Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 937–946 | Cite as

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study

  • Claudio Semplicini
  • Pascaline Letard
  • Marie De Antonio
  • Nadjib Taouagh
  • Barbara Perniconi
  • Françoise Bouhour
  • Andoni Echaniz-Laguna
  • David Orlikowski
  • Sabrina Sacconi
  • Emmanuelle Salort-Campana
  • Guilhem Solé
  • Fabien Zagnoli
  • Dalil Hamroun
  • Roseline Froissart
  • Catherine Caillaud
  • Pascal LaforêtEmail author
  • French Pompe Study Group
Glycogen Storage Disease


Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.



We are thankful to Armelle Guenegou-Arnoux for her help with statistical analyses.

We thank Genzyme-Sanofi and INSERM for the financial sponsorship of the French Pompe Registry.

French Pompe Registry Study Group:

A. Béhin2, B. Eymard2, S. Leonard-Louis2, T. Stojkovic2, G. Bassez2, P. G. Carlier4, K. Laloui4, G. Ollivier4, A. Canal4, J. Y. Hogrel4, H. Prigent19,20, C. Desnuelle9,10, J. Pouget11, M. Piraud21, A. L. Bedat-Millet22, F. Boyer23, Y. Castaing24, F. Chapon25, P. Cintas26, I. Durieu27, A. Lacour28, L. Feasson28, A. Furby28, D. Germain29, K. Benistan29, H. Journel30, V. Tiffreau31, C. Tard31, J. Deibener-Kaminsky32, A. Magot33, Y. Péréon33, M. C. Minot-Myhié34, A. Nadaj-Pakleza35, C. Nathier35, N. Pellegrini36, P. Petiot37, J. Praline38, D. Vincent39, D. Renard40, R. Y. Carlier41, F. Bouibede42, R. Juntas-Morales43, E. Krim44, E. Lagrange45, L. Magy46, M. Michaud47

20Service Physiologie et Explorations-Fonctionnelles, INSERM CIC 1429, AP-HP, Hôpital Raymond Poincaré, Garches, France

21Centre de biologie et pathologie Est, hospices civils de Lyon, Bron, France

22Centre de compétence de pathologie neuromusculaire, CHU Charles Nicolle, Rouen, France

23Service de médecine physique et de réadaptation, CHU de Reims, France

24Service de réanimation, CHU de Bordeaux, Bordeaux, France

25Centre de compétence des maladies neuromusculaires, CHU de Caen, France

26Centre SLA et maladies neuromusculaires, CHU de Toulouse-Rangueil, Toulouse, France

27Service de médecine interne, centre hospitalier Lyon Sud, Pierre-Bénit, France

28Centre de référence des maladies neuromusculaires rares Rhône-Alpes, Hôpital Nord, CHU de Saint-Etienne, France

29Service de génétique médicale, Hôpital Raymond-Poincaré, Garches, France

30Génétique médicale, centre hospitalier Bretagne-Atlantique, Vannes, France

31CHRU de Lille, centre de référence des maladies neuromusculaires de Lille, Lille, France

32Centre de référence des maladies héréditaires du métabolisme de Nancy, hôpitaux de

33Centre de référence des maladies neuromusculaires Nantes-Angers, Hôtel Dieu, Nantes, France

34Service neurologie, CHU de Rennes, Rennes, France

35Centre de référence des maladies neuromusculaires Nantes/Angers, Service de neurologie, CHU d’Angers, Angers, France

36Service de soins de suite et de réadaptation neurologie, GHI du Vexin, Aincourt, France

37Centre de référence maladies neuromusculaires de la région Rhône-Alpes, hôpital de la Croix-Rousse, Lyon, France

38Centre de compétence des maladies neuromusculaires, CHRU de Tours, Tours, France

39Service de neurologie, groupe hospitalier La Rochelle - Ré - Aunis, La Rochelle, France

40Department of Neurology, Nîmes University Hospital, 4 Rue du Pr Debré, 30029, Nîmes, France

41Department of Medical Imaging, Hôpitaux universitaires Paris Ile-de-France Ouest, Hôpital Raymond Poincaré, Garches, France

42Service de Médecine Interne, Hôpital Porte Madeleine, Orléans, France

43Clinique du motoneurone et pathologies neuromusculaires, CHRU de Montpellier, Montpellier, France

44Service de neurologie, Hôpital F. Mitterrand, 4 bd Hauterive, 64046 Pau, France

45Pôle psychiatrie, neurologie et rééducation neurologique, clinique de neurologie, CHU de Grenoble, 38000 Grenoble, France

46Department of Neurology, Reference Center for Rare Peripheral Neuropathies, University Hospital of Limoges

47Department of Neurology, Central’s Hospital, Nancy 54000, France

Funding information

Funding for the set up and maintenance of the French Pompe registry has been provided by Association Française contre les Myopathies (AFM), Association Francophone des Glycogénoses (AFG), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Veille Sanitaire (InVS) and Sanofi Genzyme Corporation.

