scholarly journals Mass Spectrometry but Not Fluorimetry Distinguishes Affected and Pseudodeficiency Patients in Newborn Screening for Pompe Disease

2017 ◽  
Vol 63 (7) ◽  
pp. 1271-1277 ◽  
Author(s):  
Hsuan-Chieh Liao ◽  
Min-Ju Chan ◽  
Chia-Feng Yang ◽  
Chuan-Chi Chiang ◽  
Dau-Ming Niu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Late Onset ◽  
Asian Population ◽  
Dried Blood Spots ◽  
Fluorimetric Assay ◽  
Analytical Range ◽  
Patient Referrals

Abstract BACKGROUND Deficiency of the lysosomal enzyme acid α-glucosidase (GAA) causes Pompe disease. Newborn screening for Pompe disease is ongoing, and improved methods for distinguishing affected patients from those with pseudodeficiency, especially in the Asian population, would substantially reduce the number of patient referrals for clinical follow-up. METHODS We measured the enzymatic activity of GAA in dried blood spots on newborn screening cards (DBS) using a tandem mass spectrometry (MS/MS) assay. The assay displayed a relatively large analytical range compared to the fluorimetric assay with 4-methylumbelliferyl-α-glucoside. DBS from newborns confirmed to have infantile-onset Pompe disease (IOPD, n = 11) or late-onset Pompe disease (LOPD) (n = 12) and those from patients bearing pseudodeficiency alleles with or without Pompe mutations, or Pompe disease carriers (n = 230) were studied. RESULTS With use of the MS/MS GAA assay in DBS, 96% of the pseudodeficiency newborns and all of the Pompe disease carriers were well separated from the IOPD and LOPD newborns. The fluorimetric assay separated <10% of the pseudodeficiencies from the IOPD/LOPD group. CONCLUSIONS The relatively large analytical range MS/MS GAA assay but not the fluorimetric assay in DBS provides a robust approach to reduce the number of referrals and should dramatically facilitate newborn screening of Pompe disease.

Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography–tandem mass spectrometry: A reliable follow-up method for propionylcarnitine-related disorders in newborn screening

2020 ◽  
pp. 096914132093772
Author(s):  
Zhenzhen Hu ◽  
Jianbin Yang ◽  
Yiming Lin ◽  
Junjuan Wang ◽  
Lingwei Hu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Newborn Screening ◽  
Methylmalonic Acid ◽  
Dried Blood Spots ◽  
Tandem Mass ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Total Homocysteine

Objectives Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography–tandem mass spectrometry has usually been used as a second-tier test to improve performance of newborn screening for propionylcarnitine-related disorders. However, factors that potentially affect its detection results have not been investigated, and we aimed to evaluate these influencing factors and explore their potential utility in newborn screening and initial follow-up for propionylcarnitine-related disorders. Methods This study comprised a prospective group (1998 healthy infants, to establish cutoff values and investigate the influencing factors) and a retrospective group (804 suspected positive cases screened from 381, 399 newborns for propionylcarnitine-related disorders by tandem mass spectrometry, to evaluate the performance of newborn screening and initial follow-up). Results Cutoff values for methylmalonic acid, 2-methylcitric acid, and total homocysteine were 2.12, 0.70, and 10.05 µmol/l, respectively. Concentration of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots is not impacted by sex, age, birth weight, gestational age, or dried blood spot storage time. A total of 75 of 804 cases were screened positive by combined tandem mass spectrometry and liquid chromatography–tandem mass spectrometry, thus eliminating 90% of the false positives without compromising sensitivity. Eighteen propionylcarnitine-related disorders were successfully identified, including one CblX case missed in the initial follow-up by tandem mass spectrometry. Conclusions Methylmalonic acid, 2-methylcitric acid, and total homocysteine detected in dried blood spots by liquid chromatography–tandem mass spectrometry is a reliable, specific, and sensitive approach for identifying propionylcarnitine-related disorders. We recommend this assay should be performed rather than tandem mass spectrometry in follow-up for propionylcarnitine-related disorders besides second-tier tests in newborn screening.

scholarly journals Current status of newborn screening for Pompe disease in Japan

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Takaaki Sawada ◽  
Jun Kido ◽  
Keishin Sugawara ◽  
Ken Momosaki ◽  
Shinichiro Yoshida ◽  
...  
Keyword(s):  
United States ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Autosomal Recessive ◽  
Late Onset ◽  
The United States ◽  
Current Status ◽  
Inherited Metabolic Disorder ◽  
Enzyme Replacement

