Pompe disease is a rare, inherited neuromuscular disorder that affects various tissues, particularly the heart and skeletal muscles. It is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. This mutation leads to a deficiency in the acid alpha-glucosidase (GAA) enzyme, which normally breaks down glycogen inside cellular compartments called lysosomes. When the enzyme is deficient, glycogen accumulates to toxic levels, causing progressive muscle damage and weakness. Calculating the exact global number of people with Pompe disease is complicated by inconsistent diagnostic methods, varying reporting standards, and the disease’s wide spectrum of severity.
Global Estimates of Pompe Disease
Historical estimates of Pompe disease incidence typically ranged from 1 in 40,000 to 1 in 300,000 live births worldwide. These early figures were based on clinically diagnosed cases, likely resulting in a significant underestimation of the true number of people with the condition. Calculating prevalence, the total number of people living with the disease, is also challenging. However, newer data derived from widespread newborn screening (NBS) programs suggest the disease is more common than previously thought.
A large 2024 analysis using NBS data from over 11 million newborns calculated the overall birth prevalence of Pompe disease to be approximately 1 in 18,711 live births. This recent figure is more than twice the previously accepted rate of 1 in 40,000, illustrating the impact of proactive screening on epidemiological data. The difference between historical and contemporary figures highlights the difficulty in counting individuals with a rare disease, especially those presenting in adulthood.
Prevalence Differences Between Infantile and Late-Onset Forms
Pompe disease primarily presents in two major forms: Infantile-Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD). These forms are distinguished by the age of symptom onset and the severity of the GAA enzyme deficiency. IOPD is the most severe and rarest form, characterized by symptoms appearing within the first few months of life, including rapid muscle weakness and severe heart involvement. The global birth prevalence for IOPD is estimated to be about 1 in 126,118 live births.
LOPD is the most frequently diagnosed form, accounting for approximately 85% of cases identified through newborn screening programs. Its global birth prevalence is estimated at about 1 in 21,902 live births. LOPD symptoms can appear anytime from childhood to adulthood, often presenting as progressive muscle weakness and respiratory problems without the severe heart involvement seen in the infantile form. Because LOPD symptoms can be subtle and mimic other neuromuscular disorders, the condition was historically often misdiagnosed or remained undiagnosed for years.
How Newborn Screening Affects Reported Numbers
The implementation of newborn screening (NBS) for Pompe disease has fundamentally changed reported prevalence figures in regions where it is mandated. NBS involves measuring GAA enzyme activity in a dried blood spot collected shortly after birth. This process allows for the identification of affected infants, particularly those with LOPD, who would otherwise not be diagnosed until years or decades later.
When a region introduces NBS, it experiences a sudden, artificial increase in its reported prevalence rate because it captures cases that were previously missed. For instance, the first year of screening in California demonstrated an overall birth prevalence of 1 in 25,200, significantly higher than traditional clinical estimates. This diagnostic shift ensures that individuals with LOPD are identified early, often before symptoms develop, which is crucial for timely intervention and better outcomes.
Geographic and Population-Specific Variations
The frequency of Pompe disease is not uniform globally but shows considerable variation influenced by specific genetic factors. These differences are often linked to a higher frequency of certain GAA gene mutations within isolated or distinct ethnic groups. Some studies have noted a higher prevalence in populations of African descent; for example, the birth prevalence among African-American newborns in California was approximately 1 in 18,700, higher than the state’s overall prevalence.
In Asia, Taiwan has reported higher rates of IOPD compared to the United States, illustrating how a specific founder effect can concentrate the severe form of the condition. Conversely, some Asian populations show a higher frequency of pseudodeficiency alleles, which can lead to false-positive screening results if genetic confirmation is not used. A study in Spain noted that most IOPD patients were of African origin, further supporting the role of ancestry in disease distribution.