A new study published in Gene identified 55 different molecular pathogenic variants of Pompe disease in the Spanish population. Twelve of these had not previously been described, and they affected the function or expression of the acid α-glucosidase (GAA) protein, which is deficient in Pompe disease.

“In this study, we describe the largest genetic characterization of patients with Pompe from the Spanish population,” the researchers wrote.

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The authors of the study, Cinthia Amiñoso and Jesús Solera, MD, PhD, from the Molecular Oncogenetics Section at Hospital La Paz in Madrid, Spain, studied 76 patients with Pompe disease in the Spanish population. Twelve of these patients had infantile-onset Pompe disease and 64 had late-onset Pompe disease. The team molecularly analyzed the exons and intron flanking fragments of the GAA gene.

Of the 12 newly identified pathogenic variants, 3 affected the splicing of the GAA messenger RNA (mRNA) and 2 caused the activation of exonic cryptic splice sites.

The researchers also found that the common intronic 1 variant c.-32-13T>G occurred at a frequency of 84.37% in patients with late-onset Pompe disease.

Finally, they identified several variants of uncertain significance. The researchers stated that according to the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) 2015 guidelines, these variants should be reclassified as likely pathogenic.

Infantile-onset Pompe disease is caused by genetic variants that mainly lead to a lack of GAA activity. In about 20% of cases, the pathogenic variants disrupt the synthesis of the GAA enzyme. In late-onset Pompe disease, molecular alterations are less damaging; GAA enzyme activity may be reduced to between 2% and 40% of normal activity.

Although the spectrum of GAA variants is very heterogeneous and distributed throughout the gene, the intron 1 variant, c.-32-13T>G, localized 5́’ of the initiation codon, usually occurs in trans with other variants. 


Amiñoso C, Solera J. Genetic analysis of 76 Spanish Pompe disease patients: identification of 12 novel pathogenic GAA variants and functional characterization of splicing variants. Gene. Published online September 14, 2021. doi:10.1016/j.gene.2021.145967