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Increased Glycogenin-Exposed Residual Glycogen in Lysosomes Is the Early Pathological Finding in Asymptomatic Pompe
Yixin Shi1, Na Zhang2, Hanhan Sun1
1Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Introduction/Aims:
Although asymptomatic or pre-symptomatic Pompe disease is increasingly recognized, early skeletal muscle pathology and the role of residual glycogen at this stage remain unclear. Here, we investigated early muscle pathological changes using human samples and an early-stage Gaa -/- mouse model, focusing on residual glycogen accumulation.
Methods:
Clinical, genetic, imaging, and muscle pathological analyses were performed in an asymptomatic Pompe disease patient carrying a novel GAA variant. Skeletal muscle samples from asymptomatic and symptomatic patients, as well as from early-stage and late-stage Gaa -/- mice, were analyzed using histochemistry, immunohistochemistry, immunofluorescence, and Western blotting to assess residual glycogen accumulation and lysosome-associated pathways.
Results:
We identified a novel mutation, c.361C > T, in an asymptomatic Pompe disease patient. Despite the lack of symptoms, residual glycogen accumulated in muscle lysosomes. Immunohistochemistry showed positive glycogenin expression, while LAMP1 and LC3 were negative, suggesting early glycogenin detection. Western blot revealed increased glycogenin and STBD1, with mild LAMP1 and LC3 upregulation. In 1-month-old Gaa -/- mice, glycogenin, LAMP1, STBD1, and LC3 were all upregulated. Furthermore, immunofluorescence further showed glycogenin/LAMP1 double-positive muscle fibers in both the patient and mice.
Discussion:
Our study shows that key pathological changes in Pompe disease occur during the asymptomatic stage, with early lysosomal accumulation of residual glycogen. This suggests residual glycogen may serve as a biomarker of early disease activity and a potential target for early intervention, informing disease monitoring and the timing of enzyme replacement therapy (ERT). Further studies are needed to validate its clinical utility and explore strategies for early clearance.
Insights
Early Pompe disease shows skeletal muscle pathology with residual glycogen accumulation in lysosomes, even before symptoms appear. This finding highlights residual glycogen as a potential biomarker for early disease detection and intervention.
Area of Science:
- Biochemistry
- Genetics
- Pathology
Background:
- Pompe disease, a lysosomal storage disorder, results from acid alpha-glucosidase (GAA) deficiency.
- Asymptomatic and pre-symptomatic stages of Pompe disease are increasingly recognized.
- Early skeletal muscle pathology and the role of residual glycogen remain unclear.
Purpose of the Study:
- To investigate early skeletal muscle pathological changes in Pompe disease.
- To focus on residual glycogen accumulation in asymptomatic individuals and early-stage mouse models.
- To identify potential biomarkers for early disease detection and intervention.
Main Methods:
- Analysis of muscle samples from an asymptomatic patient with a novel GAA variant and Gaa-/- mice.
- Histochemistry, immunohistochemistry, immunofluorescence, and Western blotting were used to assess glycogen accumulation and lysosome-associated pathways.
- Evaluation of glycogenin, LAMP1, and LC3 expression.
Main Results:
- A novel GAA mutation was identified in an asymptomatic patient.
- Residual glycogen accumulated in muscle lysosomes in asymptomatic patients and early-stage Gaa-/- mice.
- Glycogenin, STBD1, LAMP1, and LC3 were upregulated, with glycogenin/LAMP1 double-positive fibers observed.
Conclusions:
- Key Pompe disease pathology occurs during the asymptomatic stage, characterized by early lysosomal accumulation of residual glycogen.
- Residual glycogen may serve as a biomarker for early disease activity.
- These findings inform disease monitoring and the timing of enzyme replacement therapy (ERT).
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