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Newborn Screening for Pompe Disease

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A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 55297

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Prof. Dr. Wuh-Liang Hwu

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Guest Editor

Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan
Interests: inborn errors of metabolism; newborn screening; gene therapy; next generation sequencing

Prof. Dr. Yin-Hsiu Chien

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Guest Editor

Department of Medical Genetics, National Taiwan University Hospital, Taipei 10041, Taiwan

Dr. Raymond Wang

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Guest Editor

Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, CA 92868, USA

Special Issue Information

Dear Colleagues,

Newborn screening is important for the early diagnosis and treatment of Pompe disease. The initial successes of Pompe disease newborn screening were from Taiwan, and currently, a good number of newborn screening programs have already started or are in the planning stages. However, screening for Pompe disease is not without its difficulties. There are a few assays available for screening. The accuracy of the assay as well as the screening algorithm determine the false positive and negative rates. Confirming diagnosis can be difficult, and genotype–phenotype correlation may not be established. Decision about when to initiate treatment, especially for late-onset Pompe disease, is difficult. To add to this, all these problems are further diverse among different ethnic groups. Therefore, we think it is the right time to organize a Special Issue on Pompe disease newborn screening in the International Journal of Neonatal Screening. Through this Special Issue, experts in the field of newborn screening can share experiences in Pompe disease and help to accumulate data concerning prevalence, genotype, and phenotypes. More general readers of the Journal can also have the chance to understand Pompe disease and its screening. We think this Special Issue is just in time, and we thank all contributing authors in advance.

Prof. Dr. Wuh-Liang Hwu
Prof. Dr. Yin-Hsiu Chien
Dr. Raymond Wang
Guest Editors

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Keywords

Newborn screening
Pompe disease
Pseudodeficiency
Genotype–phenotype correlation
Treatment and follow up

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Published Papers (13 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 175 KiB

Open AccessEditorial

Development of Newborn Screening for Pompe Disease

by Wuh-Liang Hwu and Yin-Hsiu Chien

Int. J. Neonatal Screen. 2020, 6(1), 5; https://doi.org/10.3390/ijns6010005 - 24 Jan 2020

Cited by 3 | Viewed by 2245

Abstract

Pompe disease is an inborn error of lysosomal degradation of glycogen [...] Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

Research

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8 pages, 244 KiB

Open AccessArticle

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

by Zoltan Lukacs, Petra Oliva, Paulina Nieves Cobos, Jacob Scott, Thomas P. Mechtler and David C. Kasper

Int. J. Neonatal Screen. 2020, 6(4), 96; https://doi.org/10.3390/ijns6040096 - 21 Dec 2020

Cited by 1 | Viewed by 2592

Abstract

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. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

17 pages, 2976 KiB

Open AccessArticle

Newborn Screening for Pompe Disease: Pennsylvania Experience

by Can Ficicioglu, Rebecca C. Ahrens-Nicklas, Joshua Barch, Sanmati R. Cuddapah, Brenda S. DiBoscio, James C. DiPerna, Patricia L. Gordon, Nadene Henderson, Caitlin Menello, Nicole Luongo, Damara Ortiz and Rui Xiao

Int. J. Neonatal Screen. 2020, 6(4), 89; https://doi.org/10.3390/ijns6040089 - 13 Nov 2020

Cited by 28 | Viewed by 4874

Abstract

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. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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7 pages, 296 KiB

Open AccessArticle

Expanding Newborn Screening for Pompe Disease in the United States: The NewSTEPs New Disorders Implementation Project, a Resource for New Disorder Implementation

by Kshea Hale, Yvonne Kellar-Guenther, Sarah McKasson, Sikha Singh and Jelili Ojodu

Int. J. Neonatal Screen. 2020, 6(2), 48; https://doi.org/10.3390/ijns6020048 - 11 Jun 2020

Cited by 10 | Viewed by 3546

Abstract

Public health programs in the United States screen more than four million babies each year for at least 30 genetic disorders. The Health and Human Services (HHS) Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) recommends the disorders for state newborn screening (NBS) programs to screen. ACHDNC updated the Recommended Uniform Screening Panel (RUSP) to include Pompe disease in March 2015. To support the expansion of screening for Pompe disease, the Association of Public Health Laboratories (APHL) proposed the Newborn Screening Technical assistance and Evaluation Program (NewSTEPs) New Disorders Implementation Project, funded by the HHS’ Health Resources and Services Administration (HRSA) Maternal and Child Health Bureau (MCHB). Through this project, APHL provided financial support to 15 state NBS programs to enable full implementation of screening for Pompe disease. As of April 27, 2020, nine of the 15 programs had fully implemented Pompe disease newborn screening and six programs are currently pursuing implementation. This article will discuss how states advanced to statewide implementation of screening for Pompe disease, the challenges associated with implementing screening for this condition, the lessons learned during the project, and recommendations for implementing screening for Pompe disease. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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7 pages, 2001 KiB

