Gaucher Disease Type Research Articles

Clinical-genetic characteristics and treatment outcomes of Turkish children with Gaucher disease type 1 and type 3: A sixteen year single-center experience

Data from 38 children were retrospectively analyzed to determine the patient characteristics of Turkish children with Gaucher disease (GD) and evaluate the impact of enzyme replacement therapy (ERT) in a pediatric cohort consisting of two different sub-types of the disease, Gaucher disease type 1 (GD1) and type 3 (GD3). Both types were represented equally (GD1/GD3 = 20/18). L444P (35.5%) was the most common mutant allele while L444P/L444P (34.2%) was the most common genotype overall. Compound heterozygosity of N370S and L444P homozygosity were the dominant genotypes in Turkish children with GD1 and GD3, respectively. None of the patients had moderate to severe thrombocytopenia at last follow-up while the percent of patients with anemia decreased from 60% to 5.7% (p < 0.001). Significant improvements in mean liver (from 2.2 to 1.6 MN, p < 0.001) and spleen (from 15.5 to 7.6 MN, p < 0.001) volumes were observed in the first year of ERT. Linear growth was ameliorated as shown by the decrease in the percent of patients having short stature from 34.3% to 13.3% (p < 0.01) at year 5. Erlenmeyer flask deformity, osteopenia and scoliosis were common skeletal findings. Although none of the patients had lung disease at diagnosis, 20% developed radiological findings suggestive of pulmonary involvement. This single center experience is the first comprehensive study from Turkey not only reporting clinical and genetic characteristics of GD patients but also providing information on the outcomes of ERT in two different sub-types of GD. Genotypic background of Turkish children with GD is similar to western populations. Although visceral and hematological therapeutic goals are reached as early as one year of ERT in both sub-types, achieving normal growth takes several more years than suggested in significant number of children with GD.

Incremental biomarker and clinical outcomes after switch from enzyme therapy to eliglustat substrate reduction therapy in Gaucher disease

In Gaucher disease (GD), genetic deficiency of acid β-glucosidase leads to accumulation of its substrate glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Lipid-laden cells, most prominently seen as macrophages engorged with GlcCer and GlcSph-laden lysosomes, trigger chronic metabolic inflammation and multisystemic phenotypes. Among the pleiotropic effects of inflammatory cascades, the induction of glucosylceramide synthase accentuates the primary metabolic defect. First-line therapies for adults with GD type 1 include Enzyme Replacement Therapy (ERT) and eliglustat Substrate Reduction Therapy (SRT). The ENCORE phase 3 clinical trial of eliglustat demonstrated non-inferiority compared to ERT. It is not known whether switching stable patients from long-term ERT to SRT results in the incremental reversal of the disease phenotype and its surrogate indicators. Herein, we report real-world experience from a single tertiary referral center of 38 adult GD type 1 patients, stable on long-term ERT (mean 13.3 years), who switched to eliglustat SRT (mean 3.1 years). After switch to SRT, there was significant reduction in spleen volume (P = 0.003) while liver volume, which was normal at baseline, remained unchanged. Platelet counts increased significantly (P = 0.026). Concomitantly, there was reduction of three validated biomarkers of Gaucher disease activity: plasma GlcSph decreased from 63.7 ng/ml (95% CI, 37.6-89.8) to 26.1 ng/ml (95% CI, 15.7-36.6) (P < 0.0001); chitotriosidase fell from 1136.6 nmol/ml/h (95% CI, 144.7-2128.6) to 466.9 nmol/ml/h (95% CI, 209.9-723.9) (P = 0.002); and glycoprotein non-metastatic melanoma B (gpNMB) decreased from 59.3 ng/ml (95% CI, 39.7-78.9) to 43.6 ng/ml (95% CI, 30.7-56.6) (P = 0.0006). There were no episodes of avascular necrosis or fractures in patients on SRT. Patients reported favorable experiences of switching from alternate week infusions to oral therapy. Collectively, these results demonstrate that the switch to eliglustat SRT from ERT leads to incremental response, even in stable patients after long-term ERT.

