Wiener klinische Wochenschrift

, Volume 126, Issue 3–4, pp 133–137 | Cite as

Effects of immune modulation therapy in the first Croatian infant diagnosed with Pompe disease: a 3-year follow-up study

  • Josko MarkicEmail author
  • Branka Polic
  • Luka Stricevic
  • Vitomir Metlicic
  • Radenka Kuzmanic-Samija
  • Tanja Kovacevic
  • Ivana Erceg Ivkosic
  • Julije Mestrovic
case report


Pompe disease is a storage disorder characterized by deficient or absent activity of the enzyme acid alpha-glucosidase. As a result of ineffective metabolism, glycogen accumulates in muscle tissues. Patients with a classic infantile-onset form present by the first few months of life with hypertrophic cardiomyopathy and muscle weakness. If left untreated, these patients rapidly die of cardiorespiratory failure. A cross-reactive immunological material (CRIM)-negative status is predictive of high anti-alglucosidase alpha antibody titers. However, CRIM-positive patients also sometimes develop robust antibody titers. High antibody titers complicate therapeutic management, and those patients have a worse clinical outcome of enzyme replacement therapy (ERT).

Four years ago, we successfully used an immune modulation therapy (IMT) protocol in a CRIM-positive infantile-onset patient with Pompe disease in whom ERT had to be discontinued because of severe infusion-associated reactions. She was found to be positive for anti-alglucosidase alpha antibodies. IMT (rituximab, methotrexate, and intravenous gammaglobulin) was started, and ERT was safely reintroduced during the IMT induction phase without any complications. Antibodies disappeared; IMT was tapered and discontinued; and cardiomyopathy steadily improved. During more than 3 years of follow-up, she remained ventilator dependent, and no gains in motor skills were noticed. The antibodies are still undetectable, and no adverse reactions associated with IMT had occurred. The cardiomyopathy is gradually increasing, but there is still ~ 50 % reduction as compared with the highest value measured. Although the reversal of clinical decline in our CRIM-positive and antibody-positive infant cannot be solely attributed to IMT, this protocol proved itself efficient and safe.


Glycogen storage disease type II Infantile Immunomodulation Rituximab Cardiomyopathy 

Wirkung einer immunmodulatorischen Therapie beim ersten kroatischen Kind mit der Diagnose einer Pompe’schen Krankheit: eine Verlaufsstudie über 3 Jahre


Die Pompe’sche Krankheit ist eine Speicherkrankheit, die durch eine gestörte oder fehlende Aktivität des Enzyms saure alpha-Glucosidase gekennzeichnet ist. Als Folge des ineffizienten Stoffwechsels reichert sich Glykogen im Muskelgewebe an. Patienten mit der klassischen Form des Ausbruchs der Erkrankung im Kindesalter präsentieren sich bereits in den ersten Lebensmonaten mit einer hypertrophen Kardiomyopathie und Muskelschwäche. Unbehandelt sterben diese Patienten rasch am kardiorespiratorischen Versagen.

Ein kreuzreaktiv immunologisches Material (CRIM) negativer Status sagt hohe anti-alpha Glucosidase Antikörper voraus. CRIM positive Patienten haben allerdings auch manchmal deutlich erhöhte Antikörper Titer. Hohe Antikörper Titer machen das therapeutische Management kompliziert: diese Patienten sprechen klinisch schlechter auf eine Enzymersatz Therapie an.

Vor 4 Jahren verwendeten wir ein Protokoll einer immumodulatorischen Therapie (IMT) erfolgreich bei einer CRIM positiven Patientin mit Ausbruch der Pompe’schen Krankheit im Kindesalter, bei der die Enzymersatz-Therapie wegen schwerer infusions-assoziierter Reaktionen abgesetzt werden musste. Sie hatte anti-alpha Glucosidase Antikörper. Eine IMT bestehend aus Rituximab, Methotrexat, und intravenösem Gammaglobulin wurde begonnen. Während der IMT konnte die Enzymersatz Therapie wieder sicher ohne irgendwelche Komplikationen begonnen werden. Die Antikörper verschwanden und die IMT konnte ausgeschlichen beziehungsweise abgesetzt werden. Die Kardiomyopathie wurde kontinuierlich besser.

Während mehr als 3 Jahren follow-up blieb die Patientin Respirator abhängig – es wurde keine Besserung der motorischen Fähigkeiten beobachtet. Die Antikörper sind weiterhin unter dem Detektionslimit. Die Kardiomyopathie wird nun langsam schlechter – ist aber noch immer 50 % besser im Vergleich zum schlechtesten im Verlauf gemessenen Wert.

Obwohl die klinische Besserung unseres CRIM- und Antikörper-positiven Kindes nicht nur der IMT zugeschrieben werden kann, zeigte sich das Protokoll jedenfalls als wirksam und sicher.


Glykogen Speicher Krankheit Typ II Kindesalter Rituximab Kardiomyopathie 


Ethical approval

The immune modulation therapy protocol was approved by the University Hospital of Split Institutional Review Board, and written informed consent was obtained from the parents. All procedures were in accordance with the ethical standards and with the Helsinki Declaration of 1975.

