The genotype-phenotype correlation in Pompe disease

Am J Med Genet C Semin Med Genet. 2012 Feb 15;160C(1):59-68. doi: 10.1002/ajmg.c.31318. Epub 2012 Jan 17.


Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that is caused by acid α-glucosidase (GAA) deficiency and is due to pathogenic sequence variations in the corresponding GAA gene. The correlation between genotypes and phenotypes is strict, in that patients with the most severe phenotype, classic infantile Pompe disease, have two pathogenic mutations, one in each GAA allele, that prevent the formation of GAA or totally obliterates its function. All patients with less progressive phenotypes have at least one sequence variation that allows normal or low level synthesis of GAA leading to the formation of analytically measurable, low level GAA activity in most cases. There is an overall trend of finding higher GAA enzyme levels in patients with onset of symptoms in adulthood when compared to patients who show clinical manifestations in early childhood, aged 0-5 years, with a rapidly progressive course, but who lack the severe characteristics of classic infantile Pompe disease. However, several cases have been reported of adult-onset disease with very low GAA activity, which in all those cases corresponds with the GAA genotype. The clinical diversity observed within a large group of patients with functionally the same GAA genotype and the same c.-32-13C > T haplotype demonstrates that modifying factors can have a substantial effect on the clinical course of Pompe disease, disturbing the GAA genotype-phenotype correlation. The present day challenge is to identify these factors and explore them as therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Age of Onset
  • Genetic Association Studies*
  • Glycogen / metabolism*
  • Glycogen Storage Disease Type II / genetics*
  • Glycogen Storage Disease Type II / metabolism*
  • Glycogen Storage Disease Type II / pathology
  • Haplotypes
  • Humans
  • Mutation
  • Structure-Activity Relationship
  • alpha-Glucosidases / genetics*
  • alpha-Glucosidases / metabolism


  • Glycogen
  • alpha-Glucosidases