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Background: Early diagnosis of Gaucher disease (GD) allows for disease-specific treatment before significant symptoms arise, preventing/delaying onset of complications. Yet, many endure years-long diagnostic odysseys. We report the development of a machine learning algorithm to identify patients with GD from electronic health records., Methods: We utilized Optum's de-identified Integrated Claims-Clinical dataset (2007-2019) for feature engineering and algorithm training/testing, based on clinical characteristics of GD. Two algorithms were selected: one based on age of feature occurrence (age-based), and one based on occurrence of features (prevalence-based). Performance was compared with an adaptation of the available clinical diagnostic algorithm for identifying patients with diagnosed GD. Undiagnosed patients highly-ranked by the algorithms were compared with diagnosed GD patients., Results: Splenomegaly was the most important predictor for diagnosed GD with both algorithms, followed by geographical location (northeast USA), thrombocytopenia, osteonecrosis, bone density disorders, and bone pain. Overall, 1204 and 2862 patients, respectively, would need to be assessed with the age- and prevalence-based algorithms, compared with 20,743 with the clinical diagnostic algorithm, to identify 28 patients with diagnosed GD in the integrated dataset. Undiagnosed patients highly-ranked by the algorithms had similar clinical manifestations as diagnosed GD patients., Conclusions: The age-based algorithm identified younger patients, while the prevalence-based identified patients with advanced clinical manifestations. Their combined use better captures GD heterogeneity. The two algorithms were about 10-20-fold more efficient at identifying GD patients than the clinical diagnostic algorithm. Application of these algorithms could shorten diagnostic delay by identifying undiagnosed GD patients., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Background: Gaucher disease (GD) is one of the most prevalent lysosomal storage diseases and is associated with hormonal and metabolic abnormalities, including nutritional status disorders, hypermetabolic state with high resting energy expenditures, peripheral insulin resistance, hypoadiponectinaemia, leptin and ghrelin impairments, hypolipidaemia, linear growth deceleration and growth hormone deficiency, delayed puberty, hypocalcaemia and vitamin D deficiency. Specific treatments for GD such as enzyme replacement therapy and substrate reduction therapy display significant effects on the metabolic profile of GD patients. Hormonal and metabolic disturbances observed in both adult and paediatric patients with Gaucher disease type 1 (GD1) are discussed in this review. The PubMed database was used to identify articles on endocrine and metabolic disorders in GD1. GD1 appears to facilitate the development of disorders of nutrition, glucose metabolism and vitamin D insufficiency. Metabolic and hormonal diseases may have a significant impact on the course of the underlying disease and patient quality of life., Conclusions: Conditions relating to hormones and metabolism can be wide-ranging in GD1. Obtained findings were intrinsic to GD either as a deleterious process or a compensatory response and some changes detected may represent co-morbidities. Actively seeking and diagnosing endocrine and metabolic disorders are strongly recommended in GD1 patients to optimize healthcare.

Background: The study aim was to verify the feasibility of a diagnostic algorithm with the evaluation of beta glucocerebrosidase (GBA) activity on dried blood spots (DBS) in screening high-risk Gaucher disease (GD) children in China, and to investigate the GD prevalence in this selected population., Methods: Children were recruited from 20 departments of pediatrics or children's hospitals in Shandong Province, China, due to splenomegaly and/or thrombocytopenia associated with one or more of the following creteria: anemia, history of bone pain, monoclonal gammopathy of unknown significance (MGUS), polyclonal gammopathy and splenectomy. GBA activity on DBS was tested, and patients with DBS GBA activity under 30 nmol/h.ml were recalled to assess enzyme assay with gold standard and molecular GBA gene analysis on leukocytes., Results: A total of 73 children (47 boys and 26 girls) were enrolled in this study. GBA activity DBS < 30 nmol/h.ml was found in 18 (23.7%) children among which four (three boys and one girl) were diagnosed as GD with a median age 1.5 years, and the prevalence in this pediatric population was 5.5% (1.5%~ 13.4%). Three new mutations of GBA found in the four GD patients, L264I, A100Cfs*7 and D399E, have not been reported before., Conclusions: With evaluation of GBA activity on DBS as a preliminary screening method, the diagnostic algorithm used in this study is appropriate to make early diagnosis for GD patients with mild symptoms or atypical symptoms and avoid diagnosis delay., Trial Registration: Not applicable.