Clinical Characteristics, Molecular Background, and Survival of Egyptian Patients With Gaucher Disease Over a 20-Year Follow-up.

This study analyzes the general disease characteristics, impact of enzyme replacement therapy (ERT), and overall survival (OS) of 156 Egyptian patients with Gaucher disease (GD) enrolled on hormone replacement from 1998 to 2017. The mean age at diagnosis was 32.46±12.68 months. Anemia was noted at diagnosis in 50%, thrombocytopenia in 30.7%, severe splenomegaly in 58.7%, severe hepatomegaly in 11.9%, and skeletal findings were detected in 24.3% of the patients. The most prevalent GD type was type 3 (54.5%). Twenty-two of type 3 patients had no neurological manifestations at diagnosis, and 12 developed variable central nervous system manifestations during follow-up. The most common neurological features were limited eye movements, oculomotor apraxia, and squint. Of the 60 patients for whom genotypes were obtained, homozygous L444P was the most common (n=35/60, 58.3%). Treatment with ERT (imiglucerase) revealed significant improvements in blood indices, organ volumes, and growth parameters (P<0.05). Ten (11.7%) type 3 patients did not develop any neurological manifestations under ERT over 20 years. Mortality was 16%, and the 20-year OS was 73.3%. We conclude that in Egypt, type 3 is the most prevalent phenotype of GD, and homozygous L444P is the predominant GBA genotype of GD. Early age at diagnosis and treatment with ERT over 20 years revealed significant improvements in disease manifestations, with an OS of 73.3%.

Cardiopulmonary assessment of patients diagnosed with Gaucher's disease type I.

BackgroundUnderstanding the basis of the phenotypic variation in Gaucher's disease (GD) has proven to be challenging for efficient treatment. The current study examined cardiopulmonary characteristics of patients with GD type 1.MethodsTwenty Caucasian subjects (8/20 female) with diagnosed GD type I (GD‐S) and 20 age‐ and sex‐matched healthy controls (C), were assessed (mean age GD‐S: 32.6 ± 13.1 vs. C: 36.2 ± 10.6, p > .05) before the initiation of treatment. Standard echocardiography at rest was used to assess left ventricular ejection fraction (LVEF) and pulmonary artery systolic pressure (PASP). Cardiopulmonary exercise testing (CPET) was performed on a recumbent ergometer using a ramp protocol.ResultsLVEF was similar in both groups (GD‐S: 65.1 ± 5.2% vs. C: 65.2 ± 5.2%, p > .05), as well as PAPS (24.1 ± 4.2 mmHg vs. C: 25.5 ± 1.3 mmHg, p > .05). GD‐S had lower weight (p < .05) and worse CPET responses compared to C, including peak values of heart rate, oxygen consumption, carbondioxide production (VCO2), end‐tidal pressure of CO2, and O2 pulse, as well as HR reserve after 3 min of recovery and the minute ventilation/VCO2 slope.ConclusionsPatients with GD type I have an abnormal CPET response compared to healthy controls likely due to the complex pathophysiologic process in GD that impacts multiple systems integral to the physiologic response to exercise.

Encore: A Randomized, Controlled, Open-Label Non-Inferiority Study Comparing Eliglustat To Imiglucerase In Gaucher Disease Type 1 Patients On Enzyme Replacement Therapy Who Have Reached Therapeutic Goals