Conflict of interest

The authors declare that there is no conflict of interest.

Conflict of interest

The authors declare that there is no conflict of interest.


  1. 1.
    Hirschhorn R, Reuser A. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, editors. The Metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001. p. 3389–420.Google Scholar
  2. 2.
    van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet. 2008;372:1342–53.CrossRefGoogle Scholar
  3. 3.
    Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148:671–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Ausems MG, Verbiest J, Hermans MP, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999;7:713–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Martiniuk F, Chen A, Mack A, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998;79:69–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Scott CR, Elliott S, Buroker N, et al. Identification of infants at risk for developing Fabry, Pompe, or mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry. J Pediatr. 2013; 163(2):498–503.PubMedCrossRefGoogle Scholar
  7. 7.
    Nicolino M, Byrne B, Wraith JE, et al. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med. 2009;11:210–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 2007;68:99–109.PubMedCrossRefGoogle Scholar
  9. 9.
    Amalfitano A, Bengur AR, Morse RP, et al. Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med. 2001;3:132–8.PubMedGoogle Scholar
  10. 10.
    van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med. 2010;362:1396–406.PubMedCrossRefGoogle Scholar
  11. 11.
    Kishnani PS, Nicolino M, Voit T, et al. Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr. 2006;149:89–97.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Kishnani PS, Goldenberg PC, DeArmey SL, et al. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab. 2010;99:26–33.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Banugaria SG, Prater SN, Ng YK, et al. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med. 2011;13:729–36.PubMedCrossRefGoogle Scholar
  14. 14.
    Lipinski SE, Lipinski MJ, Burnette A, Platts-Mills TA, Wilson WG. Desensitization of an adult patient with Pompe disease and a history of anaphylaxis to alglucosidase alfa. Mol Genet Metab. 2009;98:319–21.PubMedCrossRefGoogle Scholar
  15. 15.
    Markic J, Polic B, Kuzmanic-Samija R, et al. Immune modulation therapy in a CRIM-positive and IgG antibody-positive infant with Pompe disease treated with alglucosidase alfa: a case report. JIMD Rep. 2012;2:11–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Mendelsohn NJ, Messinger YH, Rosenberg AS, Kishnani PS. Elimination of antibodies to recombinant enzyme in Pompe’s disease. N Engl J Med. 2009;360:194–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Patel TT, Banugaria SG, Case LE, Wenninger S, Schoser B, Kishnani PS. The impact of antibodies in late-onset Pompe disease: a case series and literature review. Mol Genet Metab. 2012;106:301–9.PubMedCrossRefGoogle Scholar
  18. 18.
    de Vries JM, van der Beek NA, Kroos MA, et al. High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa. Mol Genet Metab. 2010;101:338–45.PubMedCrossRefGoogle Scholar
  19. 19.
    Toscano A, Schoser B. Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. J Neurol. 2013;260:951–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Joseph A, Munroe K, Housman M, Garman R, Richards S. Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model. Clin Exp Immunol. 2008;152:138–46.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Banugaria S, Patel T, Prater S, et al. The use of non-depleting anti-CD4 monoclonal antibody for immune tolerance induction in Pompe disease. Mol Genet Metab. 2012;105:290.CrossRefGoogle Scholar
  22. 22.
    Banugaria S, Prater S, Patel T, et al. Approach to management of cross-reactive immunologic material (CRIM)-negative infantile pompe patients treated with ERT: role of immune modulation in changing the natural history. Mol Genet Metab. 2013;108:23.CrossRefGoogle Scholar
  23. 23.
    Hunley TE, Corzo D, Dudek M, et al. Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease. Pediatrics. 2004;114:532–5.CrossRefGoogle Scholar
  24. 24.
    Banugaria SG, Patel TT, Mackey J, et al. Persistence of high sustained antibodies to enzyme replacement therapy despite extensive immunomodulatory therapy in an infant with Pompe disease: need for agents to target antibody-secreting plasma cells. Mol Genet Metab. 2012;105:677–80.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Banugaria SG, Prater SN, McGann JK, et al. Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease. Genet Med. 2013;15:123–31.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Case LE, Beckemeyer AA, Kishnani PS. Infantile Pompe disease on ERT: update on clinical presentation, musculoskeletal management, and exercise considerations. Am J Med Genet C Semin Med Genet. 2012;160:69–79.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Josko Markic
    • 1
    Email author
  • Branka Polic
    • 1
  • Luka Stricevic
    • 2
  • Vitomir Metlicic
    • 2
  • Radenka Kuzmanic-Samija
    • 3
  • Tanja Kovacevic
    • 1
  • Ivana Erceg Ivkosic
    • 4
  • Julije Mestrovic
    • 1
  1. 1.Pediatric Intensive Care Unit, Department of PediatricsUniversity Hospital Centre SplitSplitCroatia
  2. 2.Division of Cardiology, Department of PediatricsUniversity Hospital Centre SplitSplitCroatia
  3. 3.Division of Neurology, Department of PediatricsUniversity Hospital Centre SplitSplitCroatia
  4. 4.Department of Obstetrics and GynecologyClinical Hospital “Sv. Duh”ZagrebCroatia

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