Background: The enzymatic replacement therapy (ERT) availability for Gaucher disease (GD) has changed the landscape of the disease, several countries have screening programs. These actions have promoted the early diagnosis and avoided many complications in pediatric patients. In Spain ERT has been available since 1993 and 386 patients have been included in the Spanish Registry of Gaucher Disease (SpRGD). The aim of this study is to analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients., Aim: To analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients., Methods: A review of data in SpRGD from patients' diagnosed before 18 years old was performed. The cohort was split according the year of diagnosis (≤1994, cohort A; ≥1995, cohort B)., Results: A total of 98 pediatric patients were included, GD1: 80, GD3: 18; mean age: 7.2 (0.17-16.5) years, 58 (59.2%) males and 40 (40.8%) females. Forty-five were diagnosed ≤ 1994 and 53 ≥ 1995. Genotype: N370S/N370S: 2 (2.0%), N370S/L444P: 27 (27.5%), N370S/other: 47 (48%), L444P/L444P: 7 (7.1%), L444P/D409H: 2 (2.0%), L444P/other: 3 (6.2%), other/other: 10 (10.2%). The mean age at diagnosis was earlier in patients diagnosed after 1995 (p < 0.001) and different between the subtypes, GD1: 8.2 (0.2-16.5) years and GD3: 2.8 (0.17-10.2) years (p < 0.001). There were more severe patients in the group diagnosed before 1994 (p = 0.045) carrying L444P (2), D409H (2), G377S (1), G195W (1) or the recombinant mutation. The patients' diagnosed ≤1994 showed worse cytopenias, higher chance of bone vascular complications at diagnosis and previous spleen removal. The patients started ERT at a median time after diagnosis of 5.2 years [cohort A] and 1.6 years [cohort B] (p < 0.001)., Conclusions: The early diagnosis of Gaucher disease in the era of ERT availability has permitted to reduce the incidence of severe and irreversible initial complication in pediatric patients, and this has permitted better development of these patients. This is the largest pediatric cohort from a national registry.

Background: Gaucher disease, an autosomal recessive condition due to deficiency of lysosomal glucocerebrosidase, is a multisystemic disease, with variable age of onset, severity and progression. It is classified into subtypes delineated by the absence (type 1) or presence (type 2 and 3) of primary nervous system involvement. The ethnically diverse, largely immigrant population in South Florida has a spectrum of Gaucher disease phenotypes, creating a challenge for optimization of disease management and an opportunity to explore treatment patterns., Methods: Ninety-three records from patients with Gaucher type I in South Florida were retrieved from the International Collaborative Gaucher Group (ICGG) Registry. Individual genotypes were correlated with severity scores and success at achieving published therapeutic goals for haemoglobin concentration, platelet count, spleen volume, liver volume and amelioration of bone pain and bone crises., Results: The majority of patients were diagnosed during the fifth decade of life. Almost two-thirds were homozygous for the N370S mutation, reflecting the large Ashkenazi Jewish population in South Florida. The majority received imiglucerase (62.8%) at various intervals. 24.5% of patients underwent splenectomy before starting enzyme replacement therapy. After a median 12 treatment years, South Florida patients matched or exceeded the ICCG 4 year therapeutic goal achievement for platelet count (85.4% vs. 79.6% success), spleen volume (93.3% vs. 78.0% success), liver volume (93.4% vs. 90.6% success), and bone crises (100% vs. 99% success). Nevertheless, fewer patients with intact spleens had sustained achievement of all 6 therapeutic goals (30.4% versus 41.4%) and only 40% of the splenectomy patients sustained achievement of 5/5 possible goals. 54.7% of the intact spleen patients continued to have bone pain vs. 29.8% in ICCG. Significantly, only 37% of the ICGG patient cohort had bone pain prior to initiation of treatment compared to 73.4% of the South Florida patients (moderate or severe pain in 59.6%)., Conclusions: Demographic characteristics are a significant determinant of the differences in response to treatment observed in South Florida Gaucher patients compared to those described in the international population enrolled in the ICGG Gaucher Registry. Individual genotypes and ethnic background are important considerations for optimizing patient care for Gaucher disease.

