Improving Health Outcomes for Infants with Pompe Disease
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Improving Health Outcomes for Infants with Pompe Disease

Date: November 24, 2020

It was terrific to see this paper by our long time collaborator Arindam Bhattacharjeeon the use of NGS as a second-tier test for Pompe Disease (PD). This is part of an important diagnostic trend of earlier (even to the point of first-line for selected infants) use of NGS as a diagnostic tool that can dramatically improve the newborn’s projected health outcome. Pompe Disease is a perfect example of how this can work.


PD is one of several glycogen storage diseases with variable timing of onset and rates of progressions. According to NORD, “Pompe disease is a rare multisystem disorder caused by pathogenic variations in the GAA gene containing the information for production and function of a protein called acid alpha-glucosidase (GAA). Because of the shortage of this protein (an enzyme), a complex sugar named ‘glycogen’ cannot be degraded to a simple sugar like glucose. This causes the glycogen to accumulate in all kinds of tissues, but primarily in skeletal muscle, smooth muscle, and cardiac muscle, where it causes damage to tissue structure and function. Pompe disease is inherited as an autosomal recessive genetic trait.” Early diagnosis and initiation of treatment are of paramount importance at no later than two weeks of age to minimize muscle damage and avoid significant negative impact on the quality of life.

Since 2015, PD has been included in the panel of genetic diseases screened for in newborns using a dried blood spot (DBS) method.  Specifically, the DBS is used to look for GAA enzyme activity – GAA enzymes are active in every healthy newborn’s blood. Since babies with PD have GAA enzymes that are either missing or not working properly, they will have reduced GAA enzyme activity. Unfortunately, DBS has a high false-positive rate. A second-tier test, therefore is needed and should, ideally, also provide information to support treatment decisions (likely age of onset, CRIM status – used to determine if immune modulation is needed before enzyme replacement therapy (ERT) is started). This paper showed, compellingly and in detail, that use of NGS did just that – confirmed both the diagnosis and provided essential data to support the treatment plan. And, importantly, NGS was able to provide the critical data within the critical 2-week window. As demonstrated in the study, “Second-tier [targeted] NGS (tNGS) workflow services, if performed end-to-end, may be completed in ~35 hours, and reports can be finalized consistently within 5–7 days of receiving the sample. If NBS programs routinely perform tNGS on-premises or use DNA sequencing services that return results within seven days, then overall reporting and treatment initiation may occur within ten days.”


With advances in NGS, particularly the wider availability and decreased cost of sequencing as well as the utilization of interpretation software such as Fabric Enterprise (which is what the team used in this study), rapid turnaround should be achieved in many of the public health laboratories tasked with these vital screening tests. We are excited to see this data to support the important use of NGS. The intent of newborn screening is to find these diseases early in life, in time to intervene to maximize the health outcome. Given the data from this study, early use of NGS for suspected PD is the best way to meet this goal.