Genetics

Pompe disease is caused by mutations of the gene encoding lysosomal acid α-glucosidase (GAA), located on chromosome 17q25.2-q25.3, and is inherited as an autosomal recessive trait.1

Inheritance patterns1

Both parents of an index case are asymptomatic heterozygotes (carriers); each carry a single copy of a GAA pathogenic variant. Each sibling of the index case has a 1:4 chance of being affected, a 1:2 chance of being an asymptomatic carrier, and a 1:4 chance of being an unaffected, non-carrier (see figure below).

At-risk siblings who have been demonstrated to be unaffected have a 2:3 chance of being a carrier. Historically, children with classic infantile-onset Pompe disease have not survived to reproduce. The offspring of an individual with late-onset Pompe disease are obligate heterozygotes (clinically unaffected individuals who carry a gene mutation based on family history analysis) and each sibling of an obligate heterozygote has a 1:2 chance of being a carrier. Genetic counseling should be offered to adults with Pompe disease and the parents of children with Pompe disease.2

Autosomal recessive inheritance of Pompe disease

Number and type of GAA mutations

Several types of deleterious mutations have been identified in patients with Pompe disease, including missense, nonsense, deletion, and splice site mutations.3 Nonsense mutations that introduce mRNA instability are more commonly seen in infantile-onset Pompe disease, whereas missense and splicing mutations are seen in both the infantile-onset and late-onset forms of the disease.1, 4

Distribution of deleterious mutations identified in patients with Pompe disease. Exons are numbered, arrows represent mutations at splice sites. Adapted from: Hirschhorn R, Reuser AJ. Glycogen storage disease type II: Acid alpha-glucosidase (acid maltase) deficiency

Genetic Mutations

Referenced adapted from [Internet]. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. .New York, NY: McGraw-Hill Medical. 2015 [cited 17/12/2015].   Available in Gallery 2nd edits.

Currently more than 500 distinct GAA mutations have been identified. Not all are considered pathogenic and the majority are private (found only in a single family),5 but several mutations have been demonstrated to be very frequent occurring in specific ethnic groups.3 The Pompe Center at the Erasmus University in Rotterdam, the Netherlands, maintains an up-to-date catalog of identified GAA mutations – the current list can be accessed at:

Genotype-phenotype correlations

In Pompe disease there is a strict genotype-phenotype correlation, such that classic infantile-onset disease results from a combination of two mutated alleles that either prevent the formation of, or stop the function of, GAA.6 It has been demonstrated that two null variants are likely in infants with no cross reactive immunological material (CRIM-negative).7 Late-onset Pompe disease patients, with less progressive phenotypes, have at least one mutated allele resulting in some residual enzyme activity.6The c.-32-13T>G mutation is the most common among adults with this disorder.

Variations in severity have been observed within families8 and within a large group of patients with the same functional GAA genotype and the same c.-32-13C > T haplotype.6 This extensive variability suggests that other genetic modifying factors, such as angiotensin converting enzyme (ACE) and alpha actinin 3 (ACTN3) polymorphisms, modulate clinical phenotype and may have a role in the clinical course of Pompe disease.9

Genotype-phenotype correlations with select GAA pathogenic mutations.1

GAA pathogenic mutation Ethnic group Affected individuals (%) Phenotype
p.Glu176ArgfsTer45 Caucasian 34% (Dutch)
9% (US)		 Infantile-onset
p.Gly828_Asn882del Caucasian 25% (Dutch)
25% (Canadian)
5% (US)		 Infantile-onset
c.336-13T>G (IVSI) Caucasian 36-90% Late-onset
p.Asp645Glu Taiwanese
Chinese		 ≤80% Infantile-onset
p.Arg854Ter African Decent ≤60% Infantile-onset

 

To learn more about the molecular aspects of Pompe disease, Erasmus MC in The Netherlands - a world leading research centre in Pompe disease have a comprehensive database to provide a list of mutations found in Pompe disease worldwide year to date. The publically accessible list is regularly updated to provide the latest information.

CLICK HERE TO ACCESS DATABASE

 

References

  1. 1.Leslie N, Tinkle BT. Glycogen Storage Disease Type II (Pompe Disease). In: Pagon RA, Adam MP, Ardinger HH, al e, editors. GeneReviews® [Internet]. 1993-2015. Seattle (WA): : University of Washington, Seattle; 2013 [Updated 2013]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1261/
  2. 2.Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE. Pompe disease diagnosis and management guideline. Genet Med. 2006;8.
  3. 3.Hirschhorn R, Reuser AJ. Glycogen storage disease type II: Acid alpha-glucosidase (acid maltase) deficiency [Internet]. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. . New York, NY: McGraw-Hill Medical. 2015 [cited 17/12/2015]. Available here.
  4. 4.Zampieri S, Buratti E, Dominissini S, et al. Splicing mutations in glycogen-storage disease type II: evaluation of the full spectrum of mutations and their relation to patients' phenotypes. European Journal of Human Genetics. 2011;19:422-31.
  5. 5.Lim JA, Li L, Raben N. Pompe disease: from pathophysiology to therapy and back again. Front Aging Neurosci. 2014;6:177.
  1. 6.Kroos M, Hoogeveen-Westerveld M, van der Ploeg A, Reuser AJ. The genotype-phenotype correlation in Pompe disease. Am J Med Genet C Semin Med Genet. 2012;160C:59-68.
  2. 7.Bali DS, Goldstein JL, Banugaria S, et al. Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet C Semin Med Genet. 2012;160C:40-9.
  3. 8.Wens SC, van Gelder CM, Kruijshaar ME, et al. Phenotypical variation within 22 families with Pompe disease. Orphanet J Rare Dis. 2013;8:182.
  4. 9.De Filippi P, Saeidi K, Ravaglia S, et al. Genotype-phenotype correlation in Pompe disease, a step forward. Orphanet J Rare Dis. 2014;9:102.