Open AccessArticle

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

by Shu-Chuan Chiang, Yin-Hsiu Chien, Kai-Ling Chang, Ni-Chung Lee and Wuh-Liang Hwu

Int. J. Neonatal Screen. 2020, 6(2), 30; https://doi.org/10.3390/ijns6020030 - 1 Apr 2020

Cited by 5 | Viewed by 3261

Abstract

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. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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11 pages, 672 KiB

Open AccessArticle

Lessons Learned from Pompe Disease Newborn Screening and Follow-up

by Tracy L. Klug, Lori B. Swartz, Jon Washburn, Candice Brannen and Jami L. Kiesling

Int. J. Neonatal Screen. 2020, 6(1), 11; https://doi.org/10.3390/ijns6010011 - 14 Feb 2020

Cited by 20 | Viewed by 5327

Abstract

In 2015, Pompe disease became the first lysosomal storage disorder to be recommended for universal newborn screening by the Secretary of the U.S. Department of Health and Human Services. Newborn screening for Pompe has been implemented in 20 states and several countries across the world. The rates of later-onset disease phenotypes for Pompe and pseudodeficiency alleles are higher than initially anticipated, and these factors must be considered during Pompe disease newborn screening. This report presents an overview of six years of data from the Missouri State Public Health Laboratory for Pompe disease newborn screening and follow-up. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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12 pages, 585 KiB

Open AccessArticle

The First Year Experience of Newborn Screening for Pompe Disease in California

by Hao Tang, Lisa Feuchtbaum, Stanley Sciortino, Jamie Matteson, Deepika Mathur, Tracey Bishop and Richard S. Olney

Int. J. Neonatal Screen. 2020, 6(1), 9; https://doi.org/10.3390/ijns6010009 - 7 Feb 2020

Cited by 34 | Viewed by 5539

Abstract

The California Department of Public Health started universal newborn screening for Pompe disease in August 2018 with a two-tier process including: (1) acid alpha-glucosidase (GAA) enzyme activity assay followed by, (2) GAA gene sequencing analysis. This study examines results from the first year of screening in a large and diverse screening population. With 453,152 screened newborns, the birth prevalence and GAA enzyme activity associated with various types of Pompe disease classifications are described. The frequency of GAA gene mutations and allele variants are reported. Of 88 screen positives, 18 newborns were resolved as Pompe disease, including 2 classic infantile-onset and 16 suspected late-onset form. The c.-32-13T>G variant was the most common pathogenic mutation reported. African American and Asian/Pacific Islander newborns had higher allele frequencies for both pathogenic and pseudodeficiency variants. After the first year of Pompe disease screening in California, the disease distribution in the population is now better understood. With the ongoing long-term follow-up system currently in place, our understanding of the complex genotype-phenotype relationships will become more evident in the future, and this should help us better understand the clinical significance of identified cases. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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8 pages, 1512 KiB

Open AccessArticle

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

by Barbara K. Burton, Joel Charrow, George E. Hoganson, Julie Fleischer, Dorothy K. Grange, Stephen R. Braddock, Lauren Hitchins, Rachel Hickey, Katherine M. Christensen, Daniel Groepper, Heather Shryock, Pamela Smith, Rong Shao and Khaja Basheeruddin

Int. J. Neonatal Screen. 2020, 6(1), 4; https://doi.org/10.3390/ijns6010004 - 21 Jan 2020

Cited by 24 | Viewed by 4839

Abstract

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. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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Review

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7 pages, 201 KiB

Open AccessReview

Establishing Pompe Disease Newborn Screening: The Role of Industry

by Joan M. Keutzer

Int. J. Neonatal Screen. 2020, 6(3), 55; https://doi.org/10.3390/ijns6030055 - 5 Jul 2020

Cited by 7 | Viewed by 3112

Abstract

When clinical trials for enzyme replacement therapy for Pompe disease commenced, a need for newborn screening (NBS) for Pompe disease was recognized. Two methods for NBS for Pompe disease by measuring acid α-glucosidase in dried blood spots on filter paper were developed in an international collaborative research effort led by Genzyme. Both methods were used successfully in NBS pilot programs to demonstrate the feasibility of NBS for Pompe disease. Since 2009, all babies born in Taiwan have been screened for Pompe disease. Pompe disease was added to the Recommended Uniform (Newborn) Screening Panel in the United States in 2015. NBS for Pompe disease is possible because of the unprecedented and selfless collaborations of countless international experts who shared their thoughts and data freely with the common goal of establishing NBS for Pompe disease expeditiously. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

12 pages, 980 KiB

Open AccessReview

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

by Laurie D. Smith, Matthew N. Bainbridge, Richard B. Parad and Arindam Bhattacharjee

Int. J. Neonatal Screen. 2020, 6(2), 32; https://doi.org/10.3390/ijns6020032 - 5 Apr 2020