BackgroundGaucher disease type 1 is a multi-systemic lysosomal storage disorder caused by acid β-glucosidase deficiency. Eliglustat is a novel oral substrate-reduction therapy in development for adults with Gaucher disease type 1. This Phase 3 trial (ENCORE, NCT00943111, sponsored by Genzyme, a Sanofi company) compares eliglustat with imiglucerase in patients who had reached pre-specified therapeutic goals on enzyme replacement therapy. MethodsENCORE is a randomized (2:1 eliglustat: imiglucerase), controlled, open-label non-inferiority trial of 159 patients previously receiving enzyme replacement therapy for ≥ 3 years who had met therapeutic goals. The primary efficacy endpoint was percent of patients remaining stable after 52 weeks of treatment (using a pre-specified composite of spleen, liver, hemoglobin, and platelet parameters). ResultsAs this was a non-inferiority trial, efficacy analyses were done on the per protocol population, which consisted of 99 eliglustat and 47 imiglucerase patients. Eliglustat was statistically non-inferior to imiglucerase: 84% of eliglustat and 94% of imiglucerase patients maintained goals for all 4 parameters (lower bound of 95% CI of difference [-18.6%] within the pre-specified [-25%] non-inferiority margin). Individually, 94% of eliglustat patients maintained stability criteria for spleen, 95% for hemoglobin, 96% for liver, and 93% for platelets. Of the 16/99 eliglustat patients who did not meet stability criteria based on change from baseline, most patients (13/16) maintained absolute values for the individual endpoints that remained within published therapeutic goals (Pastores Semin Hematol, 2004). Baseline bone mineral density scores were normal in most patients and remained normal on eliglustat. Two eliglustat patients and one imiglucerase patient (2% in each arm) discontinued because of an adverse event. Over the course of 52 weeks, 4 adverse events were observed with ≥ 10% incidence compared with imiglucerase: fatigue (14% vs. 2%) headache (13% vs. 2%), nausea (12% vs 0%), and upper abdominal pain (10% vs. 0%). The majority of adverse events were mild or moderate in severity for both groups. There were no treatment-related serious adverse events. ConclusionsIn the Phase 3 ENCORE study, eliglustat was well tolerated and was non-inferior to imiglucerase in maintaining stability for 52 weeks in previously treated patients with Gaucher disease type 1. Disclosures:Burrow:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin: Consultancy, Honoraria. Balwani:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cox:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Drelichman:Genzyme, a Sanofi company: Consultancy, Honoraria. Cravo:Genzyme, a Sanofi company: Consultancy, Honoraria. Martins:Genzyme, a Sanofi company: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria; Actelion: Consultancy, Honoraria; Biomarin: Consultancy, Honoraria. Lukina:Genzyme, a Sanofi company: Consultancy, Honoraria, Speakers Bureau. Rosenbloom:Genzyme, a Sanofi company: Consultancy, Honoraria. Ross:Genzyme, a Sanofi company: Employment. Angell:Genzyme, a Sanofi company: Employment. Puga:Genzyme, a Sanofi company: Employment.

Diagnosis and Management of Hematological Manifestations of Gaucher Disease

Gaucher disease (GD) is a lysosomal storage disorder that occurs due to an inherited inborn error of metabolism. GD manifested due to the deficient activity of the glucocerebrosidase enzyme that results in the accumulation of the harmful glucocerebrosides glycolipids in different body cells. There are three main types of GD that differ from each other in their clinical presentations. Type I characterized by the absence of any neurological involvement, unlike Type II and Type III. Patients with Gaucher can be presented with visceral manifestations (including splenomegaly, hepatomegaly, or abdominal pain), hematological manifestation (anemia or thrombocytopenia or bleeding diathesis), bone manifestations (painful limbs or pathological fractures), or neurological manifestations (including neck rigidity, swallowing disorder, or oculomotor paralysis). In the Middle East, especially Saudi Arabia, a higher prevalence of genetic diseases was observed compared to reported rates in Europe and the United States. However, published data on the characteristics and treatment patterns of Gaucher patients in Saudi Arabia are still lacking in the literature. Therefore, the present manuscript aimed to present an overview of the GD situation in Saudi Arabia by bringing together a panel of Saudi hematology experts to share their views on current trends and practices in Saudi Arabia regarding GD. The experts agreed that there is no available data regarding the prevalence and incidence of GD in Saudi Arabia, therefore the experts recommend establishing a national registry for Gaucher cases. The diagnosis of GD is challenging as the disease is rare and obscure, even to hematologists. The experts also recommend shifting from the dried blood spots test to genetic testing in the future to confirm the diagnosis of GD. The experts agreed on the need to organize awareness campaigns to familiarize the primary care physicians and junior hematologists about the common presentations and management of GD.

