Identification of proline-rich protein 11 as a major regulator in mouse spermatogonia maintenance via an increase in BMI1 protein stability

Background Despite the popularity of the NeoBase 2 Non-derivatized MSMS assay (PerkinElmer, Turku, Finland), there are no reports of its comprehensive evaluation, including the ability to distinguish transient tyrosinemia of the newborn (TTN) from tyrosinemia type 1 (TYR 1) using succinylacetone (SUAC). No newborn screening (NBS) cutoffs for preterm neonates in the Korean population have been suggested. We evaluated the NeoBase 2 assay and identified analytes requiring different cutoffs in preterm neonates. Methods Residual NBS dried blood spot samples and proficiency testing (PT) materials of the Newborn Screening Quality Assurance Program and the Korean Association of External Quality Assessment Service were used. Precision, accuracy, limit of detection (LOD), lower limit of quantification (LLOQ), linearity, recovery, carryover, and performance of SUAC were evaluated. Cutoffs were determined, and analytes requiring different cutoffs in preterm neonates were investigated. Results Mean CVs for within-run and between-day precision were within 15%. Accuracy analysis indicated high agreement with in-house derivatized assay results and results of other PT participants. All analytes demonstrated acceptable LOD, LLOQ, and linearity. Recoveries were acceptable, except for SUAC. Carryover was negligible. Cutoffs were established for all analytes; Tyr, adenosine, and C200-lysophosphatidylcholine required different cutoffs in preterm neonates. Differential diagnosis of TYR 1 and TTN was successful with simultaneous Tyr and SUAC measurement. Conclusions The NeoBase 2 assay demonstrated satisfactory performance. The additional analytes provide a wider diagnostic coverage, and the simultaneous measurement of Tyr and SUAC is efficient in excluding TYR 1. The new cutoffs for preterm neonates may decrease false-positive rates, without compromising diagnostic sensitivity.

https://www.annlabmed.org/journal/download_pdf.php?doi=10.3343/alm.2023.43.2.153

Comprehensive Evaluation of the NeoBase 2 Non-derivatized MSMS Assay and Exploration of Analytes With Significantly Different Concentrations Between Term and Preterm Neonates

Purpose Neonatal macrosomia is a known complication of maternal obesity and gestational diabetes, and it is a risk factor for obesity and diabetes in offspring. Amino acids and acylcarnitines are biomarkers for obesity in children and adults. These analytes, which are also routinely obtained on the newborn screen, have not been well-characterized in macrosomic newborns. The impact of macrosomia on rates of false-positive results in the newborn screen has also not been well-studied. We test the hypothesis that macrosomia is an interfering factor for amino acids and/or acylcarnitines on the newborn screen. Methods Newborn screening analytes determined by tandem mass spectroscopy were obtained from the Colorado Department of Public Health and Environment archives (2016-2018). This included metabolite concentrations obtained at 24-72 hours of life from newborns with birth weight 2500 to 3999 g (nonmacrosomic, n = 131 896) versus 4000 to 8000 g (macrosomic, n = 7806). Mother/infant phenotypic data were limited to information provided on the newborn screening dried blood spot card. Data were analyzed using Student t-test and chi-squared analysis. Results Macrosomic newborns had elevations in C2, C3, dicarboxylic, and long-chain acylcarnitines (specifically C16 and C18 species). C3 and C18:1 were 2 to 3 times more likely to be above predetermined state cutoffs in macrosomic versus nonmacrosomic newborns (both male and female). Main conclusions Macrosomia is an interfering factor for the analytes C3 and C18:1, leading to higher risk of false-positive results for methylmalonic/propionic acidemia and carnitine palmitoyl transferase type 2 deficiency, respectively. Analyte patterns found in macrosomic neonates correspond with similar analyte patterns in obese children and adults.

Neonatal Macrosomia is an Interfering Factor for Analytes on the Colorado State Newborn Screen.

