scholarly journals Evaluation of a Common Internal Standard Material to Reduce Inter-Laboratory Variation and Ensure the Quality, Safety and Efficacy of Expanded Newborn Screening Results When Using Flow Injection Analysis Tandem Mass Spectrometry with Internal Calibration

2020 ◽  
Vol 6 (4) ◽  
pp. 92
Author(s):  
Rachel S. Carling ◽  
Catharine John ◽  
Philippa Goddard ◽  
Caroline Griffith ◽  
Simon Cowen ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Internal Standard ◽  
Population Data ◽  
Glutaric Aciduria Type ◽  
Glutaric Aciduria Type 1 ◽  
Standard Material ◽  
Maple Syrup ◽  
Expanded Newborn Screening ◽  
Urine Disease ◽  
Set Up

In 2015, the newborn screening (NBS) programmes in England and Wales were expanded to include four additional disorders: Classical Homocystinuria, Isovaleric Acidemia, Glutaric Aciduria Type 1 and Maple Syrup Urine Disease, bringing the total number of analytes quantified to eight: phenylalanine, tyrosine, leucine, methionine, isovalerylcarnitine, glutarylcarnitine, octanoylcarnitine and decanoylcarnitine. Post-implementation, population data monitoring showed that inter-laboratory variation was greater than expected, with 90th centiles varying from 17% to 59%. We evaluated the effect of stable isotope internal standard (IS) used for quantitation on inter-laboratory variation. Four laboratories analysed routine screening samples (n > 101,820) using a common IS. Inter-laboratory variation was determined for the eight analytes and compared with results obtained using an in-house common IS (n > 102,194). A linear mixed-effects model was fitted to the data. Using a common IS mix reduced the inter-laboratory variation significantly (p < 0.05) for five analytes. For three analytes, the lack of significance was explained by use of individual laboratory “calibration factors”. For screening programmes where laboratories adhere to single analyte cut-off values (COVs), it is important that inter-laboratory variation is minimised, primarily to prevent false positive results. Whilst the use of a common IS helps achieve this, it is evident that instrument set-up also contributes to inter-laboratory variation.

scholarly journals Clinical, Biochemical, and Radiologic Characteristics of Filipino Patients with Glutaric Aciduria Type 1

2020 ◽  
Vol 54 (4) ◽  
Author(s):  
Ebner Bon G. Maceda ◽  
Mary Ann R. Abacan ◽  
Mary Anne D. Chiong
Keyword(s):  
Newborn Screening ◽  
General Hospital ◽  
Inborn Error ◽  
The Philippines ◽  
Glutaric Aciduria Type ◽  
Glutaric Aciduria Type 1 ◽  
Glutaric Aciduria ◽  
Expanded Newborn Screening ◽  
Radiologic Characteristics

Introduction. Glutaric Aciduria Type 1 (GA1) is an inborn error of metabolism included in the expanded newborn screening of the Philippines. This inborn error of metabolism is caused by glutaryl-CoA dehydrogenase deficiency which is important in the catabolism of lysine, hydroxylysine and tryptophan.Objective. This paper aimed to present the baseline data of patients with GA1 in the Philippines by describing the clinical, biochemical, and radiologic characteristics of Filipino patients with biochemically-confirmed GA1 seen at the Philippine General Hospital from January 2010 to December 2017. The cases of this condition have been increasing and are expected to increase even more with the full coverage of the expanded newborn screening.Methods. This study was a review of the medical records of the GA1 patients managed by the Division of Clinical Genetics, Department of Pediatrics of the Philippine General Hospital (PGH). Biochemical parameters, developmental  assessment, neurologic assessment, and radiologic features of the patients were reviewed and analyzed.Results. There were a total of 7 patients with GA1 at the PGH from January 2010 to December 2017. Of the 7 patients, 4 were diagnosed by expanded newborn screening (ENBS) and 3 patients had disease onset prior to diagnosis. Clinical features noted in screened patients include global developmental delay (75%), seizures (50%), dystonia (50%), truncal hypotonia (25%) and macrocephaly (25%). In unscreened patients, macrocephaly was present in 66.67 %, while the other clinical features were present in all of them. Four of the 7 patients had infection and one had vaccination, which may have led to a metabolic crisis and subsequent onset of symptoms. The plasma levels of glutarylcarnitine (C5DC) range from 2.81 to 4.58 umol/L. Grossly elevated urinary excretion of glutarylcarnitine were noted in all patients. Urinary glutaconic acid and 3-hydroxyglutaric acid were also detected in all patients. Both striatal and extra-striatal abnormalities were present in screened and unscreened patients on neuroimaging. The most common being the widening of the sylvian fissure, cerebral atrophy, and white matter abnormalities.Conclusion. Although newborn screening of GA1 and initiation of early management of this condition have been seen important, it is still prudent to continue the appropriate management and to provide timely aggressive emergency treatment in order to improve outcome of patients with GA1. With the recent Philippine Health Insurance (PhilHealth) coverage of the expanded newborn screening, it is expected that physicians will encounter more of the metabolic disorders, including GA1. Hence, it is important that physicians be more aware of the presenting signs and symptoms of this disorder, as well as its management, which can further improve the neurologic and developmental outcomes of these patients.

