Different Types of Mutations Appear to Predict Pompe Subtypes

The type of genetic mutation carried by a Pompe disease patient appears to predict whether the disease is infantile- or late-onset, according to a study.

However, newly diagnosed patients should still undergo complete genetic, cardiac, and neurological tests, scientists stated.

The study, “Phenotypic implications of pathogenic variant types in Pompe disease,” was published in the Journal of Human Genetics.

Pompe disease can be categorized as infant-onset (IOPD) or late-onset (LOPD) and the tests for either generally involve measuring the amount of active acid alpha-glucosidase enzyme (GAA) or examining the associated GAA gene for disease-causing mutations.

While GAA activity under 10% of normal is generally found in IOPD, the late-onset form associates with a wide range of enzyme activity, which do not correlate well with disease severity.

As genetic testing, particularly via newborn screening, becomes more widely available, determining how genetic alterations affect disease severity and how promptly to begin therapy grows more urgent.

A team of researchers from the University of Florida College of Medicine and the University of Minnesota Medical School analyzed the demographic, clinical, biochemical, and genetic data of 23 individuals with Pompe disease to assess whether specific genetic variants could predict disease severity.

Among the participants, six were classified as IOPD and 17 as LOPD. Mean age at diagnosis was 3 months in the infantile-onset group and 25.4 in those with late-onset Pompe. All 23 patients had genetic data and 18 also had GAA enzyme activity data.

All six children with IOPD had clinically significant cardiac hypertrophy (enlargement), received enzyme replacement therapy, and had GAA activity under 20% of normal. As for the LOPD group, no patient had significant heart muscle disease and most had elevated levels of muscle or liver damage markers.

GAA gene variations differed between the two Pompe disease classifications.

Mutations known as “splice site variants” — which can disrupt protein formation by resulting in the loss of protein-coding sequences or the inclusion of gene subsections normally removed — associated with LOPD. These splice variants often occurred in only one of the two GAA gene copies. Genes typically come in pairs, one inherited from each biological parent. Each copy is called an “allele.”

Several of the splice site variants in the study appeared to associate with milder cases, implying that disease severity might be predicted from a person’s individual genetic features — their “genotype.”

This genetic information, the researchers said, will likely assist in estimating a patient’s diagnosis, as enzyme activity levels can vary widely in LOPD.

As an example of this variance, one LOPD patient in the study was diagnosed at age 13, with 100% GAA activity, while another was diagnosed at age 26 with 0% activity.

As a possible reason for the varying enzyme activity in the late-onset group, the investigators said their results suggest that splice site variations in GAA are “leaky,” meaning that enzymes can still partially be produced and ease disease impact.

The scientists cautioned, however, that while the presence of at least one splice variant appeared to predict LOPD, “it would be premature to generalize this conclusion” because of the study’s small size.

The children with IOPD tended to have mutations in both GAA copies. Rather than splice site variants, they had mutations that result in the loss of genetic material, a change in amino acids (the building blocks of proteins), a premature stop in the coding sequence that leads to a shorter, unfinished protein, or an alteration in the way that sequence is read.

Although this study’s findings imply a greater role for genetic testing and reinforce the value of newborn screening, the remaining uncertainty involved in making predictions based on patient genotype means that “enzyme activity levels continue to have utility for supporting the diagnosis when the genetic variants are ambiguous.”

“It is important,” the team concluded, “for newly diagnosed patients with Pompe disease to have complete genetic, cardiac, and neurological evaluations.”