Researchers have identified 3 new compound heterozygous Pompe disease patients with symptoms starting in childhood. One of them had a genetic modification that lowered the activity of the acid alpha-glucosidase (GAA) enzyme, while the others had modifications that acted on processes downstream of GAA enzyme activity.

The most common genetic mutation causing Pompe disease is c.-32-13T>G/null GAA. It leads to a splicing defect and skipping of exon 2, and it causes a broad range of phenotypes in terms of age of symptom onset from early childhood to late adulthood. There are also other common GAA genotypes with large phenotypic variations. 

In the present study, a team of researchers led by W.W.M. Pim Pijnappel, PhD, used the Pompe GAA variant database to analyze variations in the age of symptom onset in the most common GAA genotypes. They published their results in Human Mutations.

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They found that in patients with the c.2647-7G>A/null genotype, symptoms always started in adulthood. On the other hand, in patients with the c.-32-13T>G/null, c.546G>T/null, c.1076-22T>G/null, c.2238G>C/null, and c.2173C>T/null genotypes, symptoms could appear any time from early childhood to late adulthood. In patients with the c.1309C>T/null genotype, symptoms usually appeared during early to late childhood.

Interestingly, when patients were homozygous for a certain genotype, symptom onset shifted toward older ages.

“These findings indicate that a broad variation in symptom onset occurs for various common GAA genotypes, suggesting the presence of modifying factors,“ the researchers concluded. 

The GAA gene encodes for the acid alpha-1,4-glucosidase enzyme, which plays an important role in the final steps of glycogenolysis. It cleaves individual glucose monosaccharides from glycogen polymers. Mutations in different regions of the GAA gene can have effects on posttranslational modifications, lysosomal trafficking, and proteolytic processing of the enzyme.


Niño MY, In’t Groen SLM, de Faria DOS, et al. Broad variation in phenotypes for common GAA genotypes in Pompe disease. Hum Mutat. Published online August 18, 2021. doi:10.1002/humu.24272