Abstract Background Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (GAA). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease. Results From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years. Conclusions The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.

scholarly journals Current Status of Newborn Screening for Pompe Disease in Japan

2021 ◽  
Author(s):  
Takaaki Sawada ◽  
Jun Kido ◽  
Keishin Sugawara ◽  
Ken Momosaki ◽  
Shinichiro Yoshida ◽  
...  
Keyword(s):  
United States ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Autosomal Recessive ◽  
Late Onset ◽  
The United States ◽  
Current Status ◽  
Inherited Metabolic Disorder ◽  
Enzyme Replacement

Abstract Background: Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (AαGlu). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease.Results: From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years.Conclusions: The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.

scholarly journals At-Risk Testing for Pompe Disease Using Dried Blood Spots: Lessons Learned for Newborn Screening

2020 ◽  
Vol 6 (4) ◽  
pp. 96
Author(s):  
Zoltan Lukacs ◽  
Petra Oliva ◽  
Paulina Nieves Cobos ◽  
Jacob Scott ◽  
Thomas P. Mechtler ◽  
...  
Keyword(s):  
At Risk ◽  
Enzyme Activity ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Age Of Onset ◽  
Late Onset ◽  
Dried Blood Spots ◽  
Lessons Learned ◽  
Unknown Etiology ◽  
Activity Measurement

Pompe disease (GSD II) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid-α-glucosidase (GAA, EC 3.2.1.20), leading to generalized accumulation of lysosomal glycogen especially in the heart, skeletal, and smooth muscle, and the nervous system. It is generally classified based on the age of onset as infantile (IOPD) presenting during the first year of life, and late onset (LOPD) when it presents afterwards. In our study, a cohort of 13,627 samples were tested between January 2017 and December 2018 for acid-α-glucosidase (GAA, EC 3.2.1.20) deficiency either by fluorometry or tandem mass spectrometry (MS). Testing was performed for patients who displayed conditions of unknown etiology, e.g., CK elevations or cardiomyopathy, in the case of infantile patients. On average 8% of samples showed activity below the reference range and were further assessed by another enzyme activity measurement or molecular genetic analysis. Pre-analytical conditions, like proper drying, greatly affect enzyme activity, and should be assessed with measurement of reference enzyme(s). In conclusion, at-risk testing can provide a good first step for the future introduction of newborn screening for Pompe disease. It yields immediate benefits for the patients regarding the availability and timeliness of the diagnosis. In addition, the laboratory can introduce the required methodology and gain insights in the evaluation of results in a lower throughput environment. Finally, awareness of such a rare condition is increased tremendously among local physicians which can aid in the introduction newborn screening.

scholarly journals Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants

2020 ◽  
Vol 6 (1) ◽  
pp. 4 ◽  
Author(s):  
Barbara K. Burton ◽  
Joel Charrow ◽  
George E. Hoganson ◽  
Julie Fleischer ◽  
Dorothy K. Grange ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Pompe Disease ◽  
Late Onset ◽  
Definitive Diagnosis ◽  
Glucosidase Activity ◽  
Alpha Glucosidase

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.

Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Yiming Lin ◽  
Weifeng Zhang ◽  
Zhixu Chen ◽  
Chunmei Lin ◽  
Weihua Lin ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Genetic Analysis ◽  
Tandem Mass Spectrometry ◽  
Newborn Screening ◽  
Dehydrogenase Deficiency ◽  
Late Onset ◽  
False Negative ◽  
Tandem Mass ◽  
Lipid Storage Myopathy ◽  
Molecular Features

Abstract Objectives Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. Methods From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. Results Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). Conclusions These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

scholarly journals Newborn Screening for Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase and Mitochondrial Trifunctional Protein Deficiencies Using Acylcarnitines Measurement in Dried Blood Spots—A Systematic Review of Test Accuracy

2021 ◽  
Vol 9 ◽  
Author(s):  
Chris Stinton ◽  
Hannah Fraser ◽  
Julia Geppert ◽  
Rebecca Johnson ◽  
Martin Connock ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Dried Blood Spots ◽  
Test Accuracy ◽  
Tandem Mass ◽  
Blood Spots ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Sensitivity Specificity ◽  
Long Chain

