Background
Gaucher’s disease (GD), a rare autosomal–recessive disorder with an approximate prevalence of 1/75,000 live births worldwide, is due to the deficiency of a lysosomal enzyme (glucocerebrosidase, glucosylceramidase or glucosidase-β acid (EC 3.2.1.45))[
1] or, more rarely, its activator (saposin C)[
2,
3]. GD diagnosis is based on deficient glucocerebrosidase activity in peripheral leukocytes or cultured skin fibroblasts. Genotyping can sometimes provide prognostic information[
4]. This lysosomal storage disease is characterized by liver and spleen enlargement, and bone manifestations (Erlenmeyer-flask deformity, osteoporosis, lytic lesions, pathological and vertebral compression fractures, bone infarcts and avascular necroses leading to degenerative arthropathy)[
1,
5]. Based on the neurological signs, 3 clinical phenotypes are recognized: type 1, the classic form usually defined by the absence of central nervous system impairment, although an association between type-1 GD and Parkinsonism has been described[
6]; types 2 and 3, both rare and severe, have neurological involvement[
7]; and the perinatal–lethal GD type, with perinatal onset and death before 3 months of age[
8]. GD signs usually appear after a symptom-free period, except in rare cases of fetal onset[
9]. Thrombocytopenia and anemia are common, and several biomarkers (chitotriosidase, ferritin, angiotensin-converting enzyme [ACE] and tartrate-resistant acid phosphatase [TRAP]) are elevated during GD evolution[
10‐
17].
Enzyme-replacement therapy (ERT; alglucerase [Ceredase©, Genzyme Corporation, available since 1991][
18], followed by imiglucerase [Cerezyme©, Genzyme Corporation, available since 1996], velaglucerase [Vpriv©, Shire, available since 2010][
19], and taliglucerase [Uplyso©, Pfizer, only authorized for temporary use][
20]), is the reference treatment. Substrate-reduction therapy (SRT), namely miglustat (Zavesca©, Actelion, available since 2002)[
21], is indicated for moderate GD when ERT is unsuitable. In June 2009, an acute imiglucerase shortage occurred because of viral contamination (Vesivirus 2117) of cell cultures and other production problems[
22]. Since then, that ERT has been in short supply, which was further aggravated in August 2009.
Genzyme Corporation developed an international registry[
23] and several countries, e.g., Spain[
24,
25], Brazil[
26] or Japan[
27], identified GD cohorts and established exhaustive national registries. While the international registry conducted many important ancillary studies[
28‐
34], its non-exhaustive cohort did not address public health issues in terms of incidence, prevalence and monitoring of care of GD patients. Since 2004, France has created referral centers dedicated to the clinical management of rare diseases, and assigned them several objectives, e.g., improving overall patient clinical care and professional practices, and collecting epidemiological data. In this context, a Referral Center for Lysosomal Diseases (RCLD) was established and a national GD-patient registry was created, in 2009, as a means to examine and meet some of those goals.
The main aims of this study were to describe the epidemiological profile of GD patients in France: GD demographic, clinical, biological and genetic features; complications in patients with follow-up (2009–2010); and treatments for those with recent (2009–2010) follow-up based on data collected since 1980 and available in the French Gaucher Disease Registry (FGDR).
Discussion
To date, no other publication has analyzed the comprehensive data entered in the FGDR for 562 patients, minus 3 who refused to participate and 97 who died, leaving 465 patients (among 65.8 million inhabitants), yielding prevalence of 1/140,000 inhabitants in France, a number that is probably underestimated. Concerning the entire cohort, although type 1 predominated (85%), types 2 and type 3 represented 4% each, along with 37 (6.9%) perinatal–lethal type. Moreover, the type-2 incidence was the same as that of type 3 but its prevalence was low because of its associated early mortality. The recent publication on the exhaustive Spanish registry[
26] reported data similar to ours, with 88.3% type 1, 6.7% type 2 and 5% type 3. Our birth incidence (1/50,000) was higher than previously reported for the GD frequency in non-Jewish populations from EU countries[
25,
39,
40], with a prevalence (1/136,000), close to that of the Spanish registry (1/149,000)[
26].
Bone-marrow aspiration (or biopsy) remained the most common laboratory test (57%) providing the GD diagnosis. It is usually the first-line analysis when thrombocytopenia is associated (or not) with splenomegaly and there is no reason to think of immune thrombocytopenia purpura. It is not mandatory and should not be done if the GD diagnosis has been established by enzymatic assay or is already strongly suspected (e.g., possible family history). Rarely, bone-marrow aspiration was considered “normal” but another sample contained the characteristic GD cells.
