Overview of Pompe Disease
Epidemiology
Genetics
Diagnosing PompeGenetics
Mode of Inheritance
Pompe disease is an autosomal recessive genetic disorder with variable penetrance that affects equal numbers of males and females. In order for a child to inherit the disease, both parents must carry one abnormal copy of the acid alpha-glucosidase (GAA) gene, traced to the long arm of chromosome 17(17q).3
Because carrier parents are heterozygous, however, there is a 1 in 4 (25%) chance that each child they conceive will receive two abnormal copies of the GAA gene and present with the disease.
Should the child inherit only one abnormal copy of the GAA gene from either parent, he or she will also become a carrier for Pompe disease. There is a 50% (2 in 4) chance this will occur.
Carriers are generally phenotypically normal and free of clinical abnormalities as the one normal gene copy produces enough GAA activity to prevent the excessive deposition of glycogen. Compared to homozygotes with two normal genes, however, carriers usually display reduced GAA activity upon testing.
Mutations
Researchers are still learning about the molecular pathology of Pompe disease and the various mutations of the GAA gene, which has been localized to the long arm of chromosome 17(17q).3 Approximately 150 distinct mutant alleles have been identified at present, with the most up-to-date catalog available from The Pompe Center at Erasmus Medical Center, Rotterdam.4
Some defects are very common, either within the general population or specific ethnic groups, while others have been identified in as few as one or two patients.5
A Closer Look: Common Mutations >
Researchers have theorized that a founder effect may be responsible for some of the more prevalent defects.3
While the Erasmus Medical Center's online mutation registry characterizes the deleterious effect of each mutation as mild, severe, or polymorphic, researchers are still investigating why a complete genotype-phenotype correlation does not appear to exist in Pompe disease.
Although a correlation can be clinically and experimentally demonstrated in most cases—and certain mutations have manifested exclusively as the late-onset form of the disease—there are several examples of genotype-phenotype discordance in the literature.3
References
1. Ausems MG, Verbiest J, Hermans MP, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counseling. Eur J Hum Genet 1999 Sep; 7(6): 713-6.
2. Martiniuk F, Chen A, Mack A, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet 1998; 79:69-72.
3. 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.
4.The Pompe Center at Erasmus Medical Center Rotterdam (The Netherlands). A registry of mutations of human acid alpha-glucosidase. Available at: http://www.2eur.nl/fgg/ch1/pompe/mutations.html. Accessed September 7, 2005.
5. Hirschhorn R, Huie ML, Caggana M, Butler J, Pass KA, Hirschorn JN. Increased frequency of Pompe disease (infantile glycogen storage disease type II) in Afro-Americans. Paper presented at 2004 Pediatric Academic Societies’ Meeting; May 1–4, 2004; San Francisco, Calif. Abstract 752296.
