The FGDR developed and maintains a designated RCLD since 2009. Its Evaluation of Gaucher-Disease–Treatment Committee (EGDTC) is a national scientific committee to monitor and optimize GD management in France. The French Data-Protection Commission’s (CNIL) approval of the FGDR required oral or written informed consent from patients or their parents. Data from patients who did not consent were not entered. The FGDR was finally certified in 2009 by the French Institute for Public Health Surveillance (InVS) and the French National Institute of Health and Medical Research (INSERM). All GD patients living in France and having ≥1 consultations (i.e., hospitalization or outpatient consultation with a GD specialist) since 1980 were included. For all patients, GD was diagnosed by demonstration of deficient glucocerebrosidase activity in leukocytes 35 or cultured skin fibroblasts. Exhaustive identification of cases was achieved through 3 sources. Only 3 diagnostic laboratories (all included in EGDTC) are accredited in France and, therefore, identify all patients with an enzymatic assay for GD. Based on our Reference Center’s expertise, the French national health insurance (Rare Disease Committee with EGDTC members) validates each GD diagnosis and authorizes coverage for its treatment. Once experts have validated the case, they can ask the treating physician to include the patient in our registry. The indications for treatment are well established to maximize efficacy and avoid unnecessary health insurance expenditures. Each treating physician contacted allowed access to the medical data entered in the FGDR, which is certified by InVS and INSERM.

Each patient’s data were also collected by RCLD physicians or clinical research assistants. The FGDR director controlled data quality. Dr D. Hamroun developed the original Internet software for the FGDR, using 4^th Dimension language from 4D ( http://www.4D.com). Data were collected retrospectively between 2009 and 2010, and as of 2011, all data have been recorded prospectively.

A standardized case-report form was used to collect the following information: initial data (age at diagnosis, sex, history related or unrelated to GD, symptoms leading to diagnosis and first symptoms, first diagnostic exam, phenotype, genotype and affected family members); clinical information during the first consultation, at diagnosis and throughout follow-up; body mass index expressed according to the World Health Organization classification; organomegaly (liver and/or spleen, ultrasound measurement of the largest diameter); biological findings initially and throughout follow-up (hemoglobin level, platelet count, leukocyte count, chitotriosidase, ferritin, ACE, TRAP, gammaglobulin (with respective normal values of >12 g/dL, >150×10³/mm³, >4 × 10³/mm³, <100 nmol/mL/h, <250 ng/L, <45 IU/L, <7 IU/L and <13 g/L). Plasma chitotriosidase activity was determined using the fluorescent substrate 4-methylumbelliferylβ-D-N N′,N′′-triacetylchitotriose 10 ; ACE, TRAP, ferritin and other markers were measured in the appropriate local laboratories. Bone findings (X-rays, magnetic resonance imaging and, for some patients, scintigraphy and dual-energy X-ray absorptiometry) were recorded during follow-up, with identification of intercurrent events, particularly bone complications. Bone events (BE) were defined clinically, using the bone indications for treatment recommended by the French National Health Authority 36 : avascular necrosis of an epiphysis, bone infarct, pathological and/or vertebral compression fracture(s). Each BE caused a clinical manifestation and was confirmed radiologically. Bone pain alone was not considered a BE without radiological confirmation. Acute bone pain defined a bone crisis. Bone crisis was included in BE only when a bone infarct was identified. Any event, GD-related or not, occurring during follow-up and monitoring of GD-specific therapy was also recorded.

This investigation was undertaken to describe and analyze clinical, biological, radiological and therapeutic data recorded in the FGDR for all patients from diagnosis until 31 December 2010, the closing date. The local Institutional Review Board of Northern Paris Hospitals, Paris–Diderot University, AP–HP (Ethics Committee) reviewed and approved the research project.

To simplify the description, we defined 4 groups: the entire cohort and its subgroups. Data from the entire cohort of patients entered in the FGDR described, when available, diagnosis characteristics for these patients, the GD-incidence rate (defined as total number of cases diagnosed between 1980 and 2010 divided by the total French population during the same period), birth incidence rate (defined as the total number of cases diagnosed between 1980 and 2010, divided by the total number of live births during the same period) and prevalence were estimated for the French population. For patients with ≥1 follow-up visits in addition to the initial assessment form, we investigated their GD complications (splenectomy, Parkinson’s disease (PD), monoclonal gammopathy (MG), BE, first treatment and deaths). Recently followed patients had consulted in 2009–2010: a map showing the locations of hospitals monitoring them was drawn. For patients seen and treated in 2009–2010, BE were analyzed, before and under (ERT and/or SRT (ERT/SRT)). Clinical, biological and radiological monitoring of these recently treated patients was also investigated. Specific GD ERT (imiglucerase, velaglucerase, taliglucerase, miglustat) was studied, particularly during the period of imiglucerase shortage (June 2009–December 2010). Patients were distinguished according to their age on 1 June 2009 (≤15 or >15 years) for the description of the shortage that began at that time. That age was chosen because it defines the limit between adult medicine and pediatrics.

