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The genotype–phenotype correlation in Pompe disease


  • Marian Kroos,

  • Marianne Hoogeveen-Westerveld,

  • Ans van der Ploeg,

  • Arnold J.J. Reuser

    Corresponding author
    • Department of Clinical Genetics, Erasmus MC University Medical Center, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
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  • About the authors: The authors, united in the, have worked together for decades in the field of Pompe disease. In 1973 the goal was to investigate whether the Pompe disease phenotypes were caused by mutations in one or in several genes. In 1985, using technology developed by Hasilik and Neufeld, all kind of abnormalities in the synthesis of acid α-glucosidase were brought to light in patients. Authors of this review and others have cloned the GAA gene. They used it to produce recombinant human acid α-glucosidase in CHO cells and in the milk of transgenic rabbits for enzyme replacement therapy: first in genetically modified mice with Pompe disease and later in patients. Maintenance of the Pompe disease mutation database at: www:// is a core activity that has facilitated the writing of this review.

  • How to cite this article: Kroos M, Hoogeveen-Westerveld M, van der Ploeg A, Reuser AJJ. 2012. The genotype–phenotype correlation in Pompe disease. Am J Med Genet Part C Semin Med Genet 160C:59–68.


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. © 2012 Wiley Periodicals, Inc.