Late onset Pompe disease revealed by newborn screening

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.

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Baseline Urinary Glucose Tetrasaccharide Concentrations in Patients with Infantile- and Late-Onset Pompe Disease Identified by Newborn Screening

JIMD Reports - JIMD Reports, Volume 19 ◽

10.1007/8904_2014_366 ◽

2014 ◽

pp. 67-73 ◽

Cited By ~ 14

Author(s):

Yin-Hsiu Chien ◽

Jennifer L. Goldstein ◽

Wuh-Liang Hwu ◽

P. Brian Smith ◽

Ni-Chung Lee ◽

...

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

Urinary Glucose ◽

Glucose Tetrasaccharide

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Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T > G “late-onset” GAA variant

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2017.12.027 ◽

2018 ◽

Vol 123 (2) ◽

pp. S21

Author(s):

Stephanie Austin ◽

Mugdha Rairikar ◽

Laura Case ◽

Lauren Bailey ◽

Zoheb Kazi ◽

...

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

The Common ◽

C 32 ◽

Insight Into

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Liquid Chromatography–Tandem Mass Spectrometry Assay of Leukocyte Acid α-Glucosidase for Post-Newborn Screening Evaluation of Pompe Disease

Clinical Chemistry ◽

10.1373/clinchem.2016.259036 ◽

2017 ◽

Vol 63 (4) ◽

pp. 842-851 ◽

Cited By ~ 10

Author(s):

Na Lin ◽

Jingyu Huang ◽

Sara Violante ◽

Joseph J Orsini ◽

Michele Caggana ◽

...

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

Treatment Options ◽

Internal Standard ◽

Lysosomal Storage ◽

Blood Samples ◽

Liquid Chromatography Tandem Mass ◽

Progressive Weakness

Abstract BACKGROUND Pompe disease (PD) is the first lysosomal storage disorder to be added to the Recommended Uniform Screening Panel for newborn screening. This condition has a broad phenotypic spectrum, ranging from an infantile form (IOPD), with severe morbidity and mortality in infancy, to a late-onset form (LOPD) with variable onset and progressive weakness and respiratory failure. Because the prognosis and treatment options are different for IOPD and LOPD, it is important to accurately determine an individual's phenotype. To date, no enzyme assay of acid α-glucosidase (GAA) has been described that can differentiate IOPD vs LOPD using blood samples. METHODS We incubated 10 μL leukocyte lysate and 25 μL GAA substrate and internal standard (IS) assay cocktail for 1 h. The reaction was purified by a liquid–liquid extraction. The extracts were evaporated and reconstituted in 200 μL methanol and analyzed by LC-MS/MS for GAA activity. RESULTS A 700-fold higher analytical range was observed with the LC-MS/MS assay compared to the fluorometric method. When GAA-null and GAA-containing fibroblast lysates were mixed, GAA activity could be measured accurately even in the range of 0%–1% of normal. The leukocyte GAA activity in IOPD (n = 4) and LOPD (n = 19) was 0.44–1.75 nmol · h−1 · mg−1 and 2.0–6.5 nmol · h−1 · mg−1, respectively, with no overlap. The GAA activity of pseudodeficiency patients ranged from 3.0–28.1 nmol · h−1 · mg−1, showing substantial but incomplete separation from the LOPD group. CONCLUSIONS This assay allows determination of low residual GAA activity in leukocytes. IOPD, LOPD, and pseudodeficiency patients can be partially differentiated by measuring GAA using blood samples.

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Newborn Screening for Pompe Disease: Pennsylvania Experience

International Journal of Neonatal Screening ◽

10.3390/ijns6040089 ◽

2020 ◽

Vol 6 (4) ◽

pp. 89

Author(s):

Can Ficicioglu ◽

Rebecca C. Ahrens-Nicklas ◽

Joshua Barch ◽

Sanmati R. Cuddapah ◽

Brenda S. DiBoscio ◽

...

Keyword(s):

Enzyme Activity ◽

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

Compound Heterozygous ◽

Variant Of Unknown Significance ◽

Unknown Significance ◽

Second Tier ◽

Alpha Glucosidase ◽

Gaa Gene

Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.

