Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe...

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Pompe disease is a lysosomal storage disorder due to acid alpha-glucosidase deficiency, impacting glycogen degradation.
• Infantile Pompe disease presents with severe cardiomyopathy and myopathy; late-onset forms primarily affect skeletal muscle.
• Autophagic inclusions are prominent in adult Pompe disease patients and mouse models.

Purpose of the Study:

• To evaluate the autophagic pathology in infants with Pompe disease before and after enzyme replacement therapy (ERT).
• To investigate the role of autophagy in infantile Pompe disease pathogenesis.
• To compare infantile Pompe disease pathology with that observed in adult patients.

Main Methods:

• Analysis of single muscle fibers from biopsies of infants before and 6 months after ERT.
• Staining for autophagosomal and lysosomal markers, followed by confocal microscopy.
• Second harmonic imaging of unstained muscle bundles.

Main Results:

• Infants displayed significantly expanded lysosomes, with negligible autophagic components, contrary to adult patients.
• Following 6 months of ERT, autophagic buildup became apparent after glycogen clearance.
• The two pathologies (expanded lysosomes and autophagy) did not appear to coexist in most muscle fibers.

Conclusions:

• Infantile Pompe disease pathogenesis differs from adult forms, characterized initially by lysosomal expansion rather than autophagy.
• Enzyme replacement therapy may reveal underlying autophagic pathology by clearing accumulated glycogen.
• These findings highlight distinct pathological mechanisms in infantile versus adult Pompe disease.