All statistical analyses were computed with SAS software (version 9.2; SAS Institute Inc; Cary, NC). Data are expressed as medians ((range) or interquartile range [IQR; Q1;Q3]) for continuous variables and numbers (%) for categorical variables. Because this was a retrospective study, some data were missing, particularly at the onset of follow-up (during the diagnosis phase) or at treatment onset. Given the demonstrated relatively stable clinical and laboratory parameters of untreated patients after GD diagnosis 37 , the biological data during the next 2 years changed only minimally and were considered similar to those at diagnosis. Likewise, data for the previous 2 years under ERT/SRT were stable compared to those at treatment onset. Under treatment data were the last values before the end of therapy or at the closing date. When ERT/SRT was interrupted for <6 months, patients were always considered to be on treatment.

Non-parametric tests were used to compare categorical variables (Fisher’s exact test) across patient subgroups. A two-sided p<0.05 was considered significant. For recently treated patients, time to first BE was estimated with the Kaplan–Meier method for 2 periods: diagnosis to treatment onset (before ERT) and first ERT to closing date (under ERT), with only the first BE occurring during each period being considered. Data were censored when no BE occurred prior to ERT start for the first analysis, and until the closing date or treatment discontinuation for the second. We aimed to study a risk effect of BE. First, the impact of splenectomy, time to treatment onset (< or ≥2 years after diagnosis, based on Mistry et al.’s demonstration of lower BE risk after the latter 38 ) or age at diagnosis (≤ or >15 years) on BE occurrence was tested using the log-rank test; second a Cox model was used to derive a predictive model. When several univariate model covariates were significant, a multivariate Cox model with backward selection was used to retain only significant ones. For BE under ERT, the impact of BE occurrence before treatment was also tested.

The FGDR contained 562 patients with confirmed GD, living in France and having ≥1 consultations between 1980 and 2011. Patient characteristics at diagnosis are reported in Table  1. The male/female ratio was 1.0151 (49.6% female), while median age at first symptoms was 15 (0–77) years. During the 31 years (1980–2010), 474 patients were diagnosed in France, with an annual median of 15 (9–32) patients. The incidence rate was estimated at 0.26 patients/10⁶ person-years and birth incidence at 1/50,000. The prevalence was 1/136,000. The most frequent first symptom leading to diagnosis (available for 232 patients) was splenomegaly and/or thrombocytopenia, although others were found, including anemia in 14, 14 splenectomies, 10 severe hemorrhages, 6 neurological symptoms, 3 avascular necroses, 1 vertebral collapse and 1 bone infarct. Although the most common diagnostic test yielding the diagnosis was bone-marrow aspiration, all patients’ diagnoses were confirmed by enzymatic assay. Genotypes were determined for 261 patients, with 203 having homo- (39 patients) or heterozygous p.N370S mutations (164 patients, including 41 with p.L444P/p.N370S mutations). Genotype distributions differed significantly (p<0.0001): L444P/L444P or L444P/other were found in 14 (6.4%) phenotype-1, 13 (100%) phenotype-2 and 12 (100%) phenotype-3 patients, while the genotypes N370S/L444P, N370S/other or N370S/N370S were identified in 203 (93.6%) phenotype-1, no phenotype-2 and no phenotype-3 patients. Other mutations found (associated or not with p.N370S or p.L444P) were: p.R48W, p.C16W, p.G193R, p.K303I, p.W312S, p.G377S, p.W393R, p.V394L, p.D409H, p.M416I, p.A446P, p.R463C, p.1416, 1417delAG and p.RecNcil. Patients were predominantly (84.7%) type 1. Among 161 patients with an affected family member, all but 3 (1 mother, 1 uncle, 1 cousin) were siblings. Ninety-seven patients died: 37 perinatal deaths (28 fetuses and 9 newborns <3 months old) and 60 later (33 type 1, 22 type 2 and 5 type 3).

Note that recent refers to 2009–2010, i.e., the last 2 years. GBA glucosidase-β acid.

*No. represents the number of patients with available information.

†Several symptoms for each patient.

‡All patients had their definitive diagnoses confirmed by enzymatic assay.