scholarly journals Epilepsy in inborn errors of metabolism: two cases with unusual presentation

2014 ◽  
Vol 01 (01) ◽  
pp. 043-046
Author(s):  
Suvasini Sharma ◽  
Puneet Jain ◽  
Chellamuthu Prabaharan ◽  
Jeedan Hemrom ◽  
Seema Kapoor ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Neurodevelopmental Outcome ◽  
Epileptic Encephalopathy ◽  
Glutaric Aciduria Type ◽  
Inborn Errors ◽  
Glutaric Aciduria Type 1 ◽  
Maple Syrup ◽  
Life Saving ◽  
Inherited Metabolic Disorders ◽  
Urine Disease

AbstractInherited metabolic disorders are a rare cause of epilepsy in children. We describe a case of Glutaric aciduria type 1 presenting with West syndrome and a case of intermittent Maple syrup urine disease presenting with epileptic encephalopathy. Early diagnosis and institution of appropriate therapy may be life saving and may improve the long term neurodevelopmental outcome in children with inherited metabolic disorders.

scholarly journals Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning

2021 ◽  
Vol 7 (2) ◽  
pp. 25
Author(s):  
Mona Sajeev ◽  
Sharon Chin ◽  
Gladys Ho ◽  
Bruce Bennetts ◽  
Bindu Parayil Sankaran ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Maple Syrup Urine Disease ◽  
Dietary Intervention ◽  
Brain Mri ◽  
Prenatal Testing ◽  
Intermediate Form ◽  
Motor Delay ◽  
Maple Syrup ◽  
Hyperintense Signal ◽  
Urine Disease

Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A>G (p. Tyr122Cys) in the DBT gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics.

scholarly journals Second-Tier Test for Quantification of Alloisoleucine and Branched-Chain Amino Acids in Dried Blood Spots to Improve Newborn Screening for Maple Syrup Urine Disease (MSUD)

2008 ◽  
Vol 54 (3) ◽  
pp. 542-549 ◽  
Author(s):  
Devin Oglesbee ◽  
Karen A Sanders ◽  
Jean M Lacey ◽  
Mark J Magera ◽  
Bruno Casetta ◽  
...  
Keyword(s):  
Amino Acids ◽  
Newborn Screening ◽  
Dried Blood Spots ◽  
Branched Chain Amino Acids ◽  
Maple Syrup ◽  
Blood Spots ◽  
Urine Disease ◽  
Second Tier ◽  
Branched Chain ◽  
Positive Results

Abstract Background: Newborn screening for maple syrup urine disease (MSUD) relies on finding increased concentrations of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine by tandem mass spectrometry (MS/MS). d-Alloisoleucine (allo-Ile) is the only pathognomonic marker of MSUD, but it cannot be identified by existing screening methods because it is not differentiated from isobaric amino acids. Furthermore, newborns receiving total parenteral nutrition often have increased concentrations of BCAAs. To improve the specificity of newborn screening for MSUD and to reduce the number of diet-related false-positive results, we developed a LC-MS/MS method for quantifying allo-Ile. Methods: Allo-Ile and other BCAAs were extracted from a 3/16-inch dried blood spot punch with methanol/H2O, dried under nitrogen, and reconstituted into mobile phase. Quantitative LC-MS/MS analysis of allo-Ile, its isomers, and isotopically labeled internal standards was achieved within 15 min. To determine a reference interval for BCAAs including allo-Ile, we analyzed 541 dried blood spots. We also measured allo-Ile in blinded samples from 16 MSUD patients and 21 controls and compared results to an HPLC method. Results: Intra- and interassay imprecision (mean CVs) for allo-Ile, leucine, isoleucine, and valine ranged from 1.8% to 7.4%, and recovery ranged from 91% to 129%. All 16 MSUD patients were correctly identified. Conclusions: The LC-MS/MS method can reliably measure allo-Ile in dried blood spots for the diagnosis of MSUD. Applied to newborn screening as a second-tier test, it will reduce false-positive results, which produce family anxiety and increase follow-up costs. The assay also appears suitable for use in monitoring treatment of MSUD patients.

Sign in / Sign up

Export Citation Format

Share Document