Pathology in late-onset Pompe disease arises from the abnormal accumulation of glycogen in the lysosomes of cells throughout various tissues in the body, particularly the skeletal muscle.¹

This excessive glycogen storage triggers lysosomal rupture, autophagy and consequent muscle damage.¹

Click on the headings to find out more.

In late-onset Pompe disease, glycogen accumulation in the respiratory skeletal muscle impairs contractility and causes gradual muscle weakness. The diaphragm appears to be the most severely affected and its involvement is a hallmark of late-onset Pompe disease.^3,6 The inspiratory and expiratory muscles – particularly those of the abdominal wall – are also impaired, along with the smooth muscle layers of the trachea and bronchi.^7,8

Neural involvement in respiratory pathophysiology 

Both human and animal models support the idea that neuropathology contributes to neuromuscular dysfunction and respiratory insufficiency in late-onset Pompe disease. This is strengthened by several patient case reports documenting glycogen accumulation in the central nervous system (CNS) and in phrenic motoneurons, key regulators of diaphragm expansion and contraction.^6,9

This graph summarises one proposed model of the relationship between declines in muscular and neural function, and the associated impact on respiratory capabilities.⁶

Reduced respiratory muscle capacity, reduced neural respiratory drive and increased load on the respiratory system will result in hypoventilation and eventual respiratory failure, with approximately 30–40% of late-onset Pompe disease patients requiring ventilation.³ 

Below, we see coronal slices through the carina for MRI breath-hold scans with the corresponding colour plots of a late-onset Pompe disease patient and a volunteer. Note the lack of diaphragm displacement in the Pompe disease patient. The colour maps represent the thickness of the segmentation in the anterior-posterior axis (red being the thickest and blue being the thinnest).¹⁰