A total of 378 patients, predominantly type 1, had ≥1 follow-up visits after their initial evaluations. The median follow-up duration was 16.2 (0.1–67.6) years. Their characteristics at diagnosis are reported in Table  1. During follow-up, 225 complained of chronic bone pain or clinical bone crisis, 231 had splenomegaly and 163 had hepatomegaly at least once.

Among followed patients, 95 had no known data during 2009–2010. Median time since the last hospital consultation for these patients was 10.7 (2.4–31.6) years. Thus, 283 patients had consulted during 2009–2010: 36 had never been treated and 247 patients had received ERT/SRT during that period. Their characteristics at diagnosis are reported in Table  1.

During 2009–2010, 247 patients (239 type 1 and 8 type 3) received treatment, with median follow-up at 19.3 (0.2–66.2) years. Among these recently treated patients, all 5 type-1 patients died at a median age of 65.8 (56.8–83.4) years. Table  2 provides clinical, biological and bone data at diagnosis, treatment onset and closing date. Clinical findings, biological values and bone findings tended to improve under ERT/SRT.

US ultrasound, MRI magnetic resonance imaging.

*Data from 31 patients were used at diagnosis and at ERT/SRT onset.

†Splenomegaly in non-splenectomized patients.

During follow-up, 190 BE (73 avascular necroses, 36 bone infarcts, 58 pathological fractures, 23 vertebral compressions) occurred in 86 patients, with a median of 1.5 (1–8) BE/patient. Figure  2 shows Kaplan–Meier estimates of the time to the first BE for the 247 recently seen and treated patients, between diagnosis and ERT/SRT onset (9.2 years of follow-up), and between the latter and the closing date (7.8 years of follow-up). Treatment at the time of BE was imiglucerase for 56 patients, alglucerase for 5 and miglustat for 4. The median imiglucerase/alglucerase dose when BE occurred in 52 patients was 120 (43.5–240) IU/kg/month; 42 patients had doses ≥120 IU/kg/month. The probabilities (95% confidence interval [CI]) of BE occurring by 10 years before and during treatment were estimated at 20.3% (14.1%–26.1%) and 19.8% (13.5%–26.1%), respectively. Before treatment, 67 patients developed 128 BE: 35 patients with 1 BE, 17 with 2 BE and 15 with ≥3 BE; whereas under treatment, 41 developed 62 BE: 28 patients with 1 BE, 8 with 2 BE and 5 with ≥3 BE, including 22 patients with BE before and under ERT/SRT.

The probabilities (95% CI) of BE occurring by 10 years before ERT/SRT were 11.5% (3.1%–19.8%) versus 24.9% (16.6%–33.2%) for age at diagnosis ≤15 years and >15 years, respectively (p=0.047). No other covariates were found to influence BE occurrence before ERT/SRT. During treatment, the probabilities (95% CI) of experiencing BE by 10 years were: 11.8% (5.9%–17.6%) and 35.9% (22.2%–49.5%) for patients without or with BE (Figure  3) before ERT/SRT, respectively, with an HR of 9.8 (5.9–16.3) (p<0.001); 29.1% (16.1%–42.1%) versus 14.7% (8.3%–21.1%) with and without splenectomy, respectively, with an HR of 2.1 (1.5–2.9) (p=0.005); 34.9% (29.8%–40.1%) vs 50.3% (46.1%-54.4%) for age at diagnosis ≤15 years and >15 years, respectively, with an HR of 0.7 (0.5–0.98) (p=0.04); and 22.3% (15.1%–29.5%) versus 8.1% (0%–17.5%) for diagnosis-to-treatment interval >2 and ≤2 years, respectively, with an HR of 0.5 (0.3–0.9) (p=0.01). Age at diagnosis >15 years was not significantly associated with BE under treatment (p=0.54). In the multivariate analysis with backward elimination, BE before treatment was the only significant risk factor retained.

Table  3 reports ERT/SRT prescribed according to the supply-shortage dates for the 247 recently treated patients. The first treatment prescribed was imiglucerase for 185 patients, alglucerase for 50, miglustat for 7, velaglucerase for 4 patients and taliglucerase for 1. The median diagnosis-to-treatment interval was 9.2 (0.0–47) years for all patients, but only 1.5 (0.0–16) years for patients diagnosed after 1991. The median treatment duration was 7.8 (0–18.3) years. During the supply shortages (June–August 2009), 106 patients discontinued their treatment, 9 switched to miglustat and 46 reduced their imiglucerase doses. Two patients received a combination of miglustat and imiglucerase, which was continued during the shortage (counted only under imiglucerase in Table  3).

Note that recent refers to 2009–2010, i.e., the last 2 years.

*Only imiglucerase was prescribed to adults (>15 years) or children (≤15 years).