Pompe disease NBS: Is early diagnosis a false promise?

Infantile-onset Pompe disease (IOPD) represents the most severe manifestation of a lysosomal storage disorder, stemming from a deficiency in acid alpha-glucosidase (GAA). This enzyme is critical for breaking down glycogen, and its absence leads to glycogen accumulation in various tissues, particularly cardiac and skeletal muscle. The rapid progression of IOPD, often leading to death within the first year of life without intervention, underscores the urgency of early diagnosis and treatment.¹

Japan initiated a regional enzymatic newborn screening program for Pompe disease in 2013, aiming to identify affected infants before symptom onset and facilitate early enzyme replacement therapy (ERT). Tocan and colleagues reported on the ERT responses of two Japanese IOPD cases: one identified through this NBS program and another diagnosed prior to its implementation. The study, published in Pediatric International, highlights the challenges of timely ERT initiation, particularly concerning the pseudodeficiency problem.¹

The Screening Dilemma

Newborn screening for Pompe disease typically relies on measuring GAA enzyme activity in dried blood spots. Low enzyme activity triggers further investigation. But GAA pseudodeficiency alleles, common in some populations, can also result in reduced enzyme activity, leading to false-positive screening results. These individuals do not develop Pompe disease, but their initial screening results are indistinguishable from those with true GAA deficiency. This creates a significant diagnostic dilemma, as unnecessary follow-up and anxiety for families can result, while delaying ERT for truly affected infants carries severe consequences.¹

The Japanese NBS program identified its first IOPD case in 2014. This infant, designated Case 1, showed low GAA activity on initial screening. Subsequent genetic testing confirmed two pathogenic GAA mutations: c.1935C>T (p.Tyr645Ter) and c.2560C>T (p.Arg854Ter). ERT with alglucosidase alfa began at 28 days of age. At 1 year old, the infant showed no cardiac hypertrophy, maintained normal left ventricular ejection fraction (LVEF), and exhibited normal motor development. This outcome contrasts sharply with historical data for untreated IOPD.¹

But the path to diagnosis is not always straightforward, even with screening. The authors noted that the time from NBS to confirmed diagnosis and ERT initiation can be prolonged due to the need for confirmatory genetic testing. This delay is precisely where the pseudodeficiency problem introduces friction. Clinicians must balance the urgency of treatment for true IOPD with the need to avoid unnecessary therapy for pseudodeficiency carriers. The complex genetics of newborn screening, particularly for conditions with pseudodeficiency alleles, demands clear communication with parents and rapid access to genetic counseling.¹

Comparing Treatment Timelines

The paper presented a compelling comparison between the NBS-identified case and an earlier case (Case 2) diagnosed before the screening program. Case 2, born in 2012, presented with symptoms including poor feeding and muscle weakness at 2 months of age. Diagnosis was confirmed by GAA enzyme activity and genetic testing, revealing the same pathogenic mutations as Case 1. But ERT for Case 2 did not start until 100 days of age.¹

The difference in outcomes was stark. Case 2 developed severe cardiac hypertrophy and dilated cardiomyopathy, with an LVEF of 30% at 3 months. Despite ERT, the infant required mechanical ventilation and died at 1 year and 1 month due to cardiorespiratory failure. Case 1, who received ERT 72 days earlier, avoided these severe cardiac complications and achieved normal development at 1 year. This comparison underscores the critical importance of early intervention in IOPD, highlighting that even a delay of a few weeks can have profound clinical consequences.¹

"The earliest enzyme replacement for infantile-onset Pompe disease in Japan."Tocan V, Mushimoto Y, Kojima-Ishii K. Pediatr Int 2022.

The challenge of pseudodeficiency is not unique to Pompe disease. Other lysosomal storage disorders, such as Fabry disease and Gaucher disease, also have pseudodeficiency alleles that can confound NBS results. This necessitates a robust confirmatory diagnostic pathway, including rapid genetic sequencing, to distinguish true disease from benign carrier states. Without this, the benefits of early screening are diluted by diagnostic uncertainty and potential treatment delays. For a comprehensive understanding of paediatric conditions, the Oxford Handbook of Paediatrics can be a valuable resource.

The Need for Speed

The Japanese experience demonstrates that while NBS successfully identifies infants with IOPD, the time from screening to ERT initiation remains a critical factor. The authors noted that the process of obtaining informed consent for genetic testing, performing the analysis, and securing approval for ERT can introduce delays. These administrative and logistical hurdles must be streamlined to maximize the benefit of NBS. The goal of NBS is not merely identification, but rapid, effective intervention.¹

The pseudodeficiency problem adds another layer of complexity. If a positive screen is due to a pseudodeficiency allele, the infant does not need ERT. But if it is true IOPD, every day of delay contributes to irreversible organ damage. This tension demands a system that can quickly and accurately differentiate between these two scenarios. The implications for primary care burnout are also clear; managing these complex genetic results and communicating them effectively to anxious parents adds significant workload.¹

The trial was a case report, not a randomized controlled trial, which is the obvious caveat. The small sample size (N=2) limits generalizability, but the stark difference in outcomes between the two cases provides a powerful illustration of the impact of early ERT. The study was also conducted in a specific regional context in Japan, and the prevalence of GAA pseudodeficiency alleles can vary significantly across different ethnic populations. This means that the specific challenges and solutions may differ in other NBS programs globally.¹

Still, the paper highlights a fundamental issue in expanding NBS programs for rare genetic diseases: the need for robust, rapid, and accurate confirmatory diagnostics. Without this, the promise of early intervention risks being undermined by diagnostic ambiguity. The next step for NBS programs must involve not just identifying more conditions, but refining the pathways to definitive diagnosis and timely treatment. This includes improving access to genetic counseling and ensuring that genetic testing results are available within days, not weeks. The question remains whether health systems can deliver on this promise, as seen in discussions around Australia's lung cancer screening.¹