Abstract
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.
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Acknowledgements
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
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.
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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.
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Figure S1
Description of the PD patient cohorts studied. (PNG 315 kb)
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)
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Table S2
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Semplicini, C., Letard, P., De Antonio, M. et al. Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study. J Inherit Metab Dis 41, 937–946 (2018). https://doi.org/10.1007/s10545-018-0243-7
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DOI: https://doi.org/10.1007/s10545-018-0243-7