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 variants have been identified, although not all are considered pathogenetic Pompe disease mutation database. Available at: http://www.pompecenter.nl. Accessed March 2018. . This information is available at the Pompe disease mutation database. New GAA variants continue to be reported and the Pompe Center at Erasmus University (Rotterdam) maintains an up-to-date catalog.
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. 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. 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. Available at: http://ommbid.mhmedical.com/book.aspx?bookid=971. Accessed February 2015. .
While mutation analysis does not necessarily predict disease outcomes, it is an important tool that should help to confirm an initial diagnosis and assist in family, carrier and prenatal testing van der Ploeg AT et al. European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience. Eur. J. Neurol 2017; 24(6):768-e31 .