Fourteen (3.7%) of our 378 followed patients had PD, reaching a prevalence comparable to that reported by Bultron et al.[
41]. MG and polyclonal gamma globulinemia occur frequently in GD[
42‐
45]. Among the 378 followed patients, 46 (12.2%) had MG, a rate within the previously reported range (1%[
42] to 35%[
45]), and median gamma globulinemia at ERT/SRT onset in recently treated patients was 21.7 g/L. Usually, MG is unaffected by ERT[
43,
44]. However, for patients whose MG was diagnosed under treatment, no pretreatment evaluation was available, and MG had probably been present at treatment onset.
Before 1991, splenectomy was the only available treatment but, since then, it should not have been performed (albeit with exceptions) as a GD treatment. However, it has been used sometimes as a diagnostic tool when splenomegaly and thrombocytopenia coexisted, but should no longer be. Fourteen splenectomies were done after 1991 and after GD diagnosis, usually for patients with splenic complications (splenic infarcts, spleen rupture or large fibrous splenomegaly not amenable to ERT) or a mistaken indication.
BE are the most serious GD complications. They are usually prevented by ERT/SRT, with substantial attenuation of bone pain, bone crises and bone-mineral density[
46], although the BE decrease is difficult to evaluate without randomized placebo-controlled trials. In addition, the definition of BE is not homogeneous across studies. Apparently, ERT/SRT does not prevent all BE, as indicated by the estimated respective probabilities of BE occurring by 10 years before and during treatment of 20.3% and 19.8%. It is likely that patients on ERT/SRT would probably have had more complications had they not been treated. Furthermore, we showed that BE before treatment increased the risk of BE under ERT/SRT and was the only factor retained in our multivariate analysis. Note that, as reported by Mistry et al.[
38], our univariate analyses also found splenectomy and treatment >2 years after GD diagnosis to increase that risk, while sex and age at diagnosis ≤15 years were associated with increased risk of BE before but not under ERT/SRT. Thus, BE persist as a problem that is not fully resolved by treatment. The continuing challenges remain how to identify patients at risk before and under ERT/SRT, and then to decide whether or not these patients would benefit from earlier treatment onset and/or dose intensification.
In summary, the FGDR strong points are its comprehensiveness, independence, accreditation and/or certification by the various health authorities and cooperation generated among the different French centers. This registry also had to manage the imiglucerase shortage, when more severe GD and children were accorded priority treatment. The FGDR also enabled, during that shortage, nationwide management of the ERT/SRT stock and selection of those patients most in need of therapy (velaglucerase and taliglucerase). In France, GD-patient management is organized so that patients receive treatment near their homes, which improves their quality of life. Even though monitoring is not centralized, the FGDR identification and tracking of patients should contribute to improving their specific care management.
Acknowledgments
The authors wish to thank Janet Jacobson for editorial assistance, the RCLD secretary, Samira Zebiche, GD patients and their physicians, who contributed to the FDGR (listed in alphabetic order followed by their city): Agape Philippe (Saint-Denis), Allanore Yannick (Paris), Amir Abdeslem (Vendôme), Amsallem Daniel (Besançon), Bauduer Fréderic (Bayonne), Benbouker Lotfi (Tours), Bergelin-Besacon Anne (Le Mans), Bergère Alain (La Flèche), Bernard Olivier (Paris), Beyler Constance (Paris), Bismuth Mickael (Montpellier), Boiffard Olivier (Saintes), Bonnet Brigitte (Le Havre), Bordessoule Dominique (Limoges), Bouheddou Nadia (Moulins), Bouteiller Gilles (Auch), Brissot Pierre (Rennes), Brottier-Mancini Elisabeth (La Rochelle), Carreiro Miguel (Montauban), Cassan-Faux Nelly (Châtellerault), Cathebras Pascal (Saint-Priest-en-Jarez), Ceccaldi Joël (Libourne), Chabrol Brigitte (Marseille), Cohen-de Lara André (Paris), Cohen-Valensi Rolande (Martigues), Colnot Fabrice (Épinal), Constantini Denis (Corbeil–Éssonne), Costello Régis (Marseille), Dalbies Florence (Brest), Danne Odile (Cergy), Deconinck Éric (Besançon), Delahaye Florence (Évreux), Delattre Pierre (Cayenne), Delieu Fabienne (Nice), Demeocq François (Clermont-Ferrand), Denis Jacques (Évry), Descos Bruno (Nice), Desmurs-Clavel Hélène (Lyon), Diallo Boubacar (Remiremont), Djerad Hama (Nevers), Dobbelaere Dries (Lilles), Dreyfus Marie (Le Kremlin–Bicêtre), Dupriez Brigitte (Lens), Durieu Isabelle (Lyon), Edan Christine (Rennes), Fabre Sylvie (Montpellier), Feillet François (Vandœuvre-les-Nancy), Ferry Régine (Charleville-Mézières), Flodrops Hugues (Saint-Pierre, La Réunion), Fontaine Bertrand (Paris), Gaches Francis (Toulouse), Gay Claire (Saint-Étienne), Germain Dominique (Garches), Gil Helder (Besançon), Granier Françoise (Mantes-la-Jolie), Guérin Jacques (Arpajon), Guillaumat Cécile (Corbeil–Éssonne), Harle Robert (Marseille), Herbrecht Raoul (Strasbourg), Hutin Pascal (Quimper), Jarnouen de Villartay Philippe (Pontoise), Jourdan Éric (Nîmes), Kpati Agbo (Lagny-sur-Marne), Kuster Alice (Nantes), Lackmy-Port-Lis Marylin (Pointe-à-Pitre), Lamagnère Jean-Pierre (Tours), Lavigne Christian (Angers), Le Bideau Marc (Saint-Nazaire), Le Coz Marie-Françoise (Lorient), Le Henaff Catherine (Morlaix), Le Lorier Bernard (Melun), Le Niger Catherine (Brest), Lefebvre Vincent (Rodez), Leguy-Seguin Vanessa (Dijon), Lejars Odile (Tours), Lèone Jean (Reims), Leporrier Michel (Caen), Lescoeur Brigitte (Paris), Lèvy Marc (Nanterre), Lidove Olivier (Paris), Linassier Claude (Tours), Lioure Bruno (Strasbourg), Macro Margaret (Caen), Maillot François (Tours), Marie Isabelle (Rouen), Mathieu Sophie (Paris), Mazodier Karine (Marseille), Morel Pierre (Lens), Navarro Robert (Montpellier), Ninet Jacques (Lyon), Noël Esther (Strasbourg), Oksenhendler Éric (Paris), Orzechowski Christine (Bry-sur-Marne), Oudot Caroline (Paris), Pan-Petesch Brigitte (Brest), Pellegrino Béatrice (Saint-Germain), Perreti Delphine (Le Kremlin–Bicêtre), Pers Yves-Marie (Montpellier), Plantier Isabelle (Roubaix), Plouvier Emmanuel (Besançon), Pujazon Marie-Christine (Toulouse), Quinsat Denis (Antibes), Rhorlich Pierre-Simon (Besançon), Rivera Serge (Bayonne), Roche Jean (Roanne), Ruivard Marc (Clermont-Ferrand), Savoye Guillaume (Rouen), Sedel Frédéric (Paris), Simon Anne (Paris), Solary Éric (Dijon), Steiger Jean-Marie (Bourges), Tchamgoue Serge (Libourne), Themelin Pascal (Beauvais), Tieule Nathalie (Nice), Trab Albert (Nice), Varet Bruno (Paris), Vives Laurent (Saint-Gaudens), Zenone Thierry (Valence), Zunic Patricia (Saint-Pierre). The salaries of a statistician and a clinical research associate who participated in this study were funded, in part, by a grant from Genzyme France. Genzyme played no role in designing the study; in collecting, analyzing and interpreting the data; writing the paper; or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval of the study’s sponsors. The development of the original software for the French Gaucher Disease Registry (FGDR) was funded by a grant from the association VML (Vaincre les Maladies Lysosomales). J. Stirnemann’s work was funded, in part, by a grant from INSERM (Institut National de la Santé et de la Recherche Médicale). The FGDR was funded, in part, by INSERM and InVS (Institut national de Veille Sanitaire).
Competing interests
Research grants from Genzyme France to University Paris–Diderot to fund statistical analyses and to AP–HP to finance data acquisition. Research grant from Shire France to APRIMI (Beaujon Hospital’s association) to finance data acquisition. C. Serratrice, L. Rossi-Semerano and B. Grosbois, received consulting fees, speaking fees, and/or honoraria from Genzyme (less than $10,000). C. Serratrice, D. Heraoui, F. Camou, A. Masseau and B. Grosbois received consulting fees, speaking fees and/or honoraria from Actelion (less than $10,000). C. Serratrice, F. Camou and B. Grosbois received consulting fees, speaking fees, and/or honoraria from Shire (less than $10,000).
Authors’ contributions
JS, FM, MV, NB, OF and BF designed research analyzed and interpreted data. All authors, except for FM, MV and DH were involved in treating patients and collecting data. JS had full access to all of the study data and takes responsibility for their integrity and the accuracy of the data analysis. DH developed the original software for the FGDR. JS, MV, NB and FM wrote the draft of the paper, which was then corrected and approved by all authors. All authors read and approved the final manuscript.