Mutations

Pompe disease is an inherited condition caused by a mutation of the acid alpha-glucosidase (GAA) gene, mapped to the long arm of chromosome 17 (location 17q25.2-q25.3).

As an autosomal recessive disorder, Pompe disease only occurs when an individual inherits two mutant alleles, one from each  parent Hirschhorn R, Reuser AJ. Glycogen Storage Disease Type II: Acid α-Glucosidase (Acid Maltase) Deficiency. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G., eds. The Online Metabolic and Molecular Bases of Inherited Disease. OMMBID. . Most patients are compound heterozygotes, meaning they have inherited two different mutations. To date, 500 distinct GAA mutations have been identified, although not all are considered pathogenetic. This information is available at the Pompe disease mutation database.  New GAA mutations continue to be reported  and the Pompe Center at Erasmus University (Rotterdam) maintains an up-to-date catalog.

Genotype-phenotype correlations

In general, genotype-phenotype correlation is not well understood and significant clinical heterogeneity can exist among patients with similar or identical mutations. One exception is the presence of two null mutations, resulting in a complete absence of GAA enzyme activity. This genotype results in very early disease presentation during infancy and severe, rapid disease progression. However, more studies are needed in order to better understand genotype-phenotype relations, and a correlation cannot be assumed for any individual  patient Hirschhorn R, Reuser AJ. Glycogen Storage Disease Type II: Acid α-Glucosidase (Acid Maltase) Deficiency. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G., eds. The Online Metabolic and Molecular Bases of Inherited Disease. OMMBID. . The progression of Pompe disease is highly variable and can be unpredictable, especially in patients with a later age of symptom onset. Researchers are still learning about the disease’s molecular pathology and the factors – both genetic and environmental – that may influence disease progression and outcome.

Mutation Analysis 

While mutation analysis does not necessarily predict disease outcomes, it is still an important tool that can help to confirm an initial diagnosis and assist in family, carrier and prenatal testing.