Long-Term Hematologic Response to Oral Eliglustat in Treatment-Naive Patients with Gaucher Disease Type 1: Final Results from a Phase 2 and the Phase 3 Engage Trials

Introduction:Gaucher disease is caused by deficient activity of the lysosomal enzyme acid β-glucosidase, leading to accumulation of glucosylceramide primarily in macrophages (Gaucher cells). Thrombocytopenia, anemia, hepatosplenomegaly, and skeletal disease are common presenting symptoms and hematologists often identify and manage the disease. Eliglustat is an oral substrate reduction therapy approved as first-line treatment for adults with Gaucher disease type 1 (GD1) who have poor, intermediate, or extensive CYP2D6-metabolizer phenotypes (>90% of patients). Unlike enzyme replacement therapy (the historic standard of care), which supplements lysosomal acid β-glucosidase in mononuclear phagocytes and is administered in biweekly infusions, oral eliglustat reduces glucosylceramide accumulation by partially inhibiting glucosylceramide synthase.Methods:We report on improvements in hemoglobin concentration and platelet count in two completed clinical trials of eliglustat in treatment-naïve adults with GD1: an open-label Phase 2 trial (N=26, NCT00358150), for which 8-year data are available, and a randomized, placebo-controlled Phase 3 trial (ENGAGE, N=40, NCT00891202) for which 4.5-year data are available. Both trials were sponsored by Sanofi Genzyme.Results:In the Phase 2 trial, the primary endpoint was met after 1 year, with 77% of patients improving in at least 2 of 3 main efficacy parameters (spleen volume, hemoglobin level, and platelet count) (Lukina et al. Blood 2010;116:816). Improvements continued or were maintained throughout the trial. Among patients with 8 years of data (n=19), mean (±SD) hemoglobin level and mean platelet count increased by 2.1±1.7 g/dL (from 11.3±1.6 to 13.4±1.3 g/dL) and 110% (from 67.5±21.1 to 130.7±59.8 x109/L), respectively, after 8 years of eliglustat. In the Phase 3 ENGAGE trial, all primary and secondary endpoints were met, with clinically meaningful improvements from baseline in platelet and hemoglobin levels and spleen and liver volumes at 9 months in eliglustat- but not placebo-treated patients (Mistry et al. JAMA 2015;313;695). During the trial extension, in which all patients received eliglustat, patients switching from placebo had the same magnitude and time course of improvement during the first 9 months as was seen with eliglustat patients in the primary analysis and all patients continued to improve over time with continued eliglustat treatment. Among patients with 4.5 years of eliglustat treatment (n=14), mean (±SD) hemoglobin level increased by 1.4±1.31 g/dL (from 12.0±2.0 g/dL to 13.4±1.9 g/dL) and mean platelet count increased by 87% (from 69.6±18.5 to 122.6±34.1 x109/L). In both trials, hematologic improvements were accompanied by clinically significant decreases in spleen and liver volumes, improvements in bone parameters, and substantive reductions in Gaucher disease biomarkers. In both trials, eliglustat was generally well-tolerated, with three withdrawals due to adverse events in the Phase 2 trial (one of which was considered related to eliglustat) and no withdrawals due to adverse events during the ENGAGE trial. Most adverse events in both trials were non-serious, considered unrelated to eliglustat, and either mild or moderate in severity.Conclusions:In previously untreated patients with GD1, clinically meaningful improvements in hematologic parameters continued or were maintained over time after 8 years of treatment with eliglustat in the Phase 2 trial and after 4.5 years of eliglustat in the Phase 3 ENGAGE trial. DisclosuresLau:Sanofi Genzyme: Other: Principal Investigator in the eliglustat Phase 2 and ENGAGE clinical trials . Lukina:Sanofi Genzyme: Honoraria, Other: Principal investigator in the eliglustat Phase 2, ENGAGE, ENCORE, and EDGE clinical trials; receives travel reimbursement; Shire: Honoraria, Other: travel reimbursement. Mistry:Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Principal investigator in the eliglustat ENGAGE and ENCORE clinical trials; received travel reimbursement, Research Funding. Wu:Sanofi Genzyme: Employment. Gaemers:Sanofi Genzyme: Employment. Peterschmitt:Sanofi Genzyme: Employment.

