Genetic diagnosis and follow-up of 49 cases neonatal hypotonia / 中国小儿急救医学

Objective:To summarize the genetic etiology, clinical characteristics and outcomes of neonatal hypotonia in the early stage of NICU, to provide basis for clinicians to early identify diseases and choose reasonable treatments.Methods:The clinical data of neonates with hypotonia admitted to the Department of Neonatology of Children′s Hospital of Xinjiang Uygur Autonomous Region and People′s Hospital of Xinjiang Uygur Autonomous Region from July 2017 to July 2020 were analyzed.Results:A total of 49 children were enrolled in the study, all clinically manifested as unexplained hypotonia, accompanied by special appearance 29 cases(59.18%), metabolic abnormality 18 cases(36.73%), and cranial imagin abnormality 23 cases(46.93%). After gene sequencing a, total of 22(44.89%)patients were confirmed.Thirteen (26.53%) of them were copy number variation, and gene mutation in nine cases(18.36%). The oldest age of these patients was 3 years and 2 months now, while the youngest was 4 months.A total of 16 patients were dead(32.65%). Four (8.16%) patients were lost to follow-up.At present, eighteen (62.07%) patients had mental retardation, and eleven (37.93%) of whom still existed severe physical retardation.Conclusion:We could conduct genetic testing in NICU to improve the diagnosis rate of neonates with unexplained hypotonia, which have high rate of adverse events.Neonates with a clear diagnosis should be treated promptly and give the genetic counseling to reduce the risk for the next children.

The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.

BACKGROUND: Neonatal hyperphenylalaninemia (HPA) screening did not begin until 2009 in the Uygur population because of poor medical and economic conditions. This study intended to investigate HPA incidence rate and characterize mutation spectrum of phenylalanine hydroxylase (PAH) gene within the Uygur population. METHODS: Cross-sectional data of National Direct Reporting System database from 2009 to 2016 were used to calculate incidence rate. All HPA positive newborns were diagnosed and confirmed by Sanger sequencing. A low Phe diet was implemented. RESULTS: A total of 580,608 Uygur neonates were screened, 111 were diagnosed with HPA with an incidence rate of 1:5,230, 58 different mutations in PAH gene were detected. Eight novel variants were found, including two nonsense mutations (L11*, L197*), two splicing mutations (IVS12-2A > C, IVS13-1G > A), one frameshift mutation (K115 > Hfs) and three missense mutations (E368K, E370G, D435V), distributing in twenty patients. A104D was the most frequent mutation in this study, and the other hot spot of R413P was found in 4 patients in a same Uygur village with a carrier rate of 1:2.1. CONCLUSIONS: This is the first study to investigate HPA incidence rate in the Uygur population. Our study highlights regional differences in PAH genotypes and mutation rates.

Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China.

BACKGROUND: Tetrahydrobiopterin (BH4 ) deficiency is an autosomal recessive disorder, which is caused by an enzyme deficiency involved in its synthetic or metabolic pathways. Clinical symptoms may include microcephaly, hypoevolutism, severe ataxia, and seizures. The purposes of this study are to analyze the genotype-phenotype and the pedigree of the first case of BH4 deficiency in the Uygur of China. METHODS: (a) This patient received tandem mass spectrometry, urinary neopterin and biopterin analysis, and determination of dihydropteridine reductase (DHPR) activity in dried blood spots. (b) Blood DNA samples of this patient and her three family members were collected for gene sequencing and mutation analysis. RESULTS: (a) The basic urinary neopterin and biopterin were 1.07 mmol/mol Cr and 3.12 mmol/mol Cr, respectively, and biopterin percentage was 74.42%. The DHPR activity of this patient was 31.11% of normal control. (b) Sanger sequencing of PAH gene in this patient was negative but positive of her sister, which carries 2 heterozygous mutation c.781C>T and c.1238G>C. Next-generation sequencing on the patient identified a homozygous mutation in the quinoid dihydropteridine reductase (QDPR) gene at c.508G>A, which was confirmed by Sanger sequencing. CONCLUSION: (a) The patient was the first case of clinical diagnosis of BH4 deficiency in the Uighur. And there are two types of hyperphenylalaninemia (HPA) in the same family. (b) The mild HPA patient with severe nervous system damage should pay more attention to the BH4 deficiency. (c) Using next-generation sequencing technology can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.