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NEUROLOGY 2007;68:110-115
© 2007 American Academy of Neurology

Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype

M. A. Kroos, MSc, R. J. Pomponio, PhD, M. L. Hagemans, PhD, J.L.M. Keulemans, MSc, M. Phipps, BA, M. DeRiso, BS, R. E. Palmer, PhD, M. G.E.M. Ausems, PhD, N. A.M.E. Van der Beek, MD, O. P. Van Diggelen, PhD, D. J.J. Halley, PhD, A. T. Van der Ploeg, MD, PhD and A. J.J. Reuser, PhD

From the Department of Clinical Genetics (M.A.K., J.L.M.K., O.P.V.D., D.J.J.H., A.J.J.R.), Erasmus MC, Rotterdam, and Departments of Neurology (N.A.M.E.V.d.B.) and Pediatrics (M.L.H., A.T.V.d.P.), Erasmus MC, Sophia, and Department of Medical Genetics (M.G.E.M.A.), University Medical Center, Utrecht, the Netherlands; and Clinical Laboratory Science: Pharmacogenetics (R.J.P., M. P., M.D.R., R.E.P.), Genzyme Corporation, Framingham, MA.

Address correspondence and reprint requests to DrJ. Reuser, Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands; e-mail: a.reuser{at}erasmusmc.nl

Background: Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid {alpha}-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype. c.-32-13T->G is the most common mutation in adults.

Objective: To delineate the disease variation among patients with this mutation and to define the c.-32-13T->G haplotypes in search for genotype–phenotype correlations.

Methods: We studied 98 compound heterozygotes with a fully deleterious mutation (11 novel mutations are described) and the common c.-32-13T->G mutation.

Results: All patients were Caucasian. None had the classic infantile form of Pompe disease. The clinical course varied far more than anticipated (age at diagnosis <1 to 78 years; age at onset: <1 to 52 years). The acid {alpha}-glucosidase activities in a subset of patients ranged from 4 to 19.9 nmol/mg/h. Twelve different c.-32-13T->G haplotypes were identified based on 17 single-nucleotide polymorphisms located in the GAA gene. In 76% of the cases, c.-32-13T->G was encountered in the second most common GAA core haplotype (DHRGEVVT). In only one case was c.-32-13T->G encountered in the major GAA core haplotype (DRHGEIVT).

Conclusion: Patients with the same c.-32-13T->G haplotype (c.q. GAA genotype) may manifest first symptoms at different ages, indicating that secondary factors may substantially influence the clinical course of patients with this mutation.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the January 9 issue to find the title link for this article.

Editorial, see page 88

See also page 99

Disclosure: This study was supported in part by a research grant from Genzyme Corporation, Boston, MA. As of August 2004, A.J.J.R. and A.T.V.d.P. provide consulting services for Genzyme Corp. under an agreement between Genzyme Corp. and Erasmus MC, Rotterdam, the Netherlands. If enzyme replacement therapy proves successful commercially, Erasmus MC and inventors for some methods of treatment may benefit financially pursuant to the Erasmus MC policy on Inventions, Patents, and Technology Transfer.

Received July 5, 2006. Accepted in final form November 2, 2006.


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