Phenotypic implications of pathogenic variant types in Pompe disease

Area of Science:

• Genetics
• Biochemistry
• Pediatrics

Background:

• Pompe disease (glycogen storage disease type II) diagnosis and management are evolving with newborn screening.
• Predicting disease severity, particularly infantile-onset Pompe disease (IOPD) versus late-onset Pompe disease (LOPD), is crucial for patient care.
• The role of genetic variants in the GAA gene versus enzyme activity in determining Pompe disease phenotype requires further clarification.

Purpose of the Study:

• To investigate whether enzyme activity or specific genetic variants in the GAA gene can predict the phenotypic severity of Pompe disease.
• To differentiate between infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD) based on genetic and enzymatic factors.
• To assess the association of different types of GAA variants (splice site vs. non-splice site) with clinical outcomes like cardiomyopathy and motor function.

Main Methods:

• Retrospective analysis of 23 genetically confirmed Pompe disease participants.
• Collection of clinical data including cardiomyopathy, age at diagnosis, and gross motor function scale (GMFS).
• Analysis of GAA gene variants, including location (exon/intron) and type (splice site/non-splice site), alongside enzyme activity levels.

Main Results:

• Combinations of GAA variant types significantly correlated with disease subtype, cardiomyopathy, age at diagnosis, GMFS, and weight stability.
• Presence of at least one splice site variant associated with LOPD; non-splice site variants on both alleles linked to IOPD.
• Enzyme activity levels alone were insufficient to predict disease subtype or major clinical features; splice site variants often indicate a milder phenotype.

Conclusions:

• Genetic variant type, particularly splice site vs. non-splice site, is a better predictor of Pompe disease severity and subtype than enzyme activity alone.
• Multiple splice site variants, beyond the classic c.-32-13T>G, are associated with milder Pompe disease phenotypes.
• Enzyme activity remains useful for diagnosis with ambiguous genetic findings; comprehensive genetic, cardiac, and neurological evaluations are essential for newly diagnosed patients.