Journal of Neurology

, Volume 260, Issue 4, pp 951–959 | Cite as

Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review

  • Antonio ToscanoEmail author
  • Benedikt Schoser


Glycogen storage disease type 2/Pompe disease is a progressive muscle disorder with a wide range of phenotypic presentations, caused by an inherited deficiency of acid alpha-glucosidase. Since 2004 only a limited number of patients have been treated with recombinant human alpha-glucosidase from rabbit milk whereas since 2006 enzyme replacement therapy (ERT) with alglucosidase alfa has been licensed for the treatment of Pompe disease. This systematic review evaluates the clinical efficacy and safety of alglucosidase alfa treatment of juvenile and adult patients with late-onset Pompe disease (LOPD). Studies of alglucosidase alfa treatment of LOPD patients—published up to January 2012—were identified by electronic searching of the EMBASE and MEDLINE databases, and manual searching of the reference lists. Data on ERT outcomes were extracted from selected papers and analyzed descriptively. No statistical analysis was performed owing to data heterogeneity. Twenty-one studies containing clinical data from 368 LOPD patients were analyzed. Overall, at least two-thirds of patients were stabilized or had improved creatine kinase levels and muscular and/or respiratory function following treatment with alglucosidase alfa. ERT was well tolerated; most adverse events were mild or moderate infusion-related reactions. In conclusion, alglucosidase alfa treatment is effective and well tolerated and attenuates progression of LOPD in most patients. Further research is required to investigate factors such as age at diagnosis, phenotypic presentation, and genotypic characteristics, identification of which may enable better clinical and therapeutic management of LOPD patients.


Late-onset Pompe disease (LOPD) Glycogen storage disease type 2 Enzyme replacement therapy Alglucosidase alfa Systematic review 



This study was funded by Genzyme Europe. The authors received editorial/writing support in the preparation of this manuscript from Alessia Piazza, PhD, of Excerpta Medica, funded by Genzyme Europe.

Conflicts of interest

AT and BS are members of the Pompe Global Advisory Board, sustained by Genzyme, and received reimbursement for participation to the board meetings and invited lectures.