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Two-Tiered Newborn Screening with Post-Analytical Tools for Pompe Disease and Mucopolysaccharidosis Type I Results in Performance Improvement and Future Direction

International Journal of Neonatal Screening ◽

10.3390/ijns6010002 ◽

2020 ◽

Vol 6 (1) ◽

pp. 2 ◽

Cited By ~ 5

Author(s):

Patricia L. Hall ◽

Rossana Sanchez ◽

Arthur F. Hagar ◽

S. Caleb Jerris ◽

Angela Wittenauer ◽

...

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

Screening Program ◽

Molecular Testing ◽

Type I ◽

Mucopolysaccharidosis Type ◽

Mucopolysaccharidosis Type I ◽

Analytical Tools ◽

Mps I

We conducted a pilot newborn screening (NBS) study for Pompe disease (PD) and mucopolysaccharidosis type I (MPS I) in the multiethnic population of Georgia. We screened 59,332 infants using a two-tier strategy of flow injection tandem mass spectrometry (FIA-MSMS) enzyme assays. The first tier of testing was a 2-plex assay measuring PD and MPS I enzyme activity, followed by a second-tier test with additional enzymes to improve specificity. Interpretation of results was performed using post-analytical tools created using Collaborative Laboratory Integrated Reports (CLIR). We identified a single case of infantile onset PD, two cases of late onset PD, and one pseudodeficiency. The positive predictive value (PPV) for PD screening during the study was 66.7%. No cases of MPS I were identified during the study period, but there were 2 confirmed cases of pseudodeficiency and 6 cases lost to follow up. The two-tier screening strategy was successful in reducing false positive results and allowed for the identification and early treatment of a case of infantile PD but the frequency of pseudodeficiency in MPS I is problematic. Molecular testing is required and should be covered by the screening program to avoid delays in case resolution.

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Using Decision Analysis to Support Newborn Screening Policy Decisions: A Case Study for Pompe Disease

MDM Policy & Practice ◽

10.1177/2381468318763814 ◽

2018 ◽

Vol 3 (1) ◽

pp. 238146831876381 ◽

Cited By ~ 5

Author(s):

Lisa A. Prosser ◽

K. K. Lam ◽

Scott D. Grosse ◽

Mia Casale ◽

Alex R. Kemper ◽

...

Keyword(s):

Health Outcomes ◽

Decision Analysis ◽

Newborn Screening ◽

Pompe Disease ◽

Early Identification ◽

Late Onset ◽

Rare Condition ◽

The United States ◽

Policy Decisions ◽

Intervention Policy

Background: Newborn screening is a public health program to identify conditions associated with significant morbidity or mortality that benefit from early intervention. Policy decisions about which conditions to include in newborn screening are complex because data regarding epidemiology and outcomes of early identification are often incomplete. Objectives: To describe expected outcomes of Pompe disease newborn screening and how a decision analysis informed recommendations by a federal advisory committee. Methods: We developed a decision tree to compare Pompe disease newborn screening with clinical identification of Pompe disease in the absence of screening. Cases of Pompe disease were classified into three types: classic infantile-onset disease with cardiomyopathy, nonclassic infantile-onset disease, and late-onset disease. Screening results and 36-month health outcomes were projected for classic and nonclassic infantile-onset cases. Input parameters were based on published and unpublished data supplemented by expert opinion. Results: We estimated that screening 4 million babies born each year in the United States would detect 40 cases (range: 13–56) of infantile-onset Pompe disease compared with 36 cases (range: 13–56) detected clinically without screening. Newborn screening would also identify 94 cases of late-onset Pompe disease that might not become symptomatic for decades. By 36 months, newborn screening would avert 13 deaths (range: 8–19) and decrease the number of individuals requiring mechanical ventilation by 26 (range: 20–28). Conclusions: Pompe disease is a rare condition, but early identification can improve health outcomes. Decision analytic modeling provided a quantitative data synthesis that informed the recommendation of Pompe disease newborn screening.

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Clinical characterization of 20 infants diagnosed with late-onset Pompe disease after positive newborn screening

Molecular Genetics and Metabolism ◽

10.1016/s1096-7192(21)00128-1 ◽

2021 ◽

Vol 132 ◽

pp. S28-S29

Author(s):

Erin Huggins ◽

Maggie Holland ◽

Stephanie Austin ◽

Janet Blount ◽

Jennifer L. Cohen ◽

...

