 1:5220), and 12 newborns and two mothers with FAO disorders (18.18%; 1:10439 or 1:12179 without mothers). Phenylketonuria and methylmalonic acidemia were the two most common disorders, accounting for 65.33% (49/75) of all confirmed newborn. Some hotspot mutations were observed for several IEMs, including PAH gene c.728G>A for phenylketonuria; MMACHC gene c.609G>A and c.567dupT, MMUT gene c.323G>A for methylmalonic acidemia and SLC25A13 gene c.852_855del for citrin deficiency. Our study provides effective clinical guidance for the popularization and application of expanded newborn screening, genetic screening, and genetic counseling of IEMs in this region.

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Section: Discussionsupporting

confidence: 92%

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Zhang

Qiang

Song

et al. 2021

Sci Rep

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“…In China, p.Arg241Cys is frequently detected in Taiwanese patients, while p.Arg243Gln is common in both the northern and southern areas of the China mainland, which is consistent with our data [ 20 , 21 ].…”

Section: Discussionsupporting

confidence: 92%

Neonatal screening and genotype-phenotype correlation of hyperphenylalaninemia in the Chinese population

Wang

et al. 2021

Orphanet J Rare Dis

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Background Hyperphenylalaninemia (HPA) is the most common amino acid metabolic disease involving phenylalanine hydroxylase (PAH, OMIM*612,349) deficiency or coenzyme tetrahydrobiopterin (BH4) deficiency. Patients with severe HPA often have a difficult life. Early diagnosis of HPA before the development of symptoms is possible via neonatal screening, facilitating appropriate treatment and reducing mortality and disability rates. This study revealed the prevalence, mutational and phenotypic spectrum, and prognosis of HPA by neonatal screening from January 2001 to September 2020 in Nanjing, Jiangsu Province, China. Methods Through a retrospective analysis of the information available in the neonatal screening database, the clinical presentations, laboratory data, molecular characteristics and treatment follow-up data of HPA patients detected by neonatal screening were evaluated. Results We diagnosed 181 patients with HPA from 1 to 957 newborns, giving an incidence of 1:6873. Among these patients, 177 were identified as PAH deficient and four patients were BH4 deficient. The average current age of the patients was 6.38 years old. The most common mutations of PAH were c.728 C > A/ p.Arg243Gln (13.83 %), c.158G > A/ p.Arg53His (9.57 %), c.611 A > G/ p.Tyr204Cys (7.44 %), and c.721 C > T/ p.Arg241Cys (6.38 %). Conclusions This study revealed the prevalence, phenotype-genotype, and prognosis of HPA in China and contributes to the updating of PAHD data for China and worldwide. Our study not only expanded the spectrum of phenotypes and genotype but also provided a valuable tool for improved genetic counseling and management of future cases.

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“…Previous studies showed that the detection rate of p.Arg241Cys in mPKU and MHP patients from southern China was higher than that in other areas [3,27,28]. The results of this study are consistent with those of previous studies [27,28], suggesting that regional and demographic differences may be represented to a certain degree in our study.…”

Section: Discussionsupporting

confidence: 92%

“…This might be due to the higher frequency of the p.Arg53His variant in this region. Finally, the p.Phe392Ile variant was only observed in patients with MHP, in line with the results of previous studies [3,17].…”

Section: Discussionsupporting

confidence: 92%

“…The variants p.Arg53His and p.Phe392Ile had a higher frequency in MPH patients (P = 0.001 and 0.014, respectively), while p.Arg241Cys and p.Arg408Gln had a higher frequency in mPKU patients. In addition, p.Arg53His variant was more frequent MHP patients, in line with the results of previous large-sample studies [3,17]. In vitro studies have reported that the residual activity of the p.Arg53His-type PAH enzyme was equivalent to 79% of that of the wild-type [12,24].…”

Section: Discussionsupporting

confidence: 89%

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Characterization of PAH Gene Mutations and Analysis of Genotype-Phenotype Correlation in Patients with Phenylalanine Hydroxylase Deficiency from Fujian Province, Southeastern China

Zhou

Luo

Zeng

et al. 2021

Preprint

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Phenylalanine hydroxylase deficiency (PAHD) is the most prevalent inborn error of amino acid metabolism in China, has a complex phenotype with many variants and genotypes among different populations. Here, we analyzed the phenylalanine hydroxylase（ PAH ） gene mutations in a cohort of 93 PAHD patients from Fujian Province. And, the analysis of genotype and phenotype correlation in patients with PAHD was also determined. 44 different pathogenic variants were identified, including five novel variants. The three most prevalent mutations among all patents were p.Arg53His (18.03%), p.Arg241Cys (14.75%), and p.Arg243Gln (7.65%). The frequency of the p.Arg53His variant was the highest in patients with mild hyperphenylalaninemia (MHP), while the frequency of the p.Val399= and p.Arg111Ter variants was the highest in patients with classic phenylketonuria(cPKU). The most abundant genotypes observed in PAHD patients were p.Arg53His/p.Arg243Gln, p.Arg53His/p.IVS4-1G>A, and p.Arg53His/p.Arg241Cysp. As for the genotype-phenotype prediction, the APV/GPV system performed well in predicting the actual phenotype, as the overall consistency rate was 85.71% for PAHD patients. In conclusion, we established a PAH gene mutation spectrum in the PAHD patients in Southeastern China. A quantitative correlation analysis between genotype and phenotype severity is helpful for genetic counseling and management.

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Mutational and phenotypic spectrum of phenylalanine hydroxylase deficiency in Zhejiang Province, China

Cited by 17 publications

References 25 publications

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

Neonatal screening and genotype-phenotype correlation of hyperphenylalaninemia in the Chinese population

Characterization of PAH Gene Mutations and Analysis of Genotype-Phenotype Correlation in Patients with Phenylalanine Hydroxylase Deficiency from Fujian Province, Southeastern China

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