  1. 1.
    Angelini C, Semplicini C, Tonin P, Filosto M, Pegoraro E, Sorarù G, Fanin M (2009) Progress in enzyme replacement therapy in glycogen storage disease type II. Ther Adv Neurol Disord 2:143–153PubMedCrossRefGoogle Scholar
  2. 2.
    Angelini C, Semplicini C, Ravaglia S, Bembi B, Servidei S, Pegoraro E, Moggio M, Filosto M, Sette E, Crescimanno G, Tonin P, Parini R, Morandi L, Marrosu G, Greco G, Musumeci O, Di Iorio G, Siciliano G, Donati MA, Carubbi F, Ermani M, Mongini T, Toscano A, The Italian GSDII Group (2011) Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years. J Neurol 259:952–958. doi: 10.1007/s00415-011-6293-5 PubMedCrossRefGoogle Scholar
  3. 3.
    Ausems MG, Verbiest J, Hermans MP, Kroos MA, Beemer FA, Wokke JH, Sandkuijl LA, Reuser AJ, van der Ploeg AT (1999) Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 7:713–716PubMedCrossRefGoogle Scholar
  4. 4.
    Bembi B, Pisa FE, Confalonieri M, Ciana G, Fiumara A, Parini R, Rigoldi M, Moglia A, Costa A, Carlucci A, Danesino C, Pittis MG, Dardis A, Ravaglia S (2010) Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II. J Inherit Metab Dis 33:727–735PubMedCrossRefGoogle Scholar
  5. 5.
    Byrne B, Barshop B, Barohn R, Falk L, Fox M, Lang W, Lossius M, McCarthy S, Vora J, LeBowitz J (2012) POM-001 phase 1/2 study of BMN 701, GILT-tagged recombinant human (rh) GAA in late-onset Pompe disease: preliminary report. Mol Genet Metab 105(2):S24Google Scholar
  6. 6.
    Chien YH, Chiang SC, Zhang XK, Keutzer J, Lee NC, Huang AC, Chen CA, Wu MH, Huang PH, Tsai FJ, Chen YT, Hwu WL (2008) Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program. Pediatrics 122:e39–e45PubMedCrossRefGoogle Scholar
  7. 7.
    Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT, AANEM Consensus Committee on Late-onset Pompe Disease (2012) Consensus treatment recommendations for late-onset Pompe Disease. Muscle Nerve 45:319–333PubMedCrossRefGoogle Scholar
  8. 8.
    de Vries JM, Brugma JD, Ozkan L, Steegers EA, Reuser AJ, van Doorn PA, van der Ploeg AT (2011) First experience with enzyme replacement therapy during pregnancy and lactation in Pompe disease. Mol Genet Metab 104:552–555PubMedCrossRefGoogle Scholar
  9. 9.
    Douillard-Guilloux G, Raben N, Takikita S, Batista L, Caillaud C, Richard E (2008) Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type II. Hum Mol Genet 17:3876–3886PubMedCrossRefGoogle Scholar
  10. 10.
    Furusawa Y, Mori-Yoshimura M, Yamamoto T, Sakamoto C, Wakita M, Kobayashi Y, Fukumoto Y, Oya Y, Fukuda T, Sugie H, Hayashi YK, Nishino I, Nonaka I, Murata M (2012) Effects of enzyme replacement therapy on five patients with advanced late-onset glycogen storage disease type II: a 2-year follow-up study. J Inherit Metab Dis 35:301–310PubMedCrossRefGoogle Scholar
  11. 11.
    Hagemans ML, Winkel LP, Hop WC, Reuser AJ, van Doorn PA, van der Ploeg AT (2005) Disease severity in children and adults with Pompe disease related to age and disease duration. Neurology 64:2139–2141PubMedCrossRefGoogle Scholar
  12. 12.
    Hobson-Webb LD, Dearmey S, Kishnani PS (2011) The clinical and electrodiagnostic characteristics of Pompe disease with post-enzyme replacement therapy findings. Clin Neurophysiol 122:2312–2317PubMedCrossRefGoogle Scholar
  13. 13.
    Jones HN, Moss T, Edwards L, Kishnani PS (2011) Increased inspiratory and expiratory muscle strength following respiratory muscle strength training (RMST) in two patients with late-onset Pompe disease. Mol Genet Metab 104:417–420PubMedCrossRefGoogle Scholar
  14. 14.
    Kishnani PS, Nicolino M, Voit T, Rogers RC, Tsai AC, Waterson J, Herman GE, Amalfitano A, Thurberg BL, Richards S, Davison M, Corzo D, Chen YT (2006) Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr 149:89–97PubMedCrossRefGoogle Scholar
