Dataset Information

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

ABSTRACT: Phenylalanine hydroxylase deficiency (PAHD), one of the genetic disorders resulting in hyperphenylalaninemia, has a complex phenotype with many variants and genotypes among different populations. Here, we describe the mutational and phenotypic spectrum of PAHD in a cohort of 420 patients from neonatal screening between 1999 and 2016. The observed phenotypes comprised 43.57% classic phenylketonuria, 33.10% mild PKU, and 23.33% mild hyperphenylalaninemia, with an overall PAHD incidence of 1 in 20,445. Genetic testing was performed for 209 patients and 72 variants including seven novel variants were identified. These included two synonymous and five pathogenic nonsynonymous variants (p.S36*, p.T186I, p.L255W, p.F302V and p.R413H). The most common variant among all patients was p.R243Q, followed by p.R241C, p.Y204C, p.R111* and c.442-1G?>?A. Variants p.R53H and p.F392I occurred only in MHP with 19.3% and 8.0% of the observed alleles respectively. The genotypes p.[R241C];[R243Q], p.[R243Q];[R243Q], and p.[Y204C];[R243Q] were abundant across all PAHD patients. The distributions of the null allele and the three defined genotypes, null/null, null/missense, and missense/missense, were significantly different between the cPKU and mPKU patients. However, no significant differences were found between mPKU and MHP patients, indicating that other modifier factors influence the phenotypic outcome in these patients. The data presented here will provide a valuable tool for improved genetic counseling and management of future cases of PAHD in China.

SUBMITTER: Chen T

PROVIDER: S-EPMC6244417 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Chen Ting T Xu Weize W Wu Dingwen D Han Jiamin J Zhu Ling L Tong Fan F Yang Rulai R Zhao Zhengyan Z Jiang Pingping P Shu Qiang Q

Scientific reports 20181120 1

Phenylalanine hydroxylase deficiency (PAHD), one of the genetic disorders resulting in hyperphenylalaninemia, has a complex phenotype with many variants and genotypes among different populations. Here, we describe the mutational and phenotypic spectrum of PAHD in a cohort of 420 patients from neonatal screening between 1999 and 2016. The observed phenotypes comprised 43.57% classic phenylketonuria, 33.10% mild PKU, and 23.33% mild hyperphenylalaninemia, with an overall PAHD incidence of 1 in 20, ...[more]

PMID: 30459323

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Project description:Context17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency.ObjectiveTo examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis.DesignCase series.Patients and resultsWe assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity.ConclusionOur findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.Significance statementHere we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.

Project description:BackgroundDengue is one of the most important vector-bore infectious diseases in China because of its drastic increase in incidence, geographic extension and profound influence on China's economy. This study aims to retrospectively uncover the epidemiological profile of dengue in Zhejiang, one of the most developed provinces in China, and to find the problem existing in dengue control and prevention.MethodologyDescriptive analyses on the dengue incidence and associated factors were performed. We also identified potential space-time cluster and generated the risk map of dengue.Principal findingsA total of 529 cases were reported in Zhejiang Province from 2005 to 2016, and 44.4% were imported. 67.7% of cases were 25~60 years old and the overall male-to-female sex ratio was 1.09:1. Dengue was reported all year round and 70.7% of cases occurred between August and October. Indigenous cases were only reported in the period between July to November and more than half occurred in September. Geographically, dengue was most distributed in Jinghua (3.62 per million), Shaoxing (1.00 per million) and Taizhou (0.81 per million) prefecture level cities. Outbreaks were confirmed in Yiwu, Keqiao and Huangyan counties in 2009, 2015, and 2016, respectively. 73.9% cases would seek medical advice within two days after onset and be confirmed within 9 days after onset. 75.6% would be recognized as dengue within 8 days after their first visit. The time intervals between onset and confirmation (median 7 vs 6 days; Wilcoxon rank sum test Z = -2.40, P = 0.016), first visit and confirmation (median 7 vs 6 days; Wilcoxon rank sum test Z = -2.59, P = 0.009) of indigenous cases were significantly longer than those of imported ones. However, the time intervals between onset and first visit for indigenous cases was shorter (median 0 vs 1 days; Wilcoxon rank sum test Z = -2.10, P = 0.036). Fever (99.1%), fatigue (81.9), rash (63.7%), headache (67.2%) and myalgia (52.60%) were the most frequently mentioned symptoms.ConclusionsZhejiang has recently witnessed an increase in incidence and geographic extension of dengue. Timely diagnosis is important to stop local transmission and outbreak.

Dataset Information

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

Publications

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

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