Health-Related Quality of Life of Twenty-Seven Patients with Gaucher Disease Type I in China

Gaucher disease (GD) is a lysosomal storage disorder characterized by the deficiency of beta-glucocerebrosidase which results in the accumulation of the glucocerebroside in macrophages throughout the body. Gaucher disease Type 1 (GD1) is the most common form. Enzyme replacement therapy (ERT) with Imiglucerase is effective for the disease. So far there is no study on the Health-Related Quality of Life (HRQoL) for patients with GD1 in China. Objects: To investigate the quality of life (QOL) of GD1 patients followed-up in Peking Union Medical Colleague Hospital(PUMCH) and analyze the possible influence factors. Method: Twenty-seven patients with GD1 diagnosed from Jan.1994 to Jul.2017 in PUMCH who were more than 18-year-old at the time of survey and willing to join the study were included. Clinical and social data form the patients were collected and Short form-36 (SF-36) score was calculated for each patient. Factors which may affect the score were further evaluated using statistical method. Results: Of the twenty-seven patients, twenty-two patients (81.5%)had received and continued to receive adequate dosage of ERT (kindly provided by Sanofi investment Co. Ltd) while the other five patients did not receive any GD related therapy. Sex, age of survey, age of disease onset, education background and economy income of the patients were shown in table 1. Next we compared the eight dimensions of SF-36 between the GD1 patients and the aged matched controls in China (from the literature). Most SF-36 scores were lower in GD1 patients, but the general health perceptions, vitality and mental health in ERT patients of 18-44 year-old were similar to those of the health controls (table 2). Further analysis of twenty-two patients treated with ERT showed age of survey had negative effect on the eight dimensions of SF-36 score while age of disease onset negatively influenced the role-physical, body pain and vitality. Time from disease onset to treatment had negative relationship with physical functioning, general health perceptions and social functioning (table 3). Conclusions: Patients in our center mainly live in undeveloped area with lower education background and lower income. Patients had lower QOL compared with normal controls but younger patients who receiving ERT may benefit in some of the dimensions of SF-36. Age of survey, age of disease onset and time from disease onset to treatment may influence the QOL in patients with ERT. DisclosuresNo relevant conflicts of interest to declare.

In Vitro Erythropoietic Response to Enzyme Replacement Therapy in Gaucher Type 1 Patients

Introduction. Gaucher disease type 1 (GD, OMIM #230800) is the most common inherited lysosomal storage disorder resulting from lysosomal glucocerebrosidase (GBA, acid-β-glucosidase) deficiency and subsequent accumulation of glucosylceramide in macrophages. This leads to anemia, thrombocytopenia and coagulopathy, visceral (hepatosplenomegaly, lungs) and skeletal manifestations (deformities, fractures, avascular osteonecrosis). Anemia is attributed to bone marrow infiltration by Gaucher cells, to inflammation and to the presence of splenomegaly; however the underlying pathophysiological mechanism hasn't been fully elucidated.