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Late Onset

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A Newborn Screening, Presymptomatically Identified Infant With Late-Onset Pompe Disease: Case Report, Parental Experience, and Recommendations

International Journal of Neonatal Screening ◽

10.3390/ijns6010022 ◽

2020 ◽

Vol 6 (1) ◽

pp. 22

Author(s):

Raymond Y. Wang

Keyword(s):

Newborn Screening ◽

Respiratory Insufficiency ◽

Pompe Disease ◽

Clinical Symptoms ◽

Late Onset ◽

Lysosomal Storage ◽

Parental Experience ◽

Screening Programs ◽

Disease Case ◽

Newborn Screen

Pompe disease is an inherited lysosomal storage disorder caused by acid alpha-glucosidase (GAA) enzyme deficiency, resulting in muscle and neuron intralysosomal glycogen storage. Clinical symptoms vary from the severe, infantile-onset form with hypertrophic cardiomyopathy, gross motor delay, and early death from respiratory insufficiency; to a late-onset form with variable onset of proximal muscle weakness and progressive respiratory insufficiency. Newborn screening programs have been instituted to presymptomatically identify neonates with infantile-onset Pompe disease for early initiation of treatment. However, infants with late-onset Pompe disease are also identified, leaving families and physicians in a state of uncertainty regarding prognosis, necessity, and timing of treatment initiation. This report presents a 31 5/7 weeks’ gestational age premature infant flagged positive for Pompe disease with low dried blood spot GAA activity; sequencing identified biparental c.-32-13T>G/c.29delA GAA variants predicting late-onset Pompe disease. The infant’s parents’ initial reactions to the positive newborn screen, subsequent experience during confirmatory testing, and post-confirmation reflections are also reported. While uncertainties regarding natural history and prognosis of presymptomatically-identified late-onset Pompe disease infants will be elucidated with additional experience, suggestions for education of first-line providers are provided to accurately communicate results and compassionately counsel families regarding anxiety-provoking positive newborn screen results.

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The Timely Needs for Infantile Onset Pompe Disease Newborn Screening—Practice in Taiwan

International Journal of Neonatal Screening ◽

10.3390/ijns6020030 ◽

2020 ◽

Vol 6 (2) ◽

pp. 30

Author(s):

Shu-Chuan Chiang ◽

Yin-Hsiu Chien ◽

Kai-Ling Chang ◽

Ni-Chung Lee ◽

Wuh-Liang Hwu

Keyword(s):

High Risk ◽

Newborn Screening ◽

Pompe Disease ◽

Chinese Population ◽

Late Onset ◽

Gene Sequencing ◽

Enzyme Replacement ◽

Screening Practice ◽

Crim Status ◽

Timely Treatment

Pompe disease Newborn screening (NBS) aims at diagnosing patients with infantile-onset Pompe disease (IOPD) early enough so a timely treatment can be instituted. Since 2015, the National Taiwan University NBS Center has changed the method for Pompe disease NBS from fluorometric assay to tandem mass assay. From 2016 to 2019, 14 newborns were reported as high-risk for Pompe disease at a median age of 9 days (range 6–13), and 18 were with a borderline risk at a median age of 13 days (9–28). None of the borderline risks were IOPD patients. Among the 14 at a high-risk of Pompe disease, four were found to have cardiomyopathy, and six were classified as potential late-onset Pompe disease. The four classic IOPD newborns, three of the four having at least one allele of the cross-reactive immunologic material (CRIM)-positive variant, started enzyme replacement therapy (ERT) at a median age of 9 days (8–14). Western Blot analysis and whole gene sequencing confirmed the CRIM-positive status in all cases. Here, we focus on the patient without the known CRIM-positive variant. Doing ERT before knowing the CRIM status created a dilemma in the decision and was discussed in detail. Our Pompe disease screening and diagnostic program successfully detected and treated patients with IOPD in time. However, the timely exclusion of a CRIM-negative status, which is rare in the Chinese population, is still a challenging task.

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