Pompe disease: Shared and unshared features of lysosomal storage disorders

Abstract

Pompe disease, an inherited deficiency of lysosomal acid α-glucosidase (GAA), is a severe metabolic myopathy with a wide range of clinical manifestations. It is the first recognized lysosomal storage disorder and the first neuromuscular disorder for which a therapy (enzyme replacement) has been approved. As GAA is the only enzyme that hydrolyses glycogen to glucose in the acidic environment of the lysosome, its deficiency leads to glycogen accumulation within and concomitant enlargement of this organelle. Since the introduction of the therapy, the overall understanding of the disease has progressed significantly, but the pathophysiology of muscle damage is still not fully understood. The emerging complex picture of the pathological cascade involves disturbance of calcium homeostasis, mitochondrial abnormalities, dysfunctional autophagy, accumulation of toxic undegradable materials, and accelerated production of lipofuscin deposits that are unrelated to aging. The relationship of Pompe disease to other lysosomal storage disorders and potential therapeutic interventions for Pompe disease are discussed.

Keywords:

• autophagy
• calcium
• lysosomal storage diseases
• lysosome
• mitochondria
• Pompe disease

Funding

This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health. Dr. Lim and Dr. Li are supported in part by a CRADA between NIH and Genzyme Corporation, from the Acid Maltase Deficiency Association, and from Ida & Joseph Kaplan Foundation.