Polymorphism in exercise genes and respiratory function in late-onset Pompe disease

Area of Science:

• Genetics and Molecular Biology
• Neuromuscular Disorders
• Respiratory Medicine

Background:

• Metabolic myopathies, including late-onset Pompe disease (LOPD), can be influenced by genetic variations affecting muscle structure and metabolism.
• Respiratory muscle dysfunction is a significant complication in LOPD, impacting patient prognosis and quality of life.
• Understanding the genetic underpinnings of respiratory involvement is crucial for predicting disease progression and tailoring therapies.

Purpose of the Study:

• To investigate the influence of various "exercise genes" on the severity and progression of respiratory dysfunction in patients with LOPD.
• To identify specific genetic polymorphisms associated with worse respiratory outcomes in LOPD patients undergoing enzyme replacement therapy (ERT).

Main Methods:

• Analysis of 43 LOPD patients with a 2-year follow-up since the initiation of ERT.
• Stratification of patients based on respiratory phenotype severity, assessed by forced vital capacity (FVC%) and postural drop in FVC%.
• Genotyping for polymorphisms in genes related to muscle function (ACE, ACTN3, PPR-α, AGT), glycogen metabolism (GYS, GSK3β), and autophagy (SIRT1, ATG7).

Main Results:

• Patients with two copies of the angiotensin-converting enzyme (ACE) D-allele (ACE-DD genotype) showed a 24-fold increased risk of severe respiratory dysfunction and progression.
• The α-actinin-3 (ACTN3) XX genotype was also associated with a worse respiratory outcome in LOPD patients.
• Genetic polymorphisms related to autophagy and glycogen metabolism did not demonstrate a significant influence on respiratory muscle function in this cohort.

Conclusions:

• Specific genetic polymorphisms, particularly ACE-DD and ACTN3-XX, are significantly associated with more severe respiratory phenotypes and progression in LOPD.
• These findings underscore the importance of studying "exercise genes" in the context of respiratory muscles due to their unique functional characteristics.
• The identified genetic markers may aid in predicting respiratory risk and guiding clinical management strategies for LOPD patients.