Faulty Cell Cleanup Causes Heart Muscle Disease in Lysosomal Storage Disorders: From Disease Understanding to Targeted Treatments

Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs).

• The cardiomyopathies of Fabry, Pompe, and Danon disease may be better understood as variations of a common issue involving the breakdown of the autophagy-lysosome system in heart cells.
• Failures in lysosomal degradation or autophagosome-lysosome fusion could lead to the accumulation of undegraded substrates and defective mitochondria, resulting in heart muscle thickening, scar tissue formation, and conduction issues.
• Danon disease exemplifies a primary defect in the autophagic process due to the loss of LAMP2, while Pompe and Fabry diseases disrupt this process through different mechanisms that ultimately cause similar heart damage.
• Shared pathobiology is suggested to extend to other storage disorders affecting the heart, such as mucopolysaccharidosis (MPS).
• Biomarkers reflecting lysosomal and autophagic dysfunction may provide better insights than those focusing solely on storage levels.
• Enzyme replacement therapy may address substrate accumulation but does not fully resolve autophagic and mitochondrial damage, indicating the need for alternative approaches like gene therapy and autophagy-targeted strategies.

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