Natural genetic variations, or polymorphisms, in the ACE gene do not account for the large variability in disease course, or the response to enzyme replacement therapy (ERT) observed among children and adults with Pompe disease, a study suggests.
More research is needed to identify the modifying factors for the variations, the investigators said.
The study, “The ACE I/D polymorphism does not explain heterogeneity of natural course and response to enzyme replacement therapy in Pompe disease,” was published in the journal PLOS ONE.
Pompe disease is a rare genetic disorder caused by mutations in the gene GAA. That gene provides instructions for making the enzyme alpha-glucosidase, necessary for the break down of glycogen, a complex sugar used for energy storage inside cells.
These mutations can stop functional alpha-glucosidase enzymes from being produced, or allow only partially functional enzymes to be made. Consequently, glycogen builds up to toxic levels inside cells, impairing certain organs and systems, particularly muscles.
A genetic disease, Pompe is inherited in an autosomal recessive pattern, meaning that a person develops the disease only if both copies of the GAA gene they inherit — one from the mother and one from the father — are faulty.
Most children and adults of European descent with Pompe disease carry a variant in one of GAA copies, called c.-32-13T>G, or IVS1. This variant is able to generate some amounts of functional GAA enzyme.
The second copy normally is a fully faulty, or null variant that does not generate any functional GAA enzyme. One example is the variant c.525delT.
Clinically, the spectrum of disease course is very broad, regardless of whether patients share the same GAA mutations, such as IVS1/c.525delT. It can range from a rapidly progressive and generally more severe classic infantile-onset to a slower progressing disease course in children and adults.
The variation between siblings is less broad, suggesting that disease progression can be modified by genetic background factors.
In addition, the response to enzyme replacement therapy (ERT) — for Pompe, the administration of recombinant human GAA enzyme — varies between patients. ERT has been shown to improve muscle ability and to stabilize lung function, but individual responses can vary considerably.
Naturally occurring variations, or polymorphism, at another gene have been suggested as disease modifiers underlying symptom onset or even response to ERT.
Specifically, an insertion or a deletion (I/D) of DNA building blocks along the ACE gene, which codes for the angiotensin I-converting enzyme, have been proposed. In the body, ACE enzyme clips certain proteins and is part of a system to regulate blood pressure, fluids, and salts.
To learn more, a team of researchers at the Erasmus MC University Medical Center, in the Netherlands, compared Pompe’s natural disease course in a group of 131 children and adults, in relation to their ACE genetic background.
They also studied the disease’s impact on response to ERT, as 112 of the enrolled patients were under treatment and were followed for five years. All participants were carriers of the IVS1 variant and a null GAA variant.
To assess clinical course, researchers registered the use of wheelchair and mechanical ventilation, muscle strength as assessed by manual tests, distance walked on the six-minute walk test (6MWT), lung function determined by forced vital capacity (FVC) and how strongly disease affected patients’ ability to carry out daily life activities (R-PAct scale).
For comparing outcomes relative to ACE polymorphisms, participants were divided three categories: carriers of insertions only, deletions only, and those who carried both insertions and deletions.
Analysis at first visit showed no differences between these patients groups with respect to age at first symptoms, diagnosis, wheelchair use, or ventilator use.
Overall, responses to ERT over five years also could not be explained by differences in ACE variations for any of the outcome measures.
The group of patients included 24 families with 54 siblings. Differences also seemed to occur between or within families, regardless of ACE polymorphisms.
“We conclude that the ACE I/D polymorphism does not explain the large variation in disease severity and response to ERT observed among Pompe patients with the same c.-32-13T>G GAA variant,” the researchers said.
“The search for modifying factors that can explain phenotypic [presentation] variation in Pompe disease should continue,” they concluded.