  15. 15.
    Koeberl DD, Luo X, Sun B, McVie-Wylie A, Dai J, Li S, Banugaria SG, Chen YT, Bali DS (2011) Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle. Mol Genet Metab 103:107–112PubMedCrossRefGoogle Scholar
  16. 16.
    Korpela MP, Paetau A, Löfberg MI, Timonen MH, Lamminen AE, Kiuru-Enari SM (2009) A novel mutation of the GAA gene in a Finnish late-onset Pompe disease patient: clinical phenotype and follow-up with enzyme replacement therapy. Muscle Nerve 40:143–148PubMedCrossRefGoogle Scholar
  17. 17.
    Mah CS, Falk DJ, Germain SA, Kelley JS, Lewis MA, Cloutier DA, DeRuisseau LR, Conlon TJ, Cresawn KO, Fraites TJ Jr, Campbell-Thompson M, Fuller DD, Byrne BJ (2010) Gel-mediated delivery of AAV1 vectors corrects ventilatory function in Pompe mice with established disease. Mol Ther 18:502–510PubMedCrossRefGoogle Scholar
  18. 18.
    Martiniuk F, Chen A, Mack A, Arvanitopoulos E, Chen Y, Rom WN, Codd WJ, Hanna B, Alcabes P, Raben N, Plotz P (1998) Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet 79:69–72PubMedCrossRefGoogle Scholar
  19. 19.
    Merk T, Wibmer T, Schumann C, Krüger S (2009) Glycogen storage disease type II (Pompe disease)—influence of enzyme replacement therapy in adults. Eur J Neurol 16:274–277PubMedCrossRefGoogle Scholar
  20. 20.
    Orlikowski D, Pellegrini N, Prigent H, Laforêt P, Carlier R, Carlier P, Eymard B, Lofaso F, Annane D (2011) Recombinant human acid alpha-glucosidase (rhGAA) in adult patients with severe respiratory failure due to Pompe disease. Neuromuscul Disord 21:477–482PubMedCrossRefGoogle Scholar
  21. 21.
    Papadimas GK, Spengos K, Konstantinopoulou A, Vassilopoulou S, Vontzalidis A, Papadopoulos C, Michelakakis H, Manta P (2011) Adult Pompe disease: clinical manifestations and outcome of the first Greek patients receiving enzyme replacement therapy. Clin Neurol Neurosurg 113:303–307PubMedCrossRefGoogle Scholar
  22. 22.
    Parenti G, Andria G (2011) Pompe disease: from new views on pathophysiology to innovative therapeutic strategies. Curr Pharm Biotechnol 12:902–915PubMedCrossRefGoogle Scholar
  23. 23.
    Porto C, Cardone M, Fontana F, Rossi B, Tuzzi MR, Tarallo A, Barone MV, Andria G, Parenti G (2009) The pharmacological chaperone N-butyldeoxynojirimycin enhances enzyme replacement therapy in Pompe disease fibroblasts. Mol Ther 17:964–971PubMedCrossRefGoogle Scholar
  24. 24.
    Ravaglia S, Danesino C, Moglia A, Costa A, Cena H, Maccarini L, Carlucci A, Pichiecchio A, Bini P, De Filippi P, Rossi M (2010) Changes in nutritional status and body composition during enzyme replacement therapy in adult-onset type II glycogenosis. Eur J Neurol 17:957–962PubMedCrossRefGoogle Scholar
  25. 25.
    Ravaglia S, Pichiecchio A, Ponzio M, Danesino C, Saeidi Garaghani K, Poloni GU, Toscano A, Moglia A, Carlucci A, Bini P, Ceroni M, Bastianello S (2010) Changes in skeletal muscle qualities during enzyme replacement therapy in late-onset type II glycogenosis: temporal and spatial pattern of mass vs. strength response. J Inherit Metab Dis 33:737–745PubMedCrossRefGoogle Scholar
  26. 26.
    Regnery C, Kornblum C, Hanisch F, Vielhaber S, Strigl-Pill N, Grunert B, Müller-Felber W, Glocker FX, Spranger M, Deschauer M, Mengel E, Schoser B (2012) 36 months observational clinical study of 38 adult Pompe patients under alglucosidase alfa enzyme replacement therapy. J Inherit Metab Dis. doi: 10.1007/s10545-012-9451-8
  27. 27.
    Rossi M, Parenti G, Della Casa R, Romano A, Mansi G, Agovino T, Rosapepe F, Vosa C, Del Giudice E, Andria G (2007) Long-term enzyme replacement therapy for Pompe disease with recombinant human alpha-glucosidase derived from chinese hamster ovary cells. J Child Neurol 22:565–573PubMedCrossRefGoogle Scholar
  28. 28.
