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Perhaps nothing says more about the medical fraternity’s view of the urgency of early diagnosis than the development of the newborn heel prick test. It is usually performed within 5 days of birth and is able to pick up a whole host of congenital diseases. 

Indeed, if medicine was a sliding scale, we have moved on from symptomatic management and inched towards early diagnosis as the golden standard of care. Studies have indicated time and again that diseases diagnosed early have better prognoses. That is why developed countries have begun to offer screening for a wide range of diseases in at-risk groups, such as breast cancer and cervical cancer screening in women, as well as colorectal and prostate screening in men. 

But the development of the newborn heel prick test stands out as a testament to our thirst for diagnosing diseases as early as possible so that treatment can be started without delay. One researcher, Joan M. Keutzer, a former employee of Sanofi Genzyme, recently set out to investigate the role of newborn screening in Pompe disease in particular. She published her work in the International Journal of Newborn Screening. We will explore some of her findings in this article. 

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A Need for Early Diagnosis 

Keutzer pointed to global efforts as the key reason from the onset for the development of a newborn screening test for Pompe disease. It ”resulted from an unprecedented international collaboration among patients with Pompe disease, the Pompe disease medical and scientific communities, government agencies, and industry,” she wrote. 

The case for newborn screening for Pompe disease was airtight: in 1998, scientists were developing an enzyme replacement therapy (ERT) for Pompe disease and realized that any uncertainty in the early diagnosis of the disease could hamper efforts to decide whether administering ERT would be a viable course of action. Too much delay could result in irreversible damage.

Read more about Pompe disease epidemiology

This is not a problem isolated to Pompe disease; in fact, the difficulty in obtaining a fast and accurate diagnosis of a disease has dogged many rare diseases for many years. If physicians cannot be sure of the diagnosis of a disease, they would be loath to start their patients on powerful drugs that might produce unwanted side effects. However, if the physician adopts a “wait and see” approach, the diagnosis would sooner or later be confirmed by undeniable late presenting symptoms, but by then the window for curative treatment might have closed. 

In the days before newborn screening for Pompe disease was available, parents reported having to wait 2 months to get a diagnosis after a skin biopsy was performed. Needless to say, by modern standards, this is an exceedingly long time that is likely to cause unnecessary anxiety and stress. But parents did not have a choice—there simply was no assay that could use blood samples to diagnose Pompe disease. 

Developing a New Test

Newborn screening was already available for other diseases, such as phenylketonuria (PKU). The screening method was simple enough: researchers measured “the accumulation of the enzyme’s substrate in dried bloodspots on filter paper (DBS) in a multiplex assay that could screen for multiple treatable lysosomal storage disorders (LSDs) simultaneously,” Keutzer wrote. 

As for Pompe disease, scientists already knew that the acid α-glucosidase enzyme was a useful biomarker. However, this was complicated by another alpha-glucosidase known as maltase glucoamylase (MGA), which can mask acid α-glucosidase deficiency at a certain pH level. Therefore, scientists focused on developing a method to inhibit MGA in an effort to quantify α-glucosidase in the blood. 

Eventually, scientists discovered that maltose could inhibit MGA, and so could 80 µM acarbose, a medication that was used to control sugar levels in type 2 diabetes. These discoveries paved the way for a new blood screening test for Pompe disease to be developed, and researchers then turned their attention to refining the testing methodology. 

Read more about Pompe disease therapies

Scientists compared maltose to 80 µM acarbose and found that 80 µM acarbose was superior to maltose in the assay. Scientists also evaluated the use of cultured skin fibroblasts in diagnosing Pompe disease and found it to be the “gold standard.” However, assays in blood samples were faster, less invasive, and easier to standardize, making them more desirable for large-scale screenings. 

In December 2006, experts gathered to “agree that the DBS assay using acarbose to inhibit MGA was useful to get a presumptive positive diagnosis for Pompe disease and that at least one secondary positive test (for example, GAA sequence analysis) would support a biochemical diagnosis of Pompe disease,” Keutzer wrote. This was a breakthrough in newborn screening for Pompe disease because finally there was an agreement on a standardized way to screen for the disease. 

Using Newborn Screening Results

Thanks to the incredible spirit of collaboration of scientists from all across the globe, an newborn screening test is available for Pompe disease on a widespread level today.

With an evidence-based newborn screening for Pompe disease in place, scientists can now turn their attention towards what comes next. And that is what they have done: authorizing guidelines such as “the initial evaluation of patients after positive newborn screening and recommended algorithms leading to a confirmed diagnosis of Pompe disease; management of confirmed newborn-screened patients with Pompe disease across the disease spectrum; and the role of genetic counseling in Pompe disease after patients are identified through [newborn screening],” Keutzer wrote. 

The drive and passion of the researchers involved in developing a newborn screening test for Pompe disease are indeed inspiring because the movement from symptomatic management towards early diagnosis vastly enlarges the scope of tools available for us to save and improve lives. May this spirit of collaboration and teamwork grow as we tackle the various medical challenges of our day. 


Kuetzer J. Establishing Pompe disease newborn screening: the role of industry. Int J Neonatal Screen. Published online July 5, 2020. doi:10.3390/ijns6030055

Pompe Disease Diagnostic Working Group, Winchester B, Bali D, et al. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab. 2008;93(3):275-81. doi:10.1016/j.ymgme.2007.09.006