Overview of Pompe Disease

Pompe disease is an autosomal recessive genetic disorder caused by a deficiency or dysfunction of the lysosomal hydrolase acid alpha-glucosidase (GAA).* This enzymatic defect results in lysosomal glycogen accumulation in multiple tissues, with cardiac and skeletal muscle tissues most seriously affected.¹

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Nomenclature

The name Pompe disease is derived from the Dutch pathologist J.C. Pompe, who first described a 7-month-old infant who died suddenly from the disease in 1932.4

Patients and medical professionals may use different pronunciations and names for Pompe disease. In the United States, it is pronounced “pom-PAY”, for example, while in Europe it is pronounced “pomp-uh”.

Patients as well as pulmonologists may refer to it as acid maltase deficiency or glycogen storage disease type II (GSD-II).

Neurologists and physiatrists may refer to it as acid maltase deficiency (AMD).

Pediatric cardiologists, geneticists, and metabolic specialists typically call it glycogen storage disease type II.

Other names used for Pompe disease include:

Acid alpha-glucosidase deficiency
Glyogenosis, type II
Lysosomal alpha-glucosidase deficiency

*NOTE: In scientific articles, the enzyme acid alpha-glucosidase may be written as acid α-glucosidase or shortened to α-glu or AGLU. It is also commonly shortened to GAA. GAA actually stands for glucosidase acid alpha, which is the name given to the gene (not the enzyme).

Normal and Affected Muscle Cells

1. Lysosomes are cellular compartments where glycogen is broken down.
2. In Pompe disease, glycogen accumulation causes the lysosomes to expand, damaging muscle cells.
3. Glycogen leaks out of the cells, impairing muscle function.

An illustration of a normal muscle vs. an affected cells

Infantile- and Late-Onset Forms

In the fatal infantile-onset form, the disease presents rapidly with hypotonia, generalized muscle weakness, and hypertrophic cardiomyopathy. Death usually occurs within one year of birth due to cardiorespiratory failure.^{1, 2}

The late-onset form of Pompe disease, which was discovered more than 30 years after the infantile-onset form, is more clinically heterogeneous, with greater variation in age of symptom onset, clinical presentation, and disease progression.¹

Late-onset patients may have residual GAA activity less than 40% of normal when measured in skin fibroblasts.³ Generally characterized by slowly progressive proximal muscle weakness and respiratory insufficiency, this form can present anytime from childhood through adulthood.¹

The late-onset form is distinguished from the infantile-onset form by the absence of severe cardiac involvement. While life expectancy can vary, death generally occurs due to respiratory failure.¹

History

Dutch pathologist J.C. Pompe first described a 7-month-old infant who died suddenly from the disease in 1932.⁴ After observing idiopathic hypertrophy of the heart and the accumulation of glycogen in all types of tissues, he labeled the disorder "cardiomegalia glycogenica diffusa."

Two other reports of infants with similar manifestations soon followed, calling the disorder Pompe disease. Nobel laureate G.T. Cori, who discovered the course of catalytic metabolism of glycogen, classified the disorder as glycogen storage disease type II (GSD-II) in 1954 to reflect the impaired glycogen metabolism of affected patients.⁵

Based on Cori's research and the discovery of a new organelle, the lysosome, Hers and colleagues in 1963 deduced the metabolic basis of Pompe disease by linking the deposition of glycogen to an inherited absence or shortage of lysosomal enzymes.⁶

As a result, Pompe disease was the first to be classified as a lysosomal storage disease (LSD). This breakthrough led to the ability to diagnose the disease and enabled the search for the chromosomal location of the genetic mutation.

In 1970, Engel published one of the early reports of a late-onset form of the disease, describing four adults with syndromes mimicking that of muscular dystrophy or other myopathies.⁷ Nine years later, the gene responsible for the disorder was localized to chromosome 17 and designated GAA on the human gene map.¹

Classifications

Pompe disease has been categorized several different ways in the literature. A neuromuscular disorder—and within that umbrella, a metabolic disease of the muscle—it is one of more than 40 diseases which share a common element of muscle wasting.

It was also the first disease to be classified as a lysosomal storage disease (LSD), a family of more than 40 diseases that interfere with the body's ability to degrade complex molecules within the lysosome.

Thirdly, Pompe disease is the most severe form of the 12 glycogen storage diseases (GSD), in which an enzymatic deficiency disrupts the normal conversion of glycogen.

References

1. Hirschhorn, Rochelle and Arnold J. J. Reuser. Glycogen Storage Disease Type II: Acid Alpha-glucosidase (Acid Maltase) Deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th Edition. New York: McGraw-Hill, 2001. 3389-3420.

2. Slonim AE, Bulone L, Ritz S et al. Identification of two subtypes of infantile acid maltase deficiency. J Pediatr 2000 Aug;137(2):283-5.

3. Chen YT, Amalfitano A. Towards a molecular therapy for glycogen storage disease type II (Pompe disease). Mol Med Today 2000 Jun; 6(6): 245-51.

4. Pompe J-C. Over idiopatische hypertropie van het hart. Ned Tijdscr Geneeskd 1932; 76:304. No abstract available.

5. Cori GT. Glycogen structure and enzyme deficiencies in glycogen storage disease. Harvey Lect 1954; 8: 145.

6. Hers HG. Alpha-glucosidase deficiency in generalized glycogen storage disease (Pompe's disease). Biochem J 1963; 86: 11.

7. Engel AG. Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies. Brain 1970; 93 (3): 599-616.