Background: Clinical features, complications and treatments of Gaucher's disease (GD), a rare autosomal-recessive disorder due to a confirmed lysosomal enzyme (glucocerebrosidase) deficiency, are described., Methods: All patients with known GD, living in France, with ≥ 1 consultations (1980-2010), were included in the French GD registry, yielding the following 4 groups: the entire cohort, with clinical description; and its subgroups: patients with ≥ 1 follow-up visits, to investigate complications; recently followed (2009-2010) patients; and patients treated during 2009-2010, to examine complications before and during treatment. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables., Results: Among the 562 registry patients, 265 (49.6%) were females; 454 (85.0%) had type 1, 22 (4.1%) type 2, 37 (6.9%) perinatal-lethal type and 21 (3.9%) type 3. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0-77) and 22 (0-84) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (37.6% and 26.3%, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 54.7% of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. For the 378 followed patients, median follow-up was 16.2 (0.1-67.6) years. Major clinical complications were bone events (BE; avascular necrosis, bone infarct or pathological fracture) for 109 patients, splenectomy for 104, and Parkinson's disease for 14; 38 patients died (neurological complications for 15 type-2 and 3 type-3 patients, GD complications for 11 type-1 and another disease for 9 type-1 patients). Forty-six had monoclonal gammopathy. Among 283 recently followed patients, 36 were untreated and 247 had been treated during 2009-2010; 216 patients received treatment in December 2010 (126 with imiglucerase, 45 velaglucerase, 24 taliglucerase, 21 miglustat). BE occurred before (130 in 67 patients) and under treatment (60 in 41 patients) with respective estimated frequencies (95% CI) of first BE at 10 years of 20.3% (14.1%-26.5%) and 19.8% (13.5%-26.1%)., Conclusion: This registry enabled the epidemiological description of GD in France and showed that BE occur even during treatment.

Background: Gaucher disease (GD) is due to deficiency of the glucocerebrosidase enzyme. It is panethnic, but its presentation reveals ethnicity-specific characteristics., Methods: We evaluated the distribution, and clinical and genetic characteristics of GD patients in the Iberian Peninsula (IP). We analysed geographical distribution, demographic, genetic and clinical data, age at diagnosis, type, and years of therapy in 436 GD patients from the IP., Results: The prevalence of GD was 1/149,000 inhabitants; 88.3% were type 1, 6.7% type 2, and 5.0% type 3. The mean age at diagnosis in type 1 was 28.7 years. A total of 72.7% were classified as having mild forms, 25.5% moderate, and 1.7% severe. Anemia and thrombocytopenia were present in 56% and 55%, respectively. Bone disease and hepatomegaly were reported in 62% and 68%, respectively, and were more likely in asplenic than in non-splenectomized patients. Sixty-nine mutant alleles were identified, and five mutations accounted for 75% of the GBA alleles. Several patients described in our series had interesting phenotypes. A total of 58.7% of patients had received enzyme replacement therapy and 12.6% were treated with miglustat., Conclusions: A broad spectrum of GBA mutations is present in the IP, with 98.2% of type 1 GD being mild and 23.0% never treated. These data highlight genetic and phenotypic heterogeneities among geographic populations.

Background: In clinical research of rare diseases, where small patient numbers and disease heterogeneity limit study design options, registries are a valuable resource for demographic and outcome information. However, in contrast to prospective, randomized clinical trials, the observational design of registries is prone to introduce selection bias and negatively impact the validity of data analyses. The objective of the study was to demonstrate the utility of case-control matching and the risk-set method in order to control bias in data from a rare disease registry. Data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were used as an example., Methods: A case-control matching analysis using the risk-set method was conducted to identify two groups of patients with type 1 Gaucher disease in the ICGG Gaucher Registry: patients with avascular osteonecrosis (AVN) and those without AVN. The frequency distributions of gender, decade of birth, treatment status, and splenectomy status were presented for cases and controls before and after matching. Odds ratios (and 95% confidence intervals) were calculated for each variable before and after matching., Results: The application of case-control matching methodology results in cohorts of cases (i.e., patients with AVN) and controls (i.e., patients without AVN) who have comparable distributions for four common parameters used in subject selection: gender, year of birth (age), treatment status, and splenectomy status. Matching resulted in odds ratios of approximately 1.00, indicating no bias., Conclusions: We demonstrated bias in case-control selection in subjects from a prototype rare disease registry and used case-control matching to minimize this bias. Therefore, this approach appears useful to study cohorts of heterogeneous patients in rare disease registries.

Introduction: Known biomarkers of Gaucher-disease activity are platelets, chitotriosidase, angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP) and ferritin. The aim of this study was to retrospectively evaluate the frequency of bone events (BE) and biomarker changes during two periods: diagnosis to first enzyme-replacement therapy (ERT) and the latter to the closing date., Methods: BE of 62 treated patients, among the 73-patient cohort followed at Beaujon Hospital, Clichy, France, were described with Kaplan-Meier curves, and linear-mixed models were used to analyze their biomarker changes and the influence of several covariates (splenectomy, diagnosis year, genotype, age at diagnosis and sex)., Results: BE occurred before (54 events in 21 patients), but also during, ERT (12 events in 10 patients), with respective frequencies (95% confidence interval) at 10 years of 22.4% (13.3 to 36.3) and 20.0% (10.2 to 36.9). Biomarker slope changes before and during ERT differed significantly for platelets (+190/mm3/year and 7,035/mm3/year, respectively; P < 0.0001) and ferritin (+4% and -14%; P < 0.0001). High ferritin levels and low platelet counts at ERT onset were significantly associated with BE during ERT (P = 0.019 and 0.039, respectively). Covariates significantly influenced biomarker changes (baseline and/or slope): splenectomy affected platelets (baseline and changes), TRAP changes and chitotriosidase changes; diagnosis date influenced ACE and TRAP baseline values; and genotype influenced chitotriosidase baseline and changes., Conclusions: Platelet counts and ferritin levels and their slope changes at ERT onset seem to predict BE during treatment. Biomarker baseline values and changes are dependent on several covariables.