Inborn errors of metabolism (IEMs) frequently result in progressive and irreversible clinical consequences if not be diagnosed or treated timely. The tandem mass spectrometry (MS/MS)-based newborn screening (NBS) facilitates early diagnosis and treatment of IEMs. The aim of this study was to determine the characteristics of IEMs and the successful deployment and application of MS/MS screening over a 19-year time period in Shanghai, China, to inform national NBS policy.The amino acids and acylcarnitines in dried blood spots from 1,176,073 newborns were assessed for IEMs by MS/MS. The diagnosis of IEMs was made through a comprehensive consideration of clinical features, biochemical performance and genetic testing results. The levels of MS/MS testing parameters were compared between various IEM subtypes and genotypes.A total of 392 newborns were diagnosed with IEMs from January 2003 to June 2022. There were 196 newborns with amino acid disorders (50.00%, 1: 5910), 115 newborns with organic acid disorders (29.59%, 1: 10,139), and 81 newborns with fatty acid oxidation disorders (20.41%; 1:14,701). Phenylalanine hydroxylase deficiency, methylmalonic acidemia and primary carnitine deficiency were the three most common disorders. Some hotspot variations in eight IEM genes (PAH, SLC22A5, MMACHC, MMUT, MAT1A, MCCC2, ACADM, ACAD8), 35 novel variants and some genotype-biochemical phenotype associations were identified.A total of 28 types of IEMs were identified, with an overall incidence of 1: 3000 in Shanghai, China. Our study offered clinical guidance for the implementation of MS/MS-based NBS and genetic counseling for IEMs in this city. 

Screening of 1.17 million newborns for inborn errors of metabolism using tandem mass spectrometry in Shanghai, China: A 19-year report

The estimated prevalence of tetrahydrobiopterin deficiency (BH4D) and the mutational spectrum of the causal 6-pyruvoyl-tetrahydropterin synthase (PTS) gene vary widely according to race and region. This study assessed the prevalence and genetic characteristics of BH4D in Fujian Province, southeastern China. A total of 3,204,067 newborns were screened between 2012 and 2022 based on the phenylalanine level and the phenylalanine/tyrosine ratio in dried blood spots. Differential diagnosis was determined by the urine purine spectrum, dihydropteridine reductase activity in red blood cells, and genetic testing. The PTS mutation spectrum and genotypes were determined by next-generation sequencing. A total of 189 newborns were diagnosed with hyperphenylalaninemia (HPA) over the study period, including 159 with phenylalanine hydroxylase deficiency and 30 with BH4D. Therefore, the prevalence of BH4D in Fujian was 9.36 per 1,000,000 live births (30/3,204,067) and the proportion of BH4D among patients with HPA was 15.87% (30/189). A total of 58 PTS alleles were identified in the 29 patients with PTS deficiency (PTPSD), and those alleles were composed of 10 different variants, including eight missense variants and two splice-site variants. The most prevalent variants were c.155A>G, p.Asn52Ser (44.83%); c.259C>T, p.Pro87Ser (39.66%); and c.84-291A>G, p.Tyr27Argfs*8 (3.45%). The predominant genotype was c [155A>G]; [259C>T] (11/29, 37.93%). The prevalence of BH4D and the spectrum of associated PTS mutations were successfully determined for the first time in Fujian Province, southeastern China. Since the mutation spectrum of PTS is region-specific, such data will facilitate molecular diagnosis and genetic counseling in PTPSD cases.

Biochemical and molecular features of tetrahydrobiopterin deficiency in Fujian Province, southeastern China

Phenylalanine hydroxylase deficiency (PAHD) is the most prevalent inherited disorder of amino acid metabolism in China. Its complex phenotype includes many variants and genotypes among different populations.In this study, we analyzed the phenylalanine hydroxylase gene (PAH) variants in a cohort of 93 PAHD patients from Fujian Province. We also assessed genotype and phenotype correlation in patients with PAHD. A total of 44 different pathogenic variants were identified, including five novel variants. The three most prevalent variants among all patents were c.158G > A, p.(Arg53His) (18.03%), c.721C > T, p.(Arg241Cys) (14.75%), and c.728G > A, p.(Arg243Gln) (7.65%). The frequency of the c.158G > A, p.(Arg53His) variant was highest in patients with mild hyperphenylalaninemia, whereas the frequency of the c.1197A > T, p.(Val399 =) and c.331C > T, p.(Arg111Ter) variants was highest in patients with classic phenylketonuria. The most abundant genotypes observed in PAHD patients were c.[158G > A];[728G > A], c.[158G > A];[442-1G > A], and c.[158G > A];[721C > T]. Comparing allelic phenotype to genotypic phenotype values yielded fairly accurate predictions of phenotype, with an overall consistency rate was 85.71% for PAHD patients.Our study identified a PAH variant spectrum in PAHD patients from Fujian Province, Southeastern China. Quantitative correlation analysis between genotype and phenotype severity is helpful for genetic counseling and management. 

/pdf/characterization-of-phenylalanine-hydroxylase-gene-variants-201o6xto.pdf

Characterization of phenylalanine hydroxylase gene variants and analysis of genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China

A verification of the application of the non-derivatized mass spectrometry method in newborns screening of metabolic disorders.

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Characterization of phenylalanine hydroxylase gene variants and analysis of genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China

A verification of the application of the non-derivatized mass spectrometry method in newborns screening of metabolic disorders.