Pathophysiology of
Pompe Disease

Underlying Pathology of Pompe Disease

Although the clinical manifestations of Pompe disease can vary widely in terms of the age of onset, severity of signs, symptoms, and rate of progression, the pathologic basis is always the same: intralysosomal accumulation of glycogen because of an enzymatic defect.

A Genetic Basis

Pompe disease is a rare autosomal recessive disorder caused by mutations in an enzyme that degrades glycogen. The gene located on chromosome 17 (17q25.2-q25.3) codes for the enzyme acid alpha-glucosidase (GAA or acid maltase), which catalyzes the hydrogenation of branched glycogen compounds (glycogen and maltose) to glucose-6-phosphate within the lysosomes. Mutations in this gene result in deficiency or absence of GAA enzyme activity, resulting in intralysosomal accumulation of glycogen, primarily in muscle cells.

GAA Gene Mutations

Currently, there are over 500 known mutations in the GAA gene, about 300 of which are pathogenic. About half of the mutations are missense mutations, with the rest consisting of nonsense, splice site, small deletions and insertions, and large deletions. Nonsense, splice site, and insertion/deletion mutations that result in reading frame shifts and subsequent premature message terminations will typically affect mRNA stability. Certain mutations appear with high frequency in the population of patients with Pompe disease, while others are quite rare. In general, genotype dictates phenotype, and patients with the most severe form of the disease have mutations in both alleles of the GAA gene that completely prevent enzyme formation or function (<1% GAA enzyme activity of normal controls). Patients with less severe forms have sequence variation that allows for at least some level of GAA gene expression and enzyme production (between around 2% and 40% of normal controls, depending on the lab that does the assay). A pseudodeficiency allele has been identified (c.1726 G>A; p.Gly576Ser) that results in an enzyme with decreased activity toward false substrates but does not result in a disease phenotype.

Cellular and Tissue Damage

GAA Enzyme

The GAA enzyme is found in all tissues, and continuous accumulation of glycogen due to a deficiency in this enzyme causes lysosomes to swell and rupture, resulting in cellular damage (Fig. 1). An accepted mechanism of pathophysiology is that this in turn leads to progressive degeneration of skeletal, respiratory, and cardiac muscles, eventually resulting in loss of function. In the severe form of the disease, glycogen accumulation in liver tissue in addition to cardiac and respiratory muscles. This leads to cardiomegaly, hepatomegaly, elevation of liver enzymes, and death due to cardiorespiratory failure. In milder forms of the disease, glycogen accumulation predominantly in skeletal muscles results in progressive weakness.

A photomicrograph of myocardium from a male infant with hypertrophic cardiomyopathy secondary to Pompe disease.

Figure 1. H&E (left) and PAS (right) of Pompe-affected cardiac myocytes. Photomicrograph of myocardium from a male infant, gestational age 37 weeks and 4 days, with hypertrophic cardiomyopathy secondary to Pompe disease. H&E, hematoxylin and eosin; PAS, periodic acid-schiff.

Research in the past decade has begun to evolve our understanding of the lysosome as more than an organelle that simply breaks down macromolecules for cellular recycling or disposal. Some additional functions of the lysosome include tissue remodeling, pathogen defense, MHC class II antigen presentation, and cell death and proliferation. A main responsibility of the lysosome is uptake and management of intracellular material via a process termed autophagy. There are at least 3 mechanisms of autophagy that have been identified:

  • Microautophagy by which intracellular material is taken up directly into the lumen of the lysosome
  • Chaperone-mediated autophagy whereby cytosolic proteins with a particular motif are chaperoned to the lysosome and translocated in via receptor (LAMP-2A)-mediated fusion with the lysosomal membrane
  • Macroautophagy (most relevant to Pompe disease) whereby the cell’s nutritional and energy needs are met during times of “starvation” via “self-digestion” of intracellular components

Autophagic Flux

Autophagic flux describes a dynamic process by which cellular material is taken up, fused with the lysosome, broken down, processed, and recycled, depending on the substrate. This flux is complete upon degradation of the lysosomal cargo. Failure of any of these steps results in autophagic block or buildup, which is evident histologically by the presence of endosomes, lysosomes, and autophagosomes visible along the length of the muscle fibers. Histologic examination of skeletal muscle biopsies from patients with the classic, infantile-onset form of the disease show greatly expanded lysosomes without clear borders, consistent with the hypothesis of lysosomal rupture and the release of lysosomal enzymes as the basis for tissue destruction. However, muscle biopsies from patients with less severe forms of the disease show autophagic buildup along muscle fibers, suggesting a defect in autophagic flux. At times, this can be more severe than lysosomal enlargement and may be the only pathology.

Lipofuscin is composed of cross-linked, undegradable protein aggregates of lipids, carbohydrates, and metals (mostly iron). Gradual lysosomal accumulation of lipofuscin is associated with cellular oxidative damage and aging and is observed in a variety of cells and tissues, including neurons, retinal epithelium, and cardiac myocytes. Muscle biopsies of children and adults with Pompe disease may show deposition of lipofuscin associated with areas of autophagic buildup. Lysosomes play a role in phagocytosis and degradation of mitochondria. Researchers have postulated that accumulation of lysosomal lipofuscin would interfere with mitochondrial degradation, leading to decreased turnover of old/damaged mitochondria, generation of reactive oxygen species, and the formation of oxidized proteins and aggregates (ie, materials that comprise lipofuscin). Lysosomal accumulation of lipofuscin also appears to interfere with normal trafficking of lysosomal enzymes, further hindering the organelle’s degradative ability.

Thus, emerging research is challenging the view of the pathology of Pompe disease as driven solely by the lysosomal accumulation of glycogen. Additional pathways including lysosomal dysfunction, lipofuscin accumulation, mitochondrial abnormalities, and others paint a picture of a disease mechanism much more complex than originally thought.

The following video gives a graphic depiction of the mechanisms of the pathogenesis of Pompe disease.