Genetics

 

Incidence and prevalence

Estimates from available data put the overall incidence of Pompe disease at approximately 1 in 40,000 live births.1, 2 However, as with any rare disease, it is difficult to know exactly how many people are actually affected. Extrapolating from the assumed incidence figures, it is estimated that the current worldwide prevalence may be 5,000 to 10,000 people. However with the advent of Newborn screening (NBS) a more accurate picture of the incidence may become clearer overtime.5

 

                                                                                           

 

 

Ethnic distribution

Several studies suggest that the incidence of Pompe disease may vary among populations, ranging from 1 in 14,000 to 1 in 300,000, depending on the geographic area or ethnic group examined.3 In infants, Pompe disease appears to be more common among African-Americans and in China.3

In terms of adults with Pompe disease, there is a comparatively high incidence of the condition in the Netherlands.1 In addition, some specific GAA gene mutations have been found to be more common within certain groups (see ‘Mutations’ section below).

 

Pompe disease is an inherited condition caused by mutations of the acid alpha-glucosidase (GAA) gene, mapped to the long arm of chromosome 17 (location 17q25.2-q25.3).3 As an autosomal recessive disorder, Pompe disease 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, more than 500 distinct GAA variants have been identified, although not all are considered pathogenic.4  New GAA variants 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. 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.3

 

 

 

Mutation Analysis

 

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. 6

 

 

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 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.

4. Pompe disease mutation database. Available at:
http://www.pompecenter.nl. Accessed March 2018.

5. Bodamer OA et all. Newborn Screening for Pompe Disease. Pediatrics 2017. 140 supplement 1

6. 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

 

GZEMEA.PD.14.11.0313c(1) – June 2018