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Pediatric Cardiology

, Volume 29, Issue 6, pp 1033–1042 | Cite as

Cardiac Remodeling After Enzyme Replacement Therapy with Acid α-Glucosidase for Infants with Pompe Disease

  • Jami C. LevineEmail author
  • Priya S. Kishnani
  • Y. T. Chen
  • J. Rene Herlong
  • Jennifer S. Li
Review

Abstract

Background

Infantile Pompe disease (glycogen storage disease type 2) is a fatal disorder caused by deficiency of acid α-glucosidase. This deficiency results in glycogen accumulation in the lysosomes of many tissues including cardiac muscle. The disease is characterized by profound hypotonia, poor growth, organomegaly, and cardiomegaly. Severe hypertrophic cardiomyopathy often is present in early infancy, and most patients die of cardiac or respiratory failure in the first year of life. This report describes the cardiac response of infants with Pompe disease to a phase 2 trial of enzyme replacement therapy (ERT).

Methods

Eight patients with classical infantile Pompe disease were given intravenous recombinant human GAA (rhGAA) for 1 year. Cardiac monitoring included echocardiography, electrocardiograms (ECGs), chest radiographs, and clinical cardiac evaluation at 4, 8, 12, 24, 36, and 52 weeks. At 52 weeks, 6 patients were alive.

Results

Most of the treated patients had rapid regression of ventricular hypertrophy in response to ERT, with near normalization of posterior wall thickness, ventricular mass, and ventricular size. Systolic ventricular function was preserved despite rapid changes in ventricular mass and size. Concomitantly, ECGs documented lengthening of the PR interval and decreased ventricular voltages, whereas chest radiographs documented a decreased cardiothoracic ratio. Symptoms of pulmonary congestion were diminished, and survival was improved.

Conclusion

The cardiovascular system responds quickly and strikingly to ERT with rhGAA, suggesting rapid reversal of excessive glycogen storage in cardiac muscle cells. Changes in ventricular mass and function are maintained throughout 1 year of follow-up evaluation and associated with decreased morbidity and prolonged survival.

Keywords

Hypertrophy Cardiomyopathy Pediatrics Genetics Trials 

Notes

Acknowledgments

We thank the study patients and their families for their participation in this clinical trial. In addition, we mention our great appreciation for the support and expertise of the physicians, study coordinators, and research assistants, without whom this study could not have been conducted. Finally, we acknowledge the tremendous input of the following individuals from the Genzyme Corporation, without whom this trial could not have been completed: Jennifer Hunt, Tara O’Meara, Florence Yong, MS PhD, and Deyanira Corzo, MD. This trial was supported by a grant from the Genzyme Corporation to the various sites at which patients were treated. Priya S. Kishnani and Y. T. Chen received research and grant support from the Genzyme Corp. Priya S. Kishnani is a member of the Pompe Disease Advisory Board for the Genzyme Corporation. Jami C. Levine and Y. T. Chen have served as consultants for the Genzyme Corporation. The U.S. FDA and the European Union have approved rhGAA, in the form of Genzyme’s product, Myozyme, as therapy for Pompe disease. Duke University and the inventors for the method of treatment and the predecessors of the cell lines used to generate the enzyme used in this clinical trial may benefit financially pursuant to the Duke University’s Policy on Inventions, Patents, and Technology Transfer. This study was supported in part by grants M01-RR30 and M01-RR01271 from the General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health and by Genzyme Corporation.

References

  1. 1.
    Kishnani P, Howell RR (2004) Pompe disease in infants and children. J Pediatrics 144:S35–S43CrossRefGoogle Scholar
  2. 2.
    Griffin JL (1984) Infantile acid maltase deficiency: muscle fiber hypertrophy and the ultrastructure of end-stage fibers. Virchows Arch Cell Pathol 45:37–50CrossRefGoogle Scholar
  3. 3.
    Martiniuk F, Chen A, Mack A et al (1998) Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Gen 79:69–72CrossRefGoogle Scholar
  4. 4.
    Van den Hout HM, Hop W, van Diggelen OP et al (2003) The natural course of infantile Pompe disease: 20 original cases compared with 133 cases from literature. Pediatrics 112:332–340PubMedCrossRefGoogle Scholar
  5. 5.
    Kishnani PS, Hwu WL, Mandel H et al (2006) A retrospective multinational multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 148:671–676PubMedCrossRefGoogle Scholar
  6. 6.
    Amalfitano A, Bengur AR, Morse RP et al (2001) Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med 3:132–138PubMedGoogle Scholar
  7. 7.
    Van den Hout H, Reuser AJ, Vulto AG et al (2000) Recombinant human α-glucosidase 17 from rabbit milk in Pompe patients. Lancet 356:397–398PubMedCrossRefGoogle Scholar
  8. 8.
    Van den Hout JMP, Kamphoven JHJ, Winkel LPF et al (2004) Long-term intravenous treatment of Pompe disease with recombinant human α-glucosidase from milk. Pediatrics 113:e448–e457PubMedCrossRefGoogle Scholar
  9. 9.
    Kishnani P, Voit T, Nicolino M et al (2003) Enzyme replacement therapy with recombinant human α-glucosidase (rhGAA) in infantile Pompe disease: results form a phase 2 study. Pediatr Res 53:259AGoogle Scholar
  10. 10.
    Klinge L, Straub V, Neudorf U et al (2005) Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial. Neuromuscular Dis 15:24–31CrossRefGoogle Scholar
  11. 11.
    Kishnani P, Nicolino M, Voit T et al (2006) Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidease in infantile-onset Pompe disease. J Pediatr 149:89–97PubMedCrossRefGoogle Scholar
  12. 12.
    Sluysman T, Colan SD (2005) Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 99:445–457CrossRefGoogle Scholar
  13. 13.
    Ansong AK, Li JS, Ing R et al (2006) Electrocardiographic changes in Pompe disease following enzyme replacement therapy for Pompe disease. Genet Med 8:297–301PubMedCrossRefGoogle Scholar
  14. 14.
    Bharati S, Serratto M, DuBrow I et al (1982) The conduction system in Pompe’s disease. Pediatr Cardiol 2:25–32PubMedCrossRefGoogle Scholar
  15. 15.
    Waldek S (2003) PR interval and the response to enzyme-replacement therapy for Fabry’s disease. N Engl J Med 348:1186–1187PubMedCrossRefGoogle Scholar
  16. 16.
    Jacob JL, Leandro RL, Parro Junior A (1999) Pompe’s disease or type IIa glycogenosis. Arq Bras Cardiol 73:435–440PubMedCrossRefGoogle Scholar
  17. 17.
    Raben N, Jatkar T, Lee A et al (2002) Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme. Mol Ther 6:601–608PubMedCrossRefGoogle Scholar
  18. 18.
    Raben N, Danon M, Gilbert AL et al (2003) Enzyme replacement therapy in the mouse model of Pompe disease. Mol Genet Metab 80:159–169PubMedCrossRefGoogle Scholar
  19. 19.
    Ing RJ, Cook DR, Bengur RA et al (2004) Anaesthetic management of infants with glycogen storage disease type II: a physiological approach. Paediatr Anaesth 14:514–519PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jami C. Levine
    • 1
    Email author
  • Priya S. Kishnani
    • 2
  • Y. T. Chen
    • 2
  • J. Rene Herlong
    • 2
  • Jennifer S. Li
    • 2
  1. 1.Department of CardiologyChildren’s Hospital Boston and Pediatrics, Harvard Medical SchoolBostonUSA
  2. 2.Department of PediatricsDuke University Medical CenterDurhamUSA

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