Pompe disease (PD) is a lysosomal disorder caused by a partial or total deficiency of the enzyme acid alpha-glucosidase (AAG). The mutational landscape and the amount of enzymatic activity determine the severity of clinical manifestations, tissue impairment, and age of disease onset.

PD has two main forms: infantile-onset PD (IOPD), also known as the classic form, and late-onset PD (LOPD), or non-classic form, which develops in childhood or adulthood. IOPD typically begins at birth, or within a short period after, and has more severe manifestations, such as cardiomyopathy and muscle weakness. Ultimately, IOPD can cause death within the first year of life. However, a few patients develop a non-classic form of IOPD, showing non-severe cardiomyopathy during the first year of life.

PD has an autosomal recessive pattern caused by a pathogenic variant in both copies of the GAA gene. “The mutational spectrum of GAA is very heterogeneous, genetic variants are often “private,” found only in a single family or in a small population,” Taverna et al say.

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Learn more about PD etiology

In June 2019 (the date of the last update), the Pompe disease GAA variant database was composed of 562 GAA variants. From those, 422 were disease-associated and 140 were considered genetic variants of unknown significance.

GAA variants can be point mutations, insertions, or deletions. These alterations seem to be mostly confined to three critical regions of the gene: exon 2 (contains the start codon), exon 10/11 (encodes the catalytic site), and exon 14 (encodes for a highly conserved region of the GAA protein).

The Classic c.-32-13T>G Variant

The variant c.-32-13T>G (IVS1-13T>G) was found as the most common mutation in the Caucasian population. This variant is responsible for a splicing alteration that leads to exon 2 skipping, which decreases the synthesis of the functional enzyme by 10%-20%.

“The individuals homozygous for c.-32-13T>G were considered asymptomatic, but this hypothesis was proven to be incorrect. Patients with homozygous c.-32-13T>G showed myalgia, exercise-induced fatigue and increase of creatine kinase (CK) serum activity, a generic marker of muscle damage,” Taverna et al explained.

According to data retrieved from the Pompe disease GAA variant database, 258 patients had the c.-32-13T>G mutation, with 5.4% being homozygous. This mutation is often associated with a second mutation in the other GAA allele, which is usually of higher severity. Most commonly, these second mutations are found in exon 2, exon 14, and intron 17. For instance, 3.1% of the c.-32-13T>G mutations were associated with deletions in exon 2 and intron 17 (c.525delT and c.2481+102_2646+31del, respectively) and 1.95% with a point mutation in exon 14 (c.1927G>A).

“Recently, very promising results have been obtained in vitro by targeting a specific silencer located within exon 2 with a combination of antisense oligonucleotides. Indeed, treatment of myotubes of patients carrying the c.-32-13T>G mutation resulted in a significant increase of exon 2 inclusion and GAA activity, and a decrease in lysosomal glycogen accumulation,” Peruzzo et al explained in a review article published Annals of Translational Medicine.

Moreover, the inclusion of exon 2 and enhancement of GAA enzyme activity might also be achieved by targeting inhibitory sequences within intron 1.

Beyond the Classic Variant

Taverna et al analyzed the distribution of the intronic and exonic GAA mutations reported in the Pompe disease GAA variant database. “These mutations are mainly reported in exon 2, in which the 49% of all variants were associated with the very severe phenotype,” they said. They also observed that most (60.71%) very severe variants were associated with a classical infantile form of PD.

In a recent study published in the Journal of Human Genetics, Viamonte et al found additional splice site variants associated with a milder PD phenotype. “The presence of at least one splice site variant (c.546 G > C/p.T182 = , c.1076–22 T > G, c.2646 + 2 T > A, and the classic c.−32–13T > G variant) was associated with LOPD, while the presence of non-splice site variants on both alleles was associated with IOPD,” they concluded. These findings result from the retrospective analysis of 23 participants with genetically confirmed PD.

In another study, Thomas et al identified c.1933G>A, c.1A>G, c.1927G>A, and c.2783G>C as common pathogenic variants in Indian PD patients (n = 64). In addition, they identified 10 novel pathogenic variants.

Though PD is a pan-ethnic disease, its prevalence varies among different countries and evidence suggests that few variants are overrepresented in specific populations. For instance, two severe mutations (c.525delT and c.2481+102_2646+31del) are known as the “Dutch mutations” due to their high recurrence in the Dutch population.

Relevance of Studying GAA Mutations

To date, no strict correlation between genotype and phenotype has been identified in PD. However, some general conclusions could be established from the currently available data.

For instance, patients diagnosed with IOPD usually harbor mutations that greatly reduce or abolish all forms of GAA expression. On the other hand, a mild mutation in one allele may prevent the occurrence of severe IOPD.

Hence, as stated by Peruzzo et al “Besides being useful for the interpretation of genetic data obtained in PD patients, the knowledge of the functional consequences of a mutant variant might be useful to select patients that could benefit from experimental therapies, such as the use of antisense oligonucleotides able to rescue splicing defects or molecular chaperons to improve GAA activity by promoting folding, processing and trafficking to the lysosome of mutated but partially active variants.”


Taverna S, Cammarata G, Colomba P, et al. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging (Albany NY). 2020;12(15):15856-15874. doi:10.18632/aging.103794

Peruzzo P, Pavan E, Dardis A. Molecular genetics of Pompe disease: a comprehensive overview. Ann Transl Med. 2019;7(13):278. doi:10.21037/atm.2019.04.13

Viamonte MA, Filipp SL, Zaidi Z, Gurka MJ, Byrne BJ, Kang PB. Phenotypic implications of pathogenic variant types in Pompe disease. J Hum Genet. 2021. doi:10.1038/s10038-021-00935-9

Thomas DC, Sharma S, Puri RD, Verma IC, Verma J. Lysosomal storage disorders: novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease. Clin Biochem. 2021;89:14-37. doi:10.1016/j.clinbiochem.2020.12.002