Broad variation in phenotypes for common GAA genotypes in Pompe disease

Area of Science:

• Genetics
• Biochemistry
• Rare Diseases

Background:

• Pompe disease is a rare genetic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene.
• The age of symptom onset in Pompe disease exhibits significant variability, impacting clinical presentation and progression.
• Understanding the influence of specific GAA genotypes on age at onset is crucial for predicting disease course and developing targeted therapies.

Purpose of the Study:

• To analyze the variation in age at symptom onset for the most common GAA genotypes in Pompe disease.
• To investigate the role of genetic modifiers in influencing the phenotypic presentation of Pompe disease.
• To expand the understanding of genotype-phenotype correlations in Pompe disease.

Main Methods:

• Utilized an updated and extended Pompe GAA variant database for analysis.
• Examined age at symptom onset across various common homozygous and compound heterozygous GAA genotypes.
• Investigated the effect of specific genetic variants, including c.510C>T, on GAA enzyme activity and symptom onset.

Main Results:

• The c.2647-7G>A/null genotype invariably presented with adult-onset symptoms.
• Several genotypes, including c.-32-13T>G/null and c.546G>T/null, showed a broad range of symptom onset from childhood to adulthood.
• Homozygous patients generally exhibited a later age at symptom onset.
• Three compound heterozygous c.-32-13T>G/null patients with the c.510C>T modifier presented with childhood onset, with c.510C>T lowering GAA enzyme activity.

Conclusions:

• Significant variation in age at symptom onset exists for multiple common GAA genotypes in Pompe disease.
• The findings suggest the presence of genetic factors that modify the phenotypic expression of Pompe disease.
• The c.510C>T variant appears to act as a genetic modifier by affecting GAA enzyme activity, while other modifiers may act downstream of enzyme function.