Pompe disease, also called glycogen storage disease type II (GSD II) or acid maltase deficiency, is a rare genetic disorder with an estimated frequency of 1:40,000. It is caused by the absence or deficiency of acid alpha glucosidase (GAA), which is a lysosomal enzyme required for breakdown of the α-1,4-glycosidic and α-1,6-glycosidic bonds of glycogen to form glucose. In the absence or reduced activity of this enzyme, excessive amounts of glycogen accumulate throughout cells. Clinical symptoms are due mainly to cardiac and skeletal muscle involvement. The numerous presentations of Pompe disease range from severe hypotonia, muscle weakness, and hypertrophic cardiomyopathy (infant onset) to a comparatively mild form characterized by slowly progressive myopathy in skeletal muscle (adult onset).1

Inheritance Pattern

Pompe disease is inherited in an autosomal recessive pattern. If both parents are carriers, the chance that a child will inherit an abnormal gene from each parent is 25%. The risk that a child will inherit an abnormal gene from 1 parent and be a carrier, like the parents, is 50%. The likelihood that a child will acquire a normal gene from each parent is 25%. The risk is the same in males and females.2

Genetic Defects

Pompe disease is caused by pathogenic variations or mutations in the acid alpha glucosidase (GAA) gene. Up to 600 variations in the GAA gene have been identified in families with this disease.2

GAA is located on the long arm of chromosome 17 (17q25.2-q25.3) and comprises 20 exons. The first is a noncoding exon; the other 19 exons encode a 952-amino acid protein with a molecular weight of 105 kDa. The first exon has 5’ untranslated sequences and is separated from the second exon by a large intron. ATG, the first start codon, is situated 32 nucleotides downstream from the beginning of exon 2.3

In 2002, it was discovered that the abnormalities of GAA variants cluster in 3 critical regions of the gene: exon 2, which includes the start codon; exons 10 and 11, which encode the catalytic site; and exon 14, which encodes a highly conserved region of GAA protein.4

The Pompe disease GAA variant database (Variant database), last updated in June 2019, lists 562 GAA variants, of which 422 are associated with the disease and 140 are termed genetic variants of unknown significance (GVUS). In addition, the database contains information about predicted disease severity with each variant.5 Each mutation in the GAA gene affects one of the multiple steps required in synthesis, post-translational modifications, lysosomal trafficking, and proteolytic processing.1

Many of the mutations tend to occur in specific ethnic populations. The c.-32-13T>G (IVS1) mutation causes a splicing defect that results in low levels (approximately 10% to 20% of normal) of normal enzyme in a Caucasian population with an adult-onset form of the disease.6,7,8 The Arg854X mutation is noted in African Americans,9 and the Asp645Glu mutation in Chinese individuals from Taiwan.10,11 Some of the mutations have been observed in cultured cells, and the observed activities of the GAA enzyme correlate with the severity and various phenotypes of the disease.12 In the Netherlands, 2 mutations–namely, c.del525T and exon 18 deletion–are common. The c.2560C>T (p.Arg854Ter) mutation is the most frequent mutation in African Americans. It originated in an ancestral population in northern Central Africa and was brought to the Americas during the slave trade.13 

The onset of the disease phenotype with the most severe symptoms is during the first few months of life. The symptoms consist of severe muscle weakness, hypotonia (“floppy baby”), and hypertrophic cardiomyopathy. Marked cardiomegaly, which can be easily seen on chest radiographs, is the most prominent sign of Pompe disease in infants. The respiratory muscle weakness and cardiomegaly usually result in reduced ventilation and frequent infections. Enlarged tongue, mild hepatomegaly, problems in feeding, and prominent delay in motor milestones are other characteristic manifestations of this rapidly progressive form of the disease. Such children do not survive beyond the first year of life and usually die of cardiac failure. This severe form, defined by Dr. Pompe as the classic infantile form, is caused by a complete or nearly complete lack of GAA enzyme activity.14,15 A similar clinical presentation in infants, but with less severe cardiomyopathy, without left ventricular outflow obstruction, and with relatively longer and better survival, is described as a nonclassic infantile form.1 

Persons with a partial reduction in GAA enzyme activity (residual activity in the range of 1% to 30%) show progressive muscle dysfunction and respiratory insufficiency without the characteristic cardiac involvement. Phenotypic and genotypic heterogeneity is typical of this milder form of Pompe disease. The paraspinal muscles and lower limbs are usually affected first, followed by the respiratory muscles (mainly the diaphragm) and the intercostal and accessory muscles. With disease progression, marked scoliosis and lumbar hyperlordosis develop in affected individuals that eventually result in wheelchair dependency and a requirement for assisted ventilation. Respiratory failure is a significant cause of the high rates of morbidity and mortality in Pompe disease.16,17 Skeletal muscle weakness is the predominant clinical manifestation; however, the involvement of tissues other than muscle is being found increasingly.18 


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Reviewed by Debjyoti Talukdar, MD, on 7/27/2021.