By Marisa Wexler | Sep 5, 2019 | Pompe Disease News

A new study reports the genetic and clinical characteristics of 113 U.S. children who have Pompe disease, the largest such group that has been uniformly assessed in this manner.

In addition to revealing four previously unreported disease-causing mutations, the data may help researchers and clinicians better understand the associations between an individual patient’s genotype and how their disease manifests.

The study with these findings, “Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease,” was published in the journal Genetics in Medicine.

The ADVANCE clinical trial (NCT01526785) was designed to evaluate the safety and effectiveness of Lumizyme (alglucosidase alfa), which is an enzyme replacement therapy for Pompe disease. It was open to any U.S. Pompe disease patients older than 1 year who were treated with Lumizyme.

Because of these relatively broad inclusion criteria, the study population represents a fairly broad sample that, the researchers wrote, represents “most U.S. children and adolescents with treated Pompe disease.”

As the patients’ data was being collected as part of the clinical trial, the researchers reasoned that looking at this information helps them better understand the range of Pompe disease presentation and how it relates to a patients’ particular mutation(s).

Based on how their disease presented, patients were divided into two groups: those with infantile-onset Pompe disease (IOPD, 87 patients), defined as the development of symptoms including cardiac (heart) involvement before they were 1 year old, and those with late-onset Pompe disease (LOPD, 26 patients), defined as the onset of symptoms after 1 year old or onset before 1 year old, but without cardiac involvement.

The researchers found that comparatively more LOPD than IOPD patients were Caucasian (88% vs. 55%), male (73% vs. 47%), ventilator-free (69% vs. 59%), and able to walk independently (27% vs. 18%) or with assistance (35% vs. 18%). LOPD patients also were less likely to have hearing loss (22% vs 12%).

By definition, all of the IOPD patients had cardiac involvement, as did six of the LOPD patients.

Generally, this data and others are indicative of a fairly wide range of disease presentations in Pompe that the dichotomy of IOPD or LOPD can’t really encapsulate fully, highlighting the need for more personalized approaches that zero in on a specific patient, rather than creating broad, but imperfect, categories.

In analyzing patients’ genetic information, the researchers identified 215 disease-causing mutations in the gene acid alpha-glucosidase (GAA, the gene that is mutated in Pompe disease) among 108 patients for whom genetic data was available. These mutations included four that had not been published previously, expanding on the number of known mutations that can cause Pompe disease.

Figuring out exactly how an individual mutation is associated with disease progression is complicated and especially hard to do in a dataset that, while quite large for such a rare disease, is still minuscule from a statistical perspective.

Still, the researchers noted a few interesting findings; for example, 12 of the LOPD patients harbored the mutation c.−32−13T>G, and none of these patients had cardiac involvement.

Additionally, some of the most common mutations — such as c.2560C>T and c.525delT — were present in both IOPD and LOPD patients, further highlighting the relatively arbitrary nature of this distinction. (All of the aforementioned mutations are named based on the particular change in the DNA sequence that defines them.)

Overall, this study highlights the wide spectrum of Pompe disease and takes some preliminary steps toward better understanding how individual mutations are (or are not) associated with particular clinical manifestations of the disease. Further research will be necessary to better understand these associations. In support of this, the researchers have pledged to make their data (without patient identifiers, for the privacy of those involved) available to “qualified researchers.”