Orphanet Journal of Rare Diseases | Impact of Enzyme Replacement Therapy on Gastrointestinal Symptoms in Late-Onset Pompe Disease

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This study systematically evaluates gastrointestinal symptoms in patients with late-onset Pompe disease and their associations with enzyme replacement therapy (ERT) dosage, household income, and organ involvement, revealing that standard-dose ERT significantly improves most GI symptoms, while long-term use may exacerbate constipation.

 

Literature Overview

The article 'Gastrointestinal manifestations and enzyme replacement therapy in late-onset Pompe disease: insights from a cross-sectional analysis,' published in Orphanet Journal of Rare Diseases, reviews and summarizes the severity of gastrointestinal (GI) symptoms in 124 patients with late-onset Pompe disease (LOPD) and their associations with enzyme replacement therapy (ERT) dosage, clinical characteristics, and socioeconomic factors. Using the Gastrointestinal Symptom Rating Scale (GSRS) for cross-sectional analysis, the study found that standard-dose ERT significantly reduces abdominal pain, diarrhea, and indigestion, whereas long-term ERT may worsen constipation. Additionally, lower household income, need for respiratory support, and tongue muscle abnormalities are associated with more severe GI symptoms. This study emphasizes the multifactorial impact on GI function in LOPD patients and provides clinical evidence for optimizing treatment strategies.

Background Knowledge

Late-onset Pompe disease (LOPD) is an autosomal recessive disorder caused by deficiency of acid alpha-glucosidase (GAA), leading to abnormal glycogen accumulation in lysosomes, primarily affecting skeletal muscle, cardiac muscle, and smooth muscle. Compared to the infantile form, LOPD has a later onset and slower progression, but is often accompanied by progressive muscle weakness and respiratory dysfunction. In recent years, increasing evidence indicates gastrointestinal (GI) system involvement, manifesting as diarrhea, constipation, bloating, abdominal pain, and halitosis, significantly impacting nutritional status and quality of life. Although enzyme replacement therapy (ERT) has become the standard treatment, significantly improving motor and respiratory function, its effects on GI symptoms remain unclear. Some case reports suggest ERT may improve swallowing and GI motility, but systematic studies on dosage, frequency, and long-term effects are still lacking. Furthermore, GI symptoms may be related to complications such as macroglossia or tongue atrophy, scoliosis, and mechanical ventilation, highlighting the complexity of multisystem involvement. Currently, there is no specific treatment for GI symptoms, and high treatment costs limit the accessibility of standard regimens. Therefore, clarifying the true effects of ERT on GI symptoms and identifying modifiable intervention targets are crucial for improving overall patient management. This study fills the evidence gap regarding the relationship between ERT dosage and GI symptoms through a large-sample cross-sectional survey, providing direction for subsequent individualized treatment and novel therapeutic development.

 

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Methods and Experiments

The study included 124 clinically confirmed late-onset Pompe disease patients, using a cross-sectional design to collect gastrointestinal symptom data from the past month. All patients completed the Gastrointestinal Symptom Rating Scale (GSRS), a 15-item instrument divided into five domains: abdominal pain, reflux syndrome, diarrhea syndrome, indigestion syndrome, and constipation syndrome. Demographic information, clinical characteristics, ERT usage (dosage, frequency, duration), use of assistive devices (e.g., ventilators, nutritional support), and comorbidities (e.g., scoliosis, tongue muscle abnormalities) were also collected. Patients were categorized into three groups based on ERT use: untreated, reduced-dose ERT (<20 mg/kg or less than once every two weeks), and standard-dose ERT (20 mg/kg every two weeks). Spearman correlation analysis and multivariable linear regression models were used to assess associations between GSRS total and domain scores and clinical variables. Kaplan-Meier curves were used to analyze time-to-event differences in the onset of significant GI symptoms across ERT dosage groups.

Key Conclusions and Insights

• Patients receiving standard-dose ERT exhibited the mildest GI symptoms, significantly outperforming untreated and reduced-dose ERT groups, with particularly notable improvements in abdominal pain, diarrhea, and indigestion
• Patients on reduced-dose or no ERT experienced more severe GI symptoms and developed significant GI symptoms earlier
• Lower household income, lower ERT dosage, need for respiratory support, and presence of tongue muscle hypertrophy or atrophy were associated with more severe GI symptoms
• As ERT dosage increased, scores for halitosis, loose stools, and indigestion improved most significantly, indicating a positive effect of ERT on functional digestive disorders
• Long-term ERT use was positively correlated with constipation severity, suggesting potential new GI side effects with prolonged treatment
• Multivariable analysis showed that tongue muscle abnormalities and ERT dosage were significant independent predictors of GSRS total and multiple symptom domain scores
• Kaplan-Meier analysis demonstrated that standard-dose ERT significantly delayed the onset of significant GI symptoms, supporting the clinical value of early and adequate treatment

Research Significance and Outlook

This study is the first to systematically reveal the multifactorial regulatory mechanisms of GI symptoms in late-onset Pompe disease patients, emphasizing that ERT not only affects muscle function but also significantly modulates gastrointestinal function. Standard-dose ERT effectively alleviates various GI symptoms, supporting its central role in comprehensive management. However, long-term ERT may exacerbate constipation, indicating the need for close monitoring of GI function and consideration of combining prokinetic agents or adjusting regimens.

Moreover, the correlation between household income and GI symptoms suggests that socioeconomic factors in disease management cannot be overlooked, potentially exacerbating symptoms indirectly through impacts on treatment adherence, nutritional support, and psychological status. Future prospective cohort studies, incorporating biomarkers and imaging techniques, are needed to further validate these findings. Gene therapy, as a potential alternative to ERT, holds promise for fundamentally correcting enzymatic deficiencies and reducing long-term side effects, warranting deeper exploration.

 

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Conclusion

This study systematically analyzes the relationship between gastrointestinal symptoms and enzyme replacement therapy in patients with late-onset Pompe disease, finding that standard-dose ERT significantly reduces GI symptoms such as abdominal pain, diarrhea, and indigestion, and delays the onset of noticeable symptoms. However, long-term ERT use is associated with worsening constipation, indicating a need to balance efficacy with potential side effects in clinical practice. Beyond treatment factors, household income level, need for respiratory support, and structural abnormalities of the tongue muscle were also confirmed as important variables influencing GI symptoms, reflecting the multidimensional nature of disease management. This study provides crucial evidence for optimizing individualized treatment strategies in LOPD patients, emphasizing the importance of initiating full-dose ERT early and regularly assessing gastrointestinal function. Future research should explore the roles of gene therapy, adjunctive medications, or nutritional interventions in improving GI symptoms to comprehensively enhance patients' quality of life and nutritional status. Simultaneously, the development of social support systems should be incorporated into the overall management framework to ensure patients receive comprehensive and sustainable care.

 

Xinting Liu, Xuejiao Li, Xinyun Yao, Linyan Hu, and Guang Yang. Gastrointestinal manifestations and enzyme replacement therapy in late-onset Pompe disease: insights from a cross-sectional analysis. Orphanet Journal of Rare Diseases.