Compliance with ethical standards

Conflict of interest

Pr Pascal Laforêt received grants and honorarium from Genzyme-Sanofi, and is a member of the board of International Pompe Registry.

C. Semplicini, P. Letard, M. De Antonio, N. Taouagh, B. Perniconi, F. Bouhour, A. Echaniz-Laguna, D. Orlikowski, S. Sacconi, E. Salort-Campana, G. Sole, F. Zagnoli, D. Hamroun, R. Froissart, and C. Caillaud declare that they have no conflict of interest.

Animal rights

This study does not use animals.

Supplementary material

10545_2018_243_Fig3_ESM.png (316 kb)
Figure S1

Description of the PD patient cohorts studied. (PNG 315 kb)

10545_2018_243_MOESM1_ESM.tif (33.2 mb)
High resolution image (TIF 33972 kb)
10545_2018_243_Fig4_ESM.png (6.5 mb)
Figure S2

Mutation spectrum in late-onset PD patients diagnosed in France. Newly described mutations are in bold. Missense mutations and in-frame small deletions are shown below and other mutations above the GAA gene. Gray squares indicate exons. (PNG 6677 kb)

10545_2018_243_MOESM2_ESM.tif (692 kb)
High resolution image (TIF 692 kb)
10545_2018_243_MOESM3_ESM.doc (36 kb)
Table S1 (DOC 35 kb)
10545_2018_243_MOESM4_ESM.doc (22 kb)
Table S2 (DOC 21 kb)
10545_2018_243_MOESM5_ESM.doc (24 kb)
Table S3 (DOC 24 kb)