    Schüller A, Wenninger S, Strigl-Pill N, Schoser B (2012) Toward deconstructing the phenotype of late-onset Pompe disease. Am J Med Genet C Semin Med Genet 160:80–88PubMedGoogle Scholar
  29. 29.
    Slonim AE, Bulone L, Goldberg T, Minikes J, Slonim E, Galanko J, Martiniuk F (2007) Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy. Muscle Nerve 35:70–77PubMedCrossRefGoogle Scholar
  30. 30.
    Strothotte S, Strigl-Pill N, Grunert B, Kornblum C, Eger K, Wessig C, Deschauer M, Breunig F, Glocker FX, Vielhaber S, Brejova A, Hilz M, Reiners K, Müller-Felber W, Mengel E, Spranger M, Schoser B (2010) Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial. J Neurol 257:91–97PubMedCrossRefGoogle Scholar
  31. 31.
    Terzis G, Dimopoulos F, Papadimas GK, Papadopoulos C, Spengos K, Fatouros I, Kavouras SA, Manta P (2011) Effect of aerobic and resistance exercise training on late-onset Pompe disease patients receiving enzyme replacement therapy. Mol Genet Metab 104:279–283PubMedCrossRefGoogle Scholar
  32. 32.
    van Capelle CI, Winkel LP, Hagemans ML, Shapira SK, Arts WF, van Doorn PA, Hop WC, Reuser AJ, van der Ploeg AT (2008) Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease. Neuromuscul Disord 18:447–452PubMedCrossRefGoogle Scholar
  33. 33.
    van Capelle CI, van der Beek NA, Hagemans ML, Arts WF, Hop WC, Lee P, Jaeken J, Frohn-Mulder IM, Merkus PJ, Corzo D, Puga AC, Reuser AJ, van der Ploeg AT (2010) Effect of enzyme therapy in juvenile patients with Pompe disease: a three-year open-label study. Neuromuscul Disord 20:775–782PubMedCrossRefGoogle Scholar
  34. 34.
    van der Beek NA, Hagemans ML, Reuser AJ, Hop WC, van der Ploeg AT, van Doorn PA, Wokke JH (2009) Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease. Neuromuscul Disord 19:113–117PubMedCrossRefGoogle Scholar
  35. 35.
    van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A, Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wasserstein M, Zivkovic SA (2010) A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 362:1396–1406PubMedCrossRefGoogle Scholar
  36. 36.
    Vielhaber S, Brejova A, Debska-Vielhaber G, Kaufmann J, Feistner H, Schoenfeld MA, Awiszus F (2011) 24-months results in two adults with Pompe disease on enzyme replacement therapy. Clin Neurol Neurosurg 113:350–357PubMedCrossRefGoogle Scholar
  37. 37.
    Winkel LP, van den Hout JM, Kamphoven JH, Disseldorp JA, Remmerswaal M, Arts WF, Loonen MC, Vulto AG, van Doorn PA, de Jong G, Hop W, Smit GP, Shapira SK, Boer MA, van Diggelen OP, Reuser AJ, van der Ploeg AT (2004) Enzyme replacement therapy in late-onset Pompe’s disease: a three-year follow-up. Ann Neurol 55:495–502PubMedCrossRefGoogle Scholar
  38. 38.
    Winkel LP, Hagemans ML, van Doorn PA, Loonen MC, Hop WJ, Reuser AJ, van der Ploeg AT (2005) The natural course of non-classic Pompe’s disease; a review of 225 published cases. J Neurol 252:875–884PubMedCrossRefGoogle Scholar
  39. 39.
    Yang CC, Chien YH, Lee NC, Chiang SC, Lin SP, Kuo YT, Chen SS, Jong YJ, Hwu WL (2011) Rapid progressive course of later-onset Pompe disease in Chinese patients. Mol Genet Metab 104:284–288PubMedCrossRefGoogle Scholar
  40. 40.
    Zhu Y, Jiang JL, Gumlaw NK, Zhang J, Bercury SD, Ziegler RJ, Lee K, Kudo M, Canfield WM, Edmunds T, Jiang C, Mattaliano RJ, Cheng SH (2009) Glycoengineered acid alpha-glucosidase with improved efficacy at correcting the metabolic aberrations and motor function deficits in a mouse model of Pompe disease. Mol Ther 17:954–963PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Neurosciences, Psychiatry and Anesthesiology, AOU Policlinico “G. Martino”University of MessinaMessinaItaly
  2. 2.Department of Neurology, Friedrich-Baur InstitutLudwig-Maximilians University MunichMunichGermany

Personalised recommendations