Pompe disease is an inherited disorder caused by a mutation of the acid alpha-glucosidase (GAA) gene, mapped to the long arm of chromosome 17 (location 17q25.2-q25.3).[1] As an autosomal recessive disorder, Pompe only occurs when an individual inherits two mutant alleles, one from each parent.

Most patients are compound heterozygotes, meaning they have inherited two different mutations. To date, almost 300 distinct GAA mutations have been identified, although not all are considered pathogenic.[2] New mutations continue to be reported.[2-3]  

New mutations continue to be reported. The Pompe Center at the Erasmus University in Rotterdam, the Netherlands, maintains an up-to-date catalog of the GAA mutations—the current list can be found on its website at

Common Alleles

The list of GAA mutations is long, and while some mutations have been identified in only one or few individuals.[5] others are more common,especially among certain ethnic and/or age groups:

  • IVS 1-13 t>g splice is the mutation found in over half of all adult Caucasian patients[6]
  • Asp645Glu is found in most infants with Pompe disease from Taiwan[7]
  • Arg854X nonsense mutation is found in many affected African or African-American infants[8]
  • del525T and del exon 18 are commonly seen in Dutch infants with the disease[4]

It has been speculated that founder effect may be responsible for some of the more prevalent mutations.[1]

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.

More studies, however, are needed in order to better understand genotype-phenotype relations, and a correlation cannot be assumed for any individual patient.[1] 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.[2], [9-12]

Mutation Analysis 

While mutation analysis does not necessarily predict disease outcomes, it is still an important tool that can help confirm an initial diagnosis and assist in family, carrier, and prenatal testing and in some cases, can predict cross-reactive immunologic material (CRIM).

Cross-Reactive Immunologic Material (CRIM)

Most patients with Pompe disease produce endogenous GAA protein. The protein is called cross-reactive immunologic material (CRIM) because it is recognized by anti-GAA antibodies on Western blot analysis. The total absence of GAA is described as CRIM negative; the presence of any GAA band is described as CRIM positive. Patients with residual GAA activity >1% are by definition CRIM positive. Patients with GAA activity <1% can be CRIM negative or CRIM positive.

CRIM Analysis

CRIM status is examined using Western blot analysis to detect endogenous GAA protein. In CRIM testing, samples of total protein from patient (unknown CRIM status) and control (CRIM positive) fibroblasts are size-fractionated by SDS PAGE gel electrophoresis and transferred to a membrane.


  1. 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.
  2. Kroos M, Pomponio RJ, van Vliet L, et al. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat. 2008;29(6):E13-26.
  3. Oba-Shinjo S, da Silva R, Andrade F, et al. Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations. J Neurol 2009;256(11):1881-90. Epub 2009 Jul 9.
  4. 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.
  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. 3395.
  6. Huie ML, Chen AS, Tsujino S, et al. Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (-13T-->G) mutation in a majority of patients and a novel IVS10 (+1GT-->CT) mutation. Hum Mol Genet 1994; 3:2231-6.
  7. Shieh JJ, Lin CY. Frequent mutation of Chinese patients with infantile type of GSD II in Taiwan: evidence for a founder effect. Hum Mutat 1998; 11:306-12.
  8. Becker JA, Vlach J, Raben N, et al. The African origin of the common mutation in African American patients with glycogen-storage disease type II. Am J Hum Genet 1998; 62:991-4.
  9. Kroos MA, Van der Kraan M, Van Diggelen OP, Kleijer WJ, Reuser AJ. Two extremes of the clinical spectrum of glycogen storage disease type II in one family: a matter of genotype. Hum Mutat 1997; 9:17-22.
  10. Busch HF, Koster JF, van Weerden TW. Infantile and adult-onset acid maltase deficiency occuring in the same family. Neurology 1979; 29:415-6.
  11. Loonen MC, Busch HF, Koster JF, et al. A family with different clinical forms of acid maltase deficiency (glycogenosis type II): biochemical and genetic studies. Neurology 1981; 31:1209-16.
  12. Lam CW, Yuen YP, Chan KY, et al. Juvenile-onset glycogen storage disease type II with novel mutations in acid alpha-glucosidase gene. Neurology 2003; 60:715-7.

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