  1. Angelini C, Semplicini C, Ravaglia S et al (2012) Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years. J Neurol 259:952–958CrossRefGoogle Scholar
  2. Ausems MG, Verbiest J, Hermans MP et al (1999) Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 7:713–716CrossRefGoogle Scholar
  3. Ausems MG, ten Berg K, Sandkuijl LA et al (2001) Dutch patients with glycogen storage disease type II show common ancestry for the 525delT and del exon 18 mutations. J Med Genet 38:527–529CrossRefGoogle Scholar
  4. Bodamer OA, Scott CR, Giugliani R, Pompe Disease Newborn Screening Working Group (2017) Newborn screening for Pompe disease. Pediatrics 140:S4–S13CrossRefGoogle Scholar
  5. Chan J, Desai AK, Kazi ZB, Corey K, Austin S, Hobson-Webb LD, Case LE, Jones HN, Kishnani PS (2017) The emerging phenotype of late-onset Pompe disease: a systematic literature review. Mol Genet Metab 120:163–172CrossRefGoogle Scholar
  6. Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ, Hwu WL (2011) Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. J Pediatr 158:1023–1027CrossRefGoogle Scholar
  7. Dardis A, Zanin I, Zampieri S et al (2014) Functional characterization of the common c.-32-13T>G mutation of GAA gene: identification of potential therapeutic agents. Nucleic Acids Res 42:1291–1302CrossRefGoogle Scholar
  8. De Filippi P, Saeidi K, Ravaglia S et al (2014) Genotype-phenotype correlation in Pompe disease, a step forward. Orphanet J Rare Dis 9:102CrossRefGoogle Scholar
  9. Echaniz-Laguna A, Carlier RY, Laloui K et al (2015) Should patients with asymptomatic Pompe disease be treated? A nationwide study in France. Muscle Nerve 51:884–889CrossRefGoogle Scholar
  10. Güngör D, Reuser AJ (2013) How to describe the clinical spectrum in Pompe disease? Am J Med Genet A 161A:399–400CrossRefGoogle Scholar
  11. Hagemans ML, Winkel LP, Van Doorn PA et al (2005) Clinical manifestation and natural course of late-onset Pompe’s disease in 54 Dutch patients. Brain 128:671–677CrossRefGoogle Scholar
  12. Hagemans ML, Hop WJ, Van Doorn PA, Reuser AJ, van der Ploeg AT (2006) Course of disability and respiratory function in untreated late-onset Pompe disease. Neurology 66:581–583CrossRefGoogle Scholar
  13. Herzog A, Hartung R, Reuser AJ et al (2012) A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations. Orphanet J Rare Dis 7:35CrossRefGoogle Scholar
  14. Hirschhorn R, Huie ML (1999) Frequency of mutations for glycogen storage disease type II in different populations: the delta525T and deltaexon 18 mutations are not generally “common” in white populations. J Med Genet 36:85–86Google Scholar
  15. Hirschhorn R, Reuser AJ (2001) Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver C, Baudet A, Sly et al (eds) The metabolic and molecular bases of inherited diseases. McGraw-Hill, New York, pp 3389–3420Google Scholar
  16. Hoefsloot LH, Hoogeveen-Westerveld M, Reuser AJ, Oostra BA (1990) Characterization of the human lysosomal alpha-glucosidase gene. Biochem J 272:493–497CrossRefGoogle Scholar
  17. Huie ML, Chen AS, Tsujino S et al (1994) Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (-13T>G) mutation in a majority of patients and a novel IVS10 (+1GT>CT) mutation. Hum Mol Genet 3:2231–2236CrossRefGoogle Scholar
  18. 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 148:671–676CrossRefGoogle Scholar
  19. Kishnani PS, Amartino HM, Lindberg C et al (2013) Timing of diagnosis of patients with Pompe disease: data from the Pompe registry. Am J Med Genet A 161A:2431–2443Google Scholar
  20. Kroos MA, Van der Kraan M, Van Diggelen OP et al (1995) Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients. J Med Genet 32:836–837CrossRefGoogle Scholar
  21. Kroos MA, Pomponio RJ, Hagemans ML et al (2007) Broad spectrum of Pompe disease in patients with the same c.-32-13T>G haplotype. Neurology 68:110–115CrossRefGoogle Scholar
  22. Kroos M, Pomponio RJ, van Vliet L et al (2008) Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat 29:E13–E26CrossRefGoogle Scholar
  23. Kroos M, Hoogeveen-Westerveld M, van der Ploeg A, Reuser AJ (2012) The genotype-phenotype correlation in Pompe disease. Am J Med Genet C Semin Med Genet 160C:59–68CrossRefGoogle Scholar
  24. Laforet P, Nicolino M, Eymard PB et al (2000) Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 55:1122–1128CrossRefGoogle Scholar
  25. Laforêt P, Laloui K, Granger B et al (2013) The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease. Rev Neurol 169:595–602CrossRefGoogle Scholar
  26. Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291CrossRefGoogle Scholar
  27. Leslie N, Bailey L (2007) Pompe disease. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews®.Seattle (WA). University of Washington, Seattle, pp 1993–2018Google Scholar
  28. 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 Genet 79:69–72CrossRefGoogle Scholar
