Study Stresses Importance of Early Treatment for Different Mutations

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by Margarida Maia |

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A better understanding of Pompe disease-causing genetic mutations may help with early treatment intervention, even if symptoms are subtle, a small Hungarian study suggests.

Researchers found that the precise localization of a mutation determines the impact on GAA enzyme activity, which in turn has been associated with disease onset.

Their study, “Correlation of GAA genotype and acid-α-glucosidase enzyme activity in Hungarian patients with Pompe disease,” was published in the journal Life.

Pompe disease is caused by mutations in the GAA gene, which provides instructions to make an enzyme called acid alpha-glucosidase (GAA). In the absence of this enzyme, or when its activity is reduced, glycogen (a sugar molecule) starts building up inside cells to toxic levels, causing damage — especially in muscles.

The type of Pompe disease is partly linked to the specific mutation affecting the GAA gene, which may impact disease severity and onset.

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In the study, researchers in Hungary searched for a link between GAA variants and enzyme activity. They also looked at how it manifests in the disease.

The study included 24 patients diagnosed with Pompe disease: 20 (83%) had late-onset Pompe disease and four (17%) had infantile-onset Pompe disease — one of whom had the non-classic type. Their age ranged from 4 to 69 years (mean 43.5 years); 16 patients were female and eight were male.

Mean age at onset for late-onset Pompe disease patients was 48.3 years, and for infantile-onset disease, it was 4.5 months.

The researchers identified 15 different disease-causing or likely disease-causing mutations in the GAA gene, including one novel variant known as c.1158_1160delGGT.

The most common mutation, found in 20 patients with late-onset disease, is known as c.-32-13T>G. Of those 20 patients, five had two copies of the c.-32-13T>G variant, while 15 had compound GAA variants — meaning different mutations in either gene copy.

Next, the researchers looked at the cross-reactive immunologic material (CRIM) status, an important predictor of a patient’s response to enzyme replacement therapy (ERT). ERT works by providing the GAA enzyme to Pompe disease patients. It is marketed as Lumizyme (alglucosidase alfa) in the U.S. and Myozyme in the European Union.

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According to the Pompe disease GAA variant database, the CRIM status was positive for eight of the variants (meaning residual enzyme activity) and negative for two of the variants, meaning no enzyme activity.

When the researchers measured enzyme activity on dried blood spots — a form of sampling where a drop of blood is blotted and dried on filter paper — they found that participants with late-onset Pompe disease had higher enzyme activity than those with infantile-onset disease. The lowest enzyme activity was found in patients who did not carry the c.-32-13T>G variant.

In addition, participants with two copies of the c.-32-13T>G variant had higher enzyme activity than those with compound GAA variants.

The researchers also found that GAA activity varied according to the specific parts of the enzyme affected by the mutations. Mutations in crucial parts of the enzyme resulted in more severe effects on enzyme activity.

Due to the small number of patients with infantile-onset Pompe, however, the scientists were unable to establish a relationship among GAA variants, enzyme activity, and age of disease onset in this group.

“Further information on the effect of GAA gene variation on the efficacy of treatment and the extent of immune response to ERT would be of importance for optimal disease management and designing effective treatment plans,” the researchers wrote.