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Five-Year Outcomes of Patients with Pompe Disease Identified by the Pennsylvania Newborn Screen
Hayley A Ron1, Owen Kane2, Rose Guo3
1Hackensack University Medical Center at Hackensack Meridian Health, Hackensack, NJ 07601, USA.
Insights
Newborn screening for Pompe disease (PD) in Pennsylvania has increased early detection, mainly of late-onset Pompe disease (LOPD). Continued data collection is crucial for developing management guidelines, including enzyme replacement therapy (ERT) timing.
Area of Science:
- Genetics and Genomics
- Metabolic Disorders
- Newborn Screening
Background:
- Pennsylvania initiated newborn screening (NBS) for Pompe disease (PD) in 2016, leading to increased early detection, predominantly of late-onset Pompe disease (LOPD).
- Current guidelines for initiating enzyme replacement therapy (ERT) in NBS-identified PD patients are lacking.
- Understanding the natural history and identifying ERT indications are critical for optimal patient management.
Purpose of the Study:
- To present long-term follow-up data for 45 patients with PD identified through NBS between 2016 and 2021.
- To characterize the natural history of PD detected via NBS.
- To inform the development of guidelines for ERT initiation in this population.
Main Methods:
- Longitudinal follow-up of 45 NBS-identified PD patients at a multidisciplinary clinic.
- Regular evaluations included physical examinations, physical therapy assessments, muscle biomarkers (creatine kinase [CK], aspartate aminotransferase [AST], alanine aminotransferase [ALT], hexosaminidase 4 [Hex4]), and cardiac evaluations (echocardiogram, EKG).
- Analysis of newborn screening acid alpha-glucosidase (GAA) enzyme levels and genotype-phenotype correlations.
Main Results:
- NBS primarily detected LOPD, with one case of infantile-onset PD (IOPD).
- Muscle biomarkers (CK, AST, ALT) were elevated at birth in LOPD patients, showing a general downward trend over time.
- NBS GAA levels and initial CK levels differentiated LOPD from unaffected infants; Hex4 was not a significant discriminator. Significant differences in GAA levels were observed between unaffected, compound heterozygote, and homozygote groups for the c.-32-13T>G variant. Cardiac evaluations were normal at initial assessment in LOPD patients.
- One LOPD patient initiated ERT at 4.5 months of age.
Conclusions:
- NBS is effective in detecting PD, particularly LOPD, at birth.
- Muscle biomarker trends and NBS GAA levels aid in differentiating PD from unaffected infants.
- Continued data collection is essential for establishing management protocols, including ERT timing and refining genotype-phenotype correlations for PD.
Abstract:
Pennsylvania started newborn screening for Pompe disease (PD) in 2016. As a result, the prevalence of PD has increased with early detection, primarily of late-onset Pompe disease (LOPD). No clear guidelines exist regarding if and when to initiate enzyme replacement therapy (ERT) in patients identified through a newborn screen (NBS). To help define the natural history and indications for starting ERT, we present the long-term follow-up data of 45 patients identified through NBS from 2016 to 2021. These patients were evaluated at regular intervals through our multi-disciplinary clinic at the Children's Hospital of Philadelphia (CHOP) with physical examinations, physical therapy evaluations, muscle biomarkers including creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hexosaminidase 4 levels (Hex4), as well as cardiac evaluation at certain points in time. We found that newborn screening of acid alpha-glucosidase (GAA) enzyme detected primarily LOPD. One case of infantile-onset PD (IOPD) was detected. Muscle biomarkers in LOPD were elevated at birth and showed a general downward trend over time. NBS GAA levels and initial CK levels helped to differentiate LOPD cases from unaffected infants (carriers, pseudodeficiency alleles), while Hex4 was not a meaningful discriminator. On repeat NBS, there was a significant difference between mean GAA levels for the unaffected vs. compound heterozygote groups and unaffected vs. homozygote groups for the common splice site pathogenic variant (c.-32-13T>G). Echocardiogram and electrocardiogram (EKG) are essentially normal at the first evaluation in LOPD. One LOPD patient was started on ERT at age 4.5 months. Continued data collection on these patients is critical for developing management guidelines, including timing of ERT and improved genotype-phenotype correlation.