  29. Montalvo AL, Bembi B, Donnarumma M et al (2006) Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat 27:999–1006CrossRefGoogle Scholar
  30. Palmer RE, Amartino HM, Niizawa G, Blanco M, Pomponio RJ, Chamoles NA (2007) Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations. Neuromuscul Disord 17:16–22CrossRefGoogle Scholar
  31. Pompe Disease Diagnostic Working Group, Winchester B, Bali D et al (2008) Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab 93:275–281CrossRefGoogle Scholar
  32. Raben N, Nichols RC, Martiniuk F, Plotz PH (1996) A model of mRNA splicing in adult lysosomal storage disease (glycogenosis type II). Hum Mol Genet 5:995–1000CrossRefGoogle Scholar
  33. Rairikar MV, Case LE, Bailey LA et al (2017) Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G “late-onset” GAA variant. Mol Genet Metab 122:99–107CrossRefGoogle Scholar
  34. Remiche G, Ronchi D, Magri F et al (2014) Extended phenotype description and new molecular findings in late onset glycogen storage disease type II: a northern Italy population study and review of the literature. J Neurol 261:83–97CrossRefGoogle Scholar
  35. Reuser AJ, Verheijen FW, Bali D et al (2011) The use of dried blood spot samples in the diagnosis of lysosomal storage disorders - current status and perspectives. Mol Genet Metab 104:144–148CrossRefGoogle Scholar
  36. Strothotte S, Strigl-Pill N, Grunert B et al (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 257:91–97CrossRefGoogle Scholar
  37. van der Ploeg AT, Reuser AJ (2008) Pompe’s disease. Lancet 372:1342–1353CrossRefGoogle Scholar
  38. van der Ploeg AT, Clemens PR, Corzo D et al (2010) A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 362:1396–1406CrossRefGoogle Scholar
  39. Wens SC, van Gelder CM, Kruijshaar ME et al (2013) Phenotypical variation within 22 families with Pompe disease. Orphanet J Rare Dis 8:182CrossRefGoogle Scholar
  40. Winkel LP, Hagemans ML, van Doorn PA et al (2005) The natural course of non–classic Pompe’s disease; a review of 225 published cases. J Neurol 252:875–884CrossRefGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  • Claudio Semplicini
    • 1
    • 2
  • Pascaline Letard
    • 3
  • Marie De Antonio
    • 2
  • Nadjib Taouagh
    • 4
  • Barbara Perniconi
    • 4
  • Françoise Bouhour
    • 5
  • Andoni Echaniz-Laguna
    • 6
  • David Orlikowski
    • 7
    • 8
  • Sabrina Sacconi
    • 9
    • 10
  • Emmanuelle Salort-Campana
    • 11
  • Guilhem Solé
    • 12
    • 13
  • Fabien Zagnoli
    • 14
  • Dalil Hamroun
    • 15
  • Roseline Froissart
    • 16
  • Catherine Caillaud
    • 3
    • 17
  • Pascal Laforêt
    • 18
    • 19
    Email author
  • French Pompe Study Group
  1. 1.Department of NeurosciencesUniversity of PadovaPadovaItaly
  2. 2.Centre de référence des pathologies neuromusculaires Nord-Est-Ile de FranceHôpital La Pitié-Salpêtrière, AP-HPParisFrance
  3. 3.Laboratoire de Biochimie Métabolomique et ProtéomiqueHôpital Universitaire Necker Enfants Malades, AP-HPParisFrance
  4. 4.Institut de MyologieHôpital La Pitié-Salpétrière, AP-HPParisFrance
  5. 5.Service ENMG et pathologies neuromusculaires, Hôpital Neurologique Pierre WertheimerHospices Civils de LyonLyonFrance
  6. 6.Department of NeurologyUniversity Hospital StrasbourgStrasbourgFrance
  7. 7.Pôle de ventilation à domicileAP-HP, Hôpital Raymond PoincaréGarchesFrance
  8. 8.CIC 1429, INSERMAP-HP, Hôpital Raymond PoincaréGarchesFrance
  9. 9.Centre de référence des Maladies NeuromusculairesHôpital ArchetNiceFrance
  10. 10.CNRS UMR7277, INSERM U1091, IBV—Institute of Biology Valrose, Faculté de MédecineUNS Université Nice Sophia-AntipolisNice CedexFrance
  11. 11.Reference Center for Neuromuscular Diseases and ALS, La Timone University HospitalAix-Marseille UniversityMarseilleFrance
  12. 12.Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux (Pellegrin Hospital)University of BordeauxBordeauxFrance
  13. 13.National reference center ‘maladies neuromusculaires du grand sud-ouest,’ CHU Bordeaux (Pellegrin Hospital)University of BordeauxBordeauxFrance
  14. 14.CHRU Cavale-BlancheBrestFrance
  15. 15.Direction de la Recherche et de l’Innovation, CHRU de MontpellierHôpital Arnaud de VilleneuveMontpellierFrance
  16. 16.Service de Biochimie et Biologie Moléculaire, Centre de Biologie et Pathologie EstHospices civils de LyonBronFrance
  17. 17.INSERM U1151, Institut Necker Enfants Malades, and Université Paris DescartesSorbonne Paris CitéParisFrance
  18. 18.Centre de Référence des Maladies Neuromusculaires Nord-Est-Ile de France, Service de NeurologieCHU Raymond Poincaré, AP-HPGarchesFrance
  19. 19.INSERM U1179, END-ICAP, équipe Biothérapies des Maladies du Système NeuromusculaireUniversité Versailles Saint-Quentin-en-YvelinesMontigny-le-BretonneuxFrance

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