New GAA Mutations ID’d as Cause of Late-onset Disease

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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GAA Mutations Identified

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Four new mutations in the GAA gene have been identified in a group of people with late-onset Pompe disease (LOPD), according to a study in Spain.

The study “Genotype–phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants” was published in the Orphanet Journal of Rare Diseases.

Pompe disease is a genetic disorder characterized by impaired production or function of the acid alpha-glucosidase (GAA) enzyme. Without functional GAA, glycogen (a complex sugar molecule) accumulates in tissues, causing damage. Affected tissues include the heart, skeletal and respiratory muscles, as well as lymphocytes (immune system cells).

To date, more than 560 genetic mutations have been identified in the GAA gene. Their frequency varies according to ethnicity, with some being more prevalent in Caucasians versus Asians, and vice versa.

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In order to establish a correlation between GAA mutations and Pompe clinical characteristics, researchers in Spain analyzed samples from a group of 2,637 patients (mean age 45.16 years) who had either a family member with the disease, or were suspected of having the disease based on specific symptoms.

The team first measured the enzymatic GAA activity in dried blood spots. Those with lower activity — below 0.75 micromol/L/h — underwent further testing (a total of 117 patients, 4.44%) in lymphocytes to confirm the enzyme diagnosis. A definite diagnosis was established when the activity was below 0.15 nanomol/min/mg protein. The remaining patients (2,520, corresponding to 95.56% of the group analyzed) were deemed negative for Pompe disease, as they had normal GAA activity.

In total, 24 patients were diagnosed with Pompe disease and all underwent genetic sequencing for the GAA gene.

The genetic analysis identified 16 different genetic mutations in 17 patients —  16 LOPD patients (seven men and nine women), and a baby boy with only two days of life who had infantile-onset Pompe disease (IOPD). The boy presented an abnormally thick heart muscle and died shortly after.

In two cases the mutations had no effect on protein production rendering the total to 14 mutations.

Four of the genetic mutations had not been described previously: c.1328A>T; c.1831G>A; c.2819C>A; and c.1889-1G>A.

In line with previous reports, the most common mutation observed in this group of patients was c.-32-13T>G, being detected in 15 patients (88.2%).

“We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant,” the researchers wrote. “As is published in the literature, [this] variant is the most common in Caucasian populations and it is present in 40–70% of the alleles in patients affected with [Pompe].”

The next most frequent disease-causing mutation present in the group was c.236_246delCCACACAGTGC. This variant was found in two unrelated patients, one of them being the child with IOPD. Researchers suggested this mutation was “associated with early disease and a worse prognosis,” they wrote.

Common symptoms seen in the diagnosed patients include muscle weakness and respiratory distress. Exercise intolerance, decreased muscle tone, swallowing difficulties, and muscle pain also were reported. Three patients were asymptomatic at the time of assessment.

Overall, “in this study fourteen genetic variants in GAA gene were identified, as cause of Pompe disease, including four new variants,” the researchers wrote.

“Our findings underscore the importance of early diagnosis and … accurate molecular analysis to improve genetic counseling in addition to enabling a better quality of life for patients,” they concluded.