Short Introduction: Gaucher's disease (GD) is an autosomal recessive disease produced by mutations of the Glucocerebrosidase gene. Carriers are considered to be healthy subjects because there is no manifestation of the disease, but they show signs of macrophage disfunction. The aim of the study was to determine if GD patients and non affected carriers risk suffering other diseases when compared to healthy non-carrier relatives., Design: Epidemiologic study of historic cohorts. The fact that they have one or two mutated alleles has been considered to be the risk factor leading to other conditions (Dementia, Parkinson disease, Ischemic stroke, Ischemic heart disease, Non rheumatic valvular disease, Cancer hematological and non-hematological, Pulmonary fibrosis, Tuberculosis, Gallstones and Schizophrenia). All people, patients, carriers and healthy controls shared the same genetical background and environmental influence. - Patients and relatives enrolled on the Spanish Gaucher Disease Registry were evaluated., Statistics: For the Relative-Risk calculation the Mantel-Haenszel test was applied. Yates' correction was used when size sample was too small. A value of p <0.05 was accepted for statistical significance., Results: 370 people, from 79 different families, were surveyed. We received evaluable information from 45 families (56%), totalling 258 people (69%): 59 healthy subjects (Mean age 32. 20, RANGE: 10-85; M 57.63%/F 42.37%), 132 carriers (Mean age 35.91, RANGE: 1-79; M 56.82%/F 43.18%) and 67 patients (Mean age 32.16, Range: 1-76; M 44.78%/F 55.22%. - Relative Risk of suffering any disease with regard to Gaucher's status: Patient vs Healthy 9.69 (95% Confidence interval [CI] 2.00-63.99; p 0.0006). Patient vs Carrier 3.74 (CI 1.53-9.27; p 0.001); Carrier vs Healthy 2.59 (CI 0. 52-12.50; p 0.21). Relative Risk of suffering any disease with regard to sex was 3.96 for female patients (CI 1.01-16.75; p 0.02) and 1.34 for female carriers (CI 0.27-6.75; p = 0.68)., Conclusion: As a group, Gaucher's patients seem to have a greater risk of suffering other common unrelated diseases than carriers or healthy relatives. This excess of risk is particularly higher among female patients and can not be explained in terms of differences in age. Carrier status doesn't seem to highten the risk of suffering other diseases.

Background: Thirty-six mutations that cause Gaucher disease, the most common glycolipid storage disorder, are known. Although both alleles of most patients with the disease contain one of these mutations, in a few patients one or both disease-producing alleles have remained unidentified. Identification of mutations in these patients is useful for genetic counseling., Materials and Methods: The DNA from 23 Gaucher disease patients in whom at least one glucocerebrosidase allele did not contain any of the 36 previously described mutations has been examined by single strand conformation polymorphism (SSCP) analysis, followed by sequencing of regions in which abnormalities were detected., Results: Eight previously undescribed mutations were detected. In exon 3, a deletion of a cytosine at cDNA nt 203 was found. In exon 6, three missense mutations were identified: a C-->A transversion at cDNA nt 644 (Ala176-->Asp), a C-->A transversion at cDNA nt 661 that resulted in a (Pro182-->Thr), and a G-->A transition at cDNA nt 721 (Gly202-->Arg). Two missense mutations were found in exon 7: a G-->A transition at cDNA nt 887 (Arg257-->Gln) and a C-->T at cDNA nt 970 (Arg285-->Cys). Two missense mutations were found in exon 9: a T-->G at cDNA nt 1249 (Trp378-->Gly) and a G-->A at cDNA nt 1255 (Asp380-->Asn). In addition to these disease-producing mutations, a silent C-->G transversion at cDNA nt 1431, occurring in a gene that already contained the 1226G mutation, was found in one family., Conclusions: The mutations described here and previously known can be classified as mild, severe, or lethal, on the basis of their effect on enzyme production and on clinical phenotype, and as polymorphic or sporadic, on the basis of the haplotype in which they are found. Rare mutations such as the new ones described here are sporadic in nature.