LOPD in Undiagnosed Patients Estimated at 1% in US and Canada
The prevalence of late-onset Pompe disease (LOPD) in people across the U.S. and in Montreal, Canada, who lack an official diagnosis but have its characteristic neuromuscular symptoms — including neck and proximal muscle weakness or elevated creatine kinase levels (a marker of muscle damage) — is estimated to be 1%.
The study reporting the finding, “Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices,” was published in Neurology Genetics.
Previous studies have estimated the prevalence of LOPD to be around 1 in 57,000 people. However, the disease’s prevalence can vary significantly across countries and ethnic populations. For instance, African Americans and Southeast Asians are known to have a higher risk of developing the disease.
To determine the prevalence of LOPD across the U.S. and in Montreal, Canada, a team of researchers looked at data from 13 academic, specialized or tertiary neuromuscular practices in a study called IPANEMA (NCT02838368).
In total, 906 patients were analyzed from July 2015 through July 2018. Of these, 55% were men, and the average age of the group was 52. Patients previously diagnosed with LOPD or a known muscle disease were excluded from the study.
All people analyzed had proximal and/or neck muscle weakness or high levels of creatine kinase; 76 patients (8%) had all three conditions.
Levels of acid alpha-glucosidase (GAA), an enzyme involved in glycogen (a complex sugar storage molecule) breakdown, were also analyzed. People with Pompe disease have mutations in the GAA gene, which provides instructions for making the GAA protein, leading to increased glycogen levels within the body. The buildup of glycogen impairs muscle and organ function.
Among the 906 patients, 820 had normal GAA results. The other 86 had abnormal GAA results (equal or less than 10 picomole/punch/h) and were automatically referred for molecular diagnostic testing.
Results showed that 38 of the 86 participants had at least one GAA gene mutation detected by gene sequencing, and nine (1% of total study population) had two disease-causing mutations in the GAA gene, indicating LOPD. To have the disease, a person must inherit two mutated copies of the GAA gene, one from each biological parent.
Of the nine patients with confirmed LOPD, eight were Caucasian and one was African American.
Seventeen patients were found to have at least one disease-causing GAA mutation, and combined with their low GAA protein levels, they may be Pompe disease carriers. Additionally, two patients were classified as “likely carriers” because they had a GAA mutation that was likely to cause the disease.
Six other patients were classified with “undetermined” status, as their exact GAA gene mutation could not be determined even though their GAA levels were low.
Nine patients had heterozygous pseudodeficiency alleles; that is, mutations in the GAA gene that may alter the GAA protein or change the gene’s expression (activity) but do not cause disease. According to the team, this was a surprising result.
“We found as many cases of pseudodeficiency as actual deficiency (9 for pseudodeficiency and 9 for LOPD). Because the pseudodeficiency alleles are more common in the Asian population (estimated to be present in 4% of Southeast Asian population), it was not surprising that 6 of the 9 participants who had pseudodeficiency alleles were Asians,” the researchers wrote. haven’t used that
The data showed no correlation between creatine kinase values and GAA enzyme values.
Based on the results, “the prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary [specialized care] neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles,” the team concluded.
The researchers also noted that the patients analyzed in the study had clinical disease manifestations, yet most had not received next-generation sequencing.
“Despite the increasing availability of next-generation sequencing, patients with rare diseases still go through a diagnostic odyssey to achieve a definitive diagnosis,” they wrote. “Different clinics have different criteria and thresholds on when to order this sequencing.”
Further, “in developing countries and countries where the health system cannot afford the economic burden of large-scale genetic testing, GAA enzyme assay as a primary screening modality is still very important,” the team added.
Nonetheless, given the rate of pseudodeficiency found in the study, the researchers emphasized that it is important to confirm the GAA enzyme levels with a second tool, such as mutation analysis.
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