Pompe disease is an autosomal recessive disorder characterized by homozygous mutations in the GAA gene which codes for acid alpha-1,4-glucosidase (GAA, or acid maltase).1 It is an inborn error of metabolism also known as glycogen storage disease type II (GSDII) and was first identified in 1962.2 Since then, more than 560 variations to GAA have been identified.1 

The GAA gene is found on the long arm of chromosome 17 (17q25.2-q25.3) and consists of 20 exons. Prevalence of specific mutations vary by geographical region and ethnicity and phenotype is determined by the level of residual enzymatic activity of GAA.1,3 Synthesis of GAA is a multi-step process involving posttranslational modification, lysosomal trafficking, and proteolytic processing. Thus, a variety of mutations can affect GAA synthesis by modifying any of these processes.1 

Missense mutations are most common (51%), followed by microdeletions (14.9%), splicing variants (12.7%), nonsense mutations (8.8%), insertions/duplications (6%), gross insertions/deletions (3.3%), small indels (2.2%) and complex rearrangements (0.9%).4

Three key regions on the GAA gene have been identified where pathologic variations tend to occur. The first region is exon 2 which contains the start codon. Exons 10 and 11 code for the catalytic site of the GAA protein. The third region is exon 14, which codes for a highly conserved region of the GAA protein. However, many mutations have been identified outside these three regions.1,5 A list of GAA variants and their phenotypic associations can be found at

Role of Acid Maltase (GAA)

GAA plays an important role in the final steps of glycogenolysis. It is responsible for cleaving α-1,4- and α-1,6-glycosidic bonds and, consequently, the liberation of individual glucose monosaccharides from the glycogen polymer. This process occurs inside lysosomes, however in GAA deficiency, low to absent enzymatic activity results in lysosomal accumulation of substrates in different tissues. The main clinical manifestations are due to accumulation inside cardiac myocytes and skeletal muscle.1 

Genotype-Phenotype Association

The most common mutation in Caucasians is c.-32-13T>G (IVS1-13T>G), which leads to a splicing defect and skipping of exon 2 and manifests as late onset Pompe disease. In The Netherlands, del525T (exon 2) and c.925G>A (exon 5) are the most common mutations, in Taiwan, c.1935C>A (exon 14) is most common while in African Americans, the most common mutation is c.2560C>T (exon 18). While much information has been accumulated about the GAA gene and pathogenic variance, there is no strict correlation between specific genotypes and disease severity. It is postulated that epigenetic factors may play a role in determining phenotype.4 

One mutation does have a strong genotype to phenotype correlation, and that is the c.-32-13T>G variant since 90% of patients with the childhood/adult phenotype harbor this mutation in one allele. This results in a splicing defect that completely or partially splices out exon 2, which contains the start codon. Consequently, low to nonexistent levels of normally spliced GAA mRNA is produced. Nonetheless, GAA activity among patients with the c.-32-13T>G variant varies at age of onset.4

Generally, mutations that lead to low to absent enzymatic activity of GAA results in infantile onset (classical) Pompe disease while mutations that preserve some GAA activity results in childhood/adult (non-classical) phenotype. 


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

2. Hers HG. α-Glucosidase deficiency in generalized glycogen-storage disease (Pompe’s disease). Biochem J. 1963;86(1):11-16.

3. Park KS. Carrier frequency and predicted genetic prevalence of pompe disease based on a general population database. Mol Genet Metab Rep. 2021;27:100734. doi:10.1016/j.ymgmr.2021.100734

4. 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

5. Fernandez-Hojas R, Huie ML, Navarro C, et al. Identification of six novel mutations in the acid alpha-glucosidase gene in three spanish patients with infantile onset glycogen storage disease type II (Pompe disease). Neuromuscul Disord NMD. 2002;12(2):159-166. doi:10.1016/s0960-8966(01)00247-4

Reviewed by Harshi Dhingra, MD, on 7/27/2021.