Two cases of late-onset Argininosuccinic aciduria with normal results at newborn screening (original) (raw)
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Liquid Chromatography tandem mass spectrometry (LC-MS/MS) is used for the diagnosis of more than 30 inborn errors of metabolisms (IEMs). Accurate and reliable diagnosis of IEMs by quantifying amino acids (AAs) and acylcarnitines (ACs) using LC-MS/MS systems depend on the establishment of age-specific cut-offs of the analytes. This study aimed to (1) determine the age-specific cut-off values of AAs and ACs in Bangladesh and (2) validate the LC-MS/MS method for diagnosis of the patients with IEMs. A total of 570 enrolled healthy participants were divided into 3 age groups, namely, (1) newborns (1-7 days), (2) 8 days-7 years, and (3) 8-17 years, to establish the age-specific cut-offs for AAs and ACs. Also, 273 suspected patients with IEMs were enrolled to evaluate the reliability of the established cut-off values. Quantitation of AAs and ACs was performed on an automated LC-MS/MS system using dried blood spot (DBS) cards. Then the specimens of the enrolled clinically suspected patients were analyzed by the established method. Nine patients came out as screening positive for different IEMs, including two borderline positive cases of medium-chain acyl-CoA dehydrogenase deficiency (MCAD). A second-tier test for confirmation of the screening positive cases was conducted by urinary metabolic profiling using gas chromatography-mass spectrometry (GC-MS). Out of 9 cases that came out as screening positive by LC-MS/MS, seven cases were confirmed by urinary GC-MS analysis including 3 cases with phenylketonuria, 1 with citrullinemia type II, 1 with methylmalonic acidemia, 1 with isovaleric acidemia and 1 with carnitine uptake defect. Two borderline positive cases with MCAD were found negative by urinary GC-MS analysis. In conclusion, along with establishment of a validated LC-MS/MS method for quantitation of AAs and ACs from the DBS cards, the study also demonstrates the presence of predominantly available IEMs in Bangladesh.
Colombia medica (Cali, Colombia), 2017
Inborn errors of metabolism (IEM) represent an important public health problem due to current diagnosis and treatment limitations, poor life quality of affected patients, and consequent untimely child death. In contrast to classical methods, tandem mass spectrometry (MS/MS) has allowed simultaneous evaluation of multiple metabolites associated with IEM offering higher sensitivity, low false positive rates and high throughput. Determine concentration levels for amino acids and acylcarnitines in blood of newborns from Colombia, to establish reference values for further use in diagnosis of IEM. Implementation of a method to determine amino acids, acylcarnitines and succinylacetone in newborn dried blood spots using MS/MS, and its application in a cross-sectional study conducted in 891 healthy neonates from Cali and Quibdo cities is described. fifty-seven analytes that allow the diagnosis of more than 40 different pathologies were tested. The method showed to be linear, precise and accu...
Four years of expanded newborn screening in Portugal with tandem mass spectrometry
Journal of Inherited Metabolic Disease, 2010
Introduction The Portuguese Neonatal Screening Programme (PNSP) was started in 1979 for phenylketonuria (2,590,700 newborns screened; prevalence 1:11,031) and, shortly after, for congenital hypothyroidism (2,558,455 newborns screened; prevalence 1:3,174). In 2004, expanded neonatal screening was implemented in the National Laboratory. The programme is not mandatory and has 99.8% coverage of the country (including Madeira and the Azores islands). Material and methods In the past 4 years, 316,243 neonates were screened with the use of tandem mass spectrometry (MS/MS) to test for selected amino acids and acylcarnitines. Results During this time, 132 patients were identified with 24 different inherited metabolic diseases (classic forms and variants). To date, the global frequency for all disorders integrated into the PNSP is estimated to be 1:1,380, with 1:2,396 for metabolic disorders. A total of 379 tests (0.12%) were classified as having false positive results, yielding an overall specificity of 99.9%. Despite the low frequency of several disorders, the positive predictive value of the overall MS/MS screening was found to be 26%, reflecting high diagnostic specificity of the method. Diagnostic sensitivity of extended screening for the different groups of disorders was 100%. Eight cases of maternal disorders [three glutaric aciduria type I, one carnitine transporter defect, and four 3-methylcrotonyl coenzyme A (CoA) carboxylase deficiency] were also detected through newborn screening. Conclusions Our data support the advantage of a centralised laboratory for screening an elevated number of samples and making decisions if relying on a clinical network able to provide fast treatment and a good outcome in the screened cases.
Clinical Epidemiology and Global Health, 2021
To evaluate the diagnostic accuracy of a set of predefined biomarkers (index test) in diagnosing diseases targeted in expanded newborn screening (ENS) namely organic acidemias, fatty acid oxidation disorders, and amino acid disorders. Methods: This was a prospective study. The study population consisted of out born neonates admitted to a teaching hospital for the study duration of 12 months. The presence of any of the predefined biomarkers was considered index test positive. Tandem Mass Spectrometry on dried blood samples along with urinary gas chromatography mass spectrometry (GCMS) was considered the gold standard (reference test) for diagnosis of diseases targeted in ENS. Results: A total of 783 out born neonates were evaluated using the index test and 30 tested positive, out of which, 18 were reference test positive. All index test negative neonates (n = 30) were reference test negative. The index test had a sensitivity of 100%, specificity of 71.42%, with 60% positive predictive value and 100% negative predictive value. The area under ROC curve for the index test was 80%. Conclusions: In the absence of universal screening programs, the evaluated biomarkers (index test) can be useful to decide which cases should be selectively referred for mass spectrometric techniques. Further multicentric studies are required to assess these biomarkers before incorporating them in national programs.
