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Genetic Disorders - Pompe

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Pompe disease is a type II glycogen storage disease where glycogen accumulates in the lysosomes of certain organs and tissues, especially muscles, impeding their function. This is due to deficiency of the lysosomal acid alpha-1,4 glucosidase enzyme, which hydrolyses the alpha 1–4 and alpha 1–6 bonds in lysosomal glucose polymers. Pompe disease is classified into three groups depending on severity (alpha-glucosidase levels) and age of onset. These types are known as classic infantile-onset, non-classic infantile-onset, and late-onset.

Process for Diagnosis

Diagnosis is made by estimating the acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy or in white blood cells. In general, less than 3% of normal enzyme activity is found in severe infantile cases and residual levels ranging 3-30% of normal levels are found in less severe late onset form.

Genes Affected and Chromosomal Locus

The disease is caused by a mutation in the acid alpha glucosidase gene, which codes for the enzyme acid alpha-1,4 glucosidase, on long arm of chromosome 17 at 17q25.2-q25.3. The gene spans approximately 20 kb and contains 20 exons with the first exon being noncoding. There are over 300 mutations associated with the disorder, however, the transversion (T → G) mutation, which interrupts the RNA splicing, is the most common mutation among adults with this disorder. Additionally, a large deletion of exon 18 has been identified in 58% of GAA alleles in patients with both infantile and adult-onset Pompe from diverse ethnic backgrounds.

The chromosomal locus of the acid aloha glucosidase gene.

The chromosomal locus of the acid aloha glucosidase gene.

Metabolic Pathways Disrupted

Acid alpha 1,4 glucosidase cleaves glycogen 1,4 and 1,6 alpha-glycosidic linkages. Its action gives rise to free glucose molecules. Thus, a lack of the enzyme results in a build-up of glycogen in the lysosomes, lysosomal swelling, cellular damage and dysfunction.

Inheritance Pattern and Frequency

The condition is autosomal recessive, with both parents having one copy of the mutated gene but not displaying the symptoms themselves. It has been suggested that the frequency of Pompe’s disease is around 1 in 40,000 people.

Effect of Mutation on RNA Product

Frameshift mutations of GAA, which have been found to be associated with most early-onset phenotypes, lead to a truncated alpha-glucosidase protein with a loss of function.

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Effect of Mutation on Cellular Function and Phenotype

The cellular pathology mainly affects muscle fibers (they displace their myofibrils which ultimately leads to skeletal muscle weakness), but also other tissues such as cardiac and smooth muscle cells. The classical form occurs soon after birth and is characterized by hypertrophic cardiomyopathy, cardiorespiratory failure and generalized marked muscle weakness with floppy infant syndrome; if not diagnosed and early treated, the infants rarely survive beyond the first year of life.

The later onset forms have generally a milder phenotype than the classical form and can present with symptoms any time after age 1 year. Cardiac involvement is very rare and symptoms are dominated by significant involvement of skeletal muscles with a gradually progressing myopathy and respiratory insufficiency.


Enzyme replacement therapy with recombinant human acid α-glucosidase can be used to treat all types of Pompes disease, and studies have shown that the therapy significantly prolongs survival, decreases cardiomegaly, and improves cardiac and skeletal muscle function.

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