Background: Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies are rare autosomal recessive fatty acid β-oxidation disorders. Their clinical presentations are variable, and premature death is common. They are included in newborn blood spot screening programs in many countries around the world. The current process of screening, through the measurement of acylcarnitines (a metabolic by-product) in dried blood spots with tandem mass spectrometry, is subject to uncertainty regarding test accuracy.Methods: We conducted a systematic review of literature published up to 19th June 2018. We included studies that investigated newborn screening for LCHAD or MTP deficiencies by tandem mass spectrometry of acylcarnitines in dried blood spots. The reference standards were urine organic acids, blood acylcarnitine profiles, enzyme analysis in cultured fibroblasts or lymphocytes, mutation analysis, or at least 10-year follow-up. The outcomes of interest were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Assessment of titles, abstracts, and full-text papers and quality appraisal were carried out independently by two reviewers. One reviewer extracted study data. This was checked by a second reviewer.Results: Ten studies provided data on test accuracy. LCHAD or MTP deficiencies were identified in 23 babies. No cases of LCHAD/MTP deficiencies were identified in four studies. PPV ranged from 0% (zero true positives and 28 false positives from 276,565 babies screened) to 100% (13 true positives and zero false positives from 2,037,824 babies screened). Sensitivity, specificity, and NPV could not be calculated as there was no systematic follow-up of babies who screened negative.Conclusions: Test accuracy estimates of screening for LCHAD and MTP deficiencies with tandem mass spectrometry measurement of acylcarnitines in dried blood were variable in terms of PPVs. Screening methods (including markers and thresholds) varied between studies, and sensitivity, specificity, and NPVs are unknown.

scholarly journals M Mode Ultrasound and Tissue Doppler Imaging to Assess Diaphragm Function in Late Onset Pompe Disease

2020 ◽  
Author(s):  
Paris Meng ◽  
Adam Ogna ◽  
Abdallah Fayssoil
Keyword(s):  
Tissue Doppler Imaging ◽  
Pompe Disease ◽  
Skeletal Muscles ◽  
Storage Disease ◽  
Late Onset ◽  
Tissue Doppler ◽  
Doppler Imaging ◽  
Lysosomal Storage ◽  
Diaphragm Function

Late onset Pompe disease is a recessive lysosomal storage disease. Clinical features include skeletal muscles deficiency and diaphragm weakness. Clinical management relies on supportive treatment and mechanical ventilation in patents with chronic respiratory failure. M mode ultrasound and tissue Doppler imaging can be used to assess and to follow up diaphragm function.

scholarly journals National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Follow-Up Testing for Metabolic Disease Identified by Expanded Newborn Screening Using Tandem Mass Spectrometry; Executive Summary

2009 ◽  
Vol 55 (9) ◽  
pp. 1615-1626 ◽  
Author(s):  
Dennis J Dietzen ◽  
Piero Rinaldo ◽  
Ronald J Whitley ◽  
William J Rhead ◽  
W Harry Hannon ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Amino Acids ◽  
Tandem Mass Spectrometry ◽  
Organic Acids ◽  
Newborn Screening ◽  
Tandem Mass ◽  
Confirmatory Testing ◽  
The Us ◽  
The Impact

Abstract Background: Almost all newborns in the US are screened at birth for multiple inborn errors of metabolism using tandem mass spectrometry. Screening tests are designed to be sufficiently sensitive so that cases are not missed. The NACB recognized a need for standard guidelines for laboratory confirmation of a positive newborn screen such that all babies would benefit from equal and optimal follow-up by confirmatory testing. Methods: A committee was formed to review available data pertaining to confirmatory testing. The committee evaluated previously published guidelines, published methodological and clinical studies, clinical case reports, and expert opinion to support optimal confirmatory testing. Grading was based on guidelines adopted from criteria derived from the US Preventive Services Task Force and on the strength of recommendations and the quality of the evidence. Three primary methods of analyte measurement were evaluated for confirmatory testing including measurement of amino acids, organic acids, and carnitine esters. The committee graded the evidence for diagnostic utility of each test for the screened conditions. Results: Ample data and experience were available to make strong recommendations for the practice of analyzing amino acids, organic acids, and acylcarnitines. Likewise, strong recommendations were made for the follow-up test menu for many disorders, particularly those with highest prevalence. Fewer data exist to determine the impact of newborn screening on patient outcomes in all but a few disorders. The guidelines also provide an assessment of developing technology that will fuel a refinement of current practice and ultimate expansion of the diseases detectable by tandem mass spectrometry. Conclusions: Guidelines are provided for optimal follow-up testing for positive newborn screens using tandem mass spectrometry. The committee regards these tests as reliable and currently optimal for follow-up testing. .

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