Cited by 17 | Viewed by 3895

Abstract

Pompe disease (PD) is screened by a two tier newborn screening (NBS) algorithm, the first tier of which is an enzymatic assay performed on newborn dried blood spots (DBS). As first tier enzymatic screening tests have false positive results, an immediate second tier test on the same sample is critical in resolving newborn health status. Two methodologies have been proposed for second tier testing: (a) measurement of enzymatic activities such as of Creatine/Creatinine over alpha-glucosidase ratio, and (b) DNA sequencing (a molecular genetics approach), such as targeted next generation sequencing. (tNGS). In this review, we discuss the tNGS approach, as well as the challenges in providing second tier screening and follow-up care. While tNGS can predict genotype-phenotype effects when known, these advantages may be diminished when the variants are novel, of unknown significance or not discoverable by current test methodologies. Due to the fact that criticisms of screening algorithms that utilize tNGS are based on perceived complexities, including variant detection and interpretation, we clarify the actual limitations and present the rationale that supports optimizing a molecular genetic testing approach with tNGS. Second tier tNGS can benefit clinical decision-making through the use of the initial NBS DBS punch and rapid turn-around time methodology for tNGS, that includes copy number variant analysis, variant effect prediction, and variant ‘cut-off’ tools for the reduction of false positive results. The availability of DNA sequence data will contribute to the improved understanding of genotype-phenotype associations and application of treatment. The ultimate goal of second tier testing should enable the earliest possible diagnosis for the earliest initiation of the most effective clinical interventions in infants with PD. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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16 pages, 711 KiB

Open AccessReview

Newborn Screening for Pompe Disease

by Takaaki Sawada, Jun Kido and Kimitoshi Nakamura

Int. J. Neonatal Screen. 2020, 6(2), 31; https://doi.org/10.3390/ijns6020031 - 5 Apr 2020

Cited by 38 | Viewed by 5820

Abstract

Glycogen storage disease type II (also known as Pompe disease (PD)) is an autosomal recessive disorder caused by defects in α-glucosidase (AαGlu), resulting in lysosomal glycogen accumulation in skeletal and heart muscles. Accumulation and tissue damage rates depend on residual enzyme activity. Enzyme replacement therapy (ERT) should be started before symptoms are apparent in order to achieve optimal outcomes. Early initiation of ERT in infantile-onset PD improves survival, reduces the need for ventilation, results in earlier independent walking, and enhances patient quality of life. Newborn screening (NBS) is the optimal approach for early diagnosis and treatment of PD. In NBS for PD, measurement of AαGlu enzyme activity in dried blood spots (DBSs) is conducted using fluorometry, tandem mass spectrometry, or digital microfluidic fluorometry. The presence of pseudodeficiency alleles, which are frequent in Asian populations, interferes with NBS for PD, and current NBS systems cannot discriminate between pseudodeficiency and cases with PD or potential PD. The combination of GAA gene analysis with NBS is essential for definitive diagnoses of PD. In this review, we introduce our experiences and discuss NBS programs for PD implemented in various countries. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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14 pages, 442 KiB

Open AccessReview

Is Newborn Screening the Ultimate Strategy to Reduce Diagnostic Delays in Pompe Disease? The Parent and Patient Perspective

by Raymond Saich, Renee Brown, Maddy Collicoat, Catherine Jenner, Jenna Primmer, Beverley Clancy, Tarryn Holland and Steven Krinks

Int. J. Neonatal Screen. 2020, 6(1), 1; https://doi.org/10.3390/ijns6010001 - 9 Jan 2020

Cited by 9 | Viewed by 5187

Abstract

Pompe disease (PD) is a rare, autosomal-recessively inherited deficiency in the enzyme acid α-glucosidase. It is a spectrum disorder; age at symptom onset and rate of deterioration can vary considerably. In affected infants prognosis is poor, such that without treatment most infants die within the first year of life. To lose a baby in their first year of life to a rare disease causes much regret, guilt, and loneliness to parents, family, and friends. To lose a baby needlessly when there is an effective treatment amplifies this sadness. With so little experience of rare disease in the community, once a baby transfers to their home they are subject to a very uncertain and unyielding diagnostic journey while their symptomology progresses and their health deteriorates. With a rare disease like PD, the best opportunity to diagnose a baby is at birth. PD is not yet included in the current newborn screening (NBS) panel in Australia. Should it be? In late 2018 the Australian Pompe Association applied to the Australian Standing committee on Newborn Screening to have PD included. The application was not upheld. Here we provide an overview of the rationale for NBS, drawing on the scientific literature and perspectives from The Australian Pompe Association, its patients and their families. In doing so, we hope to bring a new voice to this very important debate. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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Other

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8 pages, 216 KiB

Open AccessCase Report

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

by Raymond Y. Wang

Int. J. Neonatal Screen. 2020, 6(1), 22; https://doi.org/10.3390/ijns6010022 - 14 Mar 2020

Cited by 7 | Viewed by 3552

Abstract

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. Full article

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