Study: Pompe More Common Than Previously Estimated

The number of people with Pompe disease varies according to ethnic group and may be higher among all ethnicities than previously estimated, a study suggests.

According to the investigator, the study stresses the importance of analyzing genetic disorders in the general population to improve predictive and preventive medicine.

“With this novel and alternative approach, Pompe disease (1:23,232)” — occurring in one in every 23,232 individuals — “is estimated to be more frequent than formerly accepted (1:40,000),” or 1 in every 40,000 people, the investigator said.

The study, “Carrier frequency and predicted genetic prevalence of Pompe disease based on a general population database,” was published in the journal Molecular Genetics and Metabolism Reports.

Pompe disease is caused by a mutation in the GAA gene that is responsible for producing the acid alpha-glucosidase enzyme. This enzyme is crucial for breaking down glycogen, a complex sugar.

Mutations in GAA lead to glycogen accumulation inside cells, up to toxic levels. Excess glycogen is particularly harmful to muscles, causing damage in the skeletal and heart muscles.

Because Pompe is inherited in an autosomal recessive pattern, a person develops the disease only if both copies of the GAA gene they inherit — one from each parent — are mutated.

People with a single mutated copy of the gene are called carriers. Although they do not have any Pompe symptoms, they can pass the mutated gene to their offspring. When both parents are carriers, each of their children has a 25% probability of having Pompe disease.

Screening for genetic alterations has a key role in identifying who is at risk of having or developing a disease, with the aim of preventing it or treating the condition as early as possible.

As such, a researcher in Korea now assessed how the genetic information of a generally healthy population predicts the probability of developing Pompe, and how that probability differs in terms of disease severity within different ethnic groups.

According to the scientist, this was the first time that Pompe has been studied throughout genetic data of the general population. It also is the first study on this disease that is based on estimated carriers frequency — the proportion of people who have one copy of the mutated GAA gene — and the genetic prevalence of the disease in different ethnic groups. Genetic prevalence, or GP, is the total number of individuals who have a genetic profile consistent with Pompe.

The study comprised seven ethnic groups: the African/African-American group, which included 12,487 individuals; the Latino/Admixed American, with 17,720 people; the Ashkenazi Jewish, composed of 5,185 participants; the East Asian group, with 9,977 individuals; the Finnish group, including 12,562 individuals; the non-Finnish European, with 64,603 people; and the South Asian, where 15,308 individuals were included.

The predicted GP of Pompe disease was determined based on the percentage of individuals who had disease-causing variants in GAA. These variants were analyzed using the Genome Aggregation Database (gnomAD), a general population dataset, as well as the ClinVar, Pompe disease GAA variant database, and the Pompe Registry.

Both carrier frequency and predicted GP were estimated based on presumed pathogenic or likely pathogenic variants (PLPVs) in the GAA gene. Notably, PLPVs is a classification that follows the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines, and means that the probability of a variant being disease-causing is greater than 90%.

According to clinical severity and age at symptom onset, patients were classified as classic infantile Pompe, childhood Pompe, and adult-onset Pompe.

The results showed that, in the overall population, the frequency of unaffected carriers was 1.3%, while predicted GP was at a proportion of 4.30 individuals per 100,000 births, or 1 in every 23,232 individuals.

These results indicate that the genetic prevalence of Pompe disease may be higher than estimated previously (1 in 40,000).

The study also found that the East Asian group had the highest carrier frequency (1.8%), followed by non-Finnish European (1.7%), Ashkenazi Jewish (1.3%), African/African-American (1.2%), Latino/Admixed American (0.8%), South Asian (0.7%), and the Finnish group (0.2%).

The East Asian group also had the highest predicted GP per 100,000 births, at 8.25, followed by Non-Finnish European at 7.27, Ashkenazi Jewish at 4.38, and the African/AfricanAmerican group at 3.76. Following were the Latino/Admixed American group at 1.74, then the South Asian group at 1.07, and the Finnish group at 0.09.

These results are in accordance with those from newborn screening programs that stated a predicted GP ranging between 1 in 10,000 and 1 in 30,000, the investigator said.

The proportions of PLPVs associated with classic infantile Pompe disease also varied by population. Of the seven ethnic groups, the East Asian and African groups showed higher proportions of PLPVs causing this type of the disease.

Overall, “knowledge of the GAA PLPVs combined with clinical severity in a particular continental population could be valuable for setting up a screening program,” the researcher wrote. Accurately detecting cases of classic infantile-onset disease is of particular importance, he added.

“This approach to analyze genomic information of Mendelian disorders in the general population suggests another helpful direction for predictive and preventive medicine,” he concluded.