Analytical Chemistry, 2008
The advent of electrospray-ionization mass spectrometry (ESI-MS) has given rise to expanded newborn screening programs for the early detection of inborn errors of metabolism (IEM). Despite the benefit of high-throughput screening for disease prognosis, conventional ESI-MS methods are limited by inadequate specificity, complicated sample handling, and low positive predictive outcome that can contribute to a high rate of false-positives. Herein, we report a robust strategy for neonatal screening based on capillary electrophoresis-electrospray ionizationmass spectrometry (CE-ESI-MS) that offers a convenient platform for the direct analysis of amino acids, acylcarnitines, and their stereoisomers from dried blood spot (DBS) extracts without chemical derivatization. On-line sample preconcentration with desalting by CE-ESI-MS allowed for improved concentration sensitivity when detecting poorly responsive metabolites in complex biological samples without ionization suppression or isomeric/ isobaric interferences. Method validation demonstrated that accurate yet precise quantification can be achieved for 20 different amino acid and acylcarnitine biomarkers associated with IEMs when using a single non-deuterated internal standard. CE-ESI-MS represents a promising second-tier method in newborn screening programs that is compatible with ESI-MS/MS technology in cases when improved specificity and sensitivity is warranted for diagnosis confirmation and subsequent monitoring.
International Journal of Clinical Biochemistry and Research, 2023
Background: Inborn errors of metabolism are rare inherited disorders which leads to significant morbidity and mortality in patients. Very few studies have been conducted in India to assess prevalence of Inborn Errors of Metabolism (IEM) in newborns. We proposed testing by TMS/TR-FIA followed by NGS. This pilot study would be one of the ?rst expanded NBS studies in India. Objectives: The aim of this study was to determine the prevalence of IEM in newborns based on the samples received at Metropolis Global Reference Lab, India. Next-generation sequencing (NGS) was done as a con?rmational analysis for patients tested presumptive positive on Newborn screening using Tandem Mass spectrometry (TMS) and Time-resolved fluoroimmunoassay (TR-FIA). Materials and Methods: Two years retrospective study was conducted based on incidences of IEM using TMS and TR-FIA. NGS testing was performed on presumptive positive newborns for cystic fibrosis (CF), galactosemia and urea cycle disorder/ organic academia (UCD /OA) who had undergone NBS by TMS and TR-FIA. Results: Highest prevalence of 1.98% & 1.58% was detected for G6PD and TSH respectively by TR-FIA. Prevalence of AA disorders (3.20%), OA (1.60%) and UCD (1.43%) was observed to be the highest amongst the diseases detected by TMS. Presumptive positive case of Argininemia and Cystic Fibrosis were found to be concordant with NGS. Out of three presumptive positive cases, one presumptive positive case of CF and two of galactose were found discordant. Conclusions: Our prevalence study showed similarities to the prevalence reports published by other Asian countries. Expanded NBS program can be improved by including NGS as a first follow-up test after detection of abnormal metabolites in DBS. This approach will help in reducing the encumbrance of false-positive as well as false-negative cases. Our study will be influential in conducting more prospective studies and routine implementation of NGS-based analysis in NBS in India. Keywords: NBS, IEM, TMS, TR-FIA, Prevalence, NGS.
Methods in molecular biology (Clifton, N.J.), 2011
The analysis of organic acids in urine is commonly included in routine procedures for detecting many inborn errors of metabolism. Many analytical methods allow for both qualitative and quantitative determination of organic acids, mainly in urine but also in plasma, serum, whole blood, amniotic fluid, and cerebrospinal fluid. Liquid-liquid extraction and solid-phase extraction using anion exchange or silica columns are commonly employed approaches for sample treatment. Before analysis can be carried out using gas chromatography-mass spectrometry, organic acids must be converted into more thermally stable, volatile, and chemically inert forms, mainly trimethylsilyl ethers, esters, or methyl esters.
Targeted metabolomics in the expanded newborn screening for inborn errors of metabolism
Mol. BioSyst., 2015
Inborn errors of metabolism are genetic disorders due to impaired activity of enzymes, transporters, or cofactors resulting in accumulation of abnormal metabolites proximal to the metabolic block, lack of essential products or accumulation of by-products. Many of these disorders have serious clinical consequences for affected neonates, and an early diagnosis allows presymptomatic treatment which can prevent severe permanent sequelae and in some cases death. Expanded newborn screening for these diseases is a promising field of targeted metabolomics. Here we report the application, between 2007 and 2014, of this approach to the identification of newborns in southern Italy at risk of developing a potentially fatal disease. The analysis of amino acids and acylcarnitines in dried blood spots by tandem mass spectrometry revealed 24 affected newborns among 45 466 infants evaluated between 48 and 72 hours of life (overall incidence: 1 : 1894). Diagnoses of newborns with elevated metabolites were confirmed by gas chromatography-mass spectrometry, biochemical studies, and genetic analysis. Five infants were diagnosed with medium-chain acyl CoA dehydrogenase deficiency, 1 with methylmalonic acidemia with homocystinuria type CblC, 2 with isolated methylmalonic acidemia, 1 with propionic acidemia, 1 with isovaleric academia, 1 with isobutyryl-CoA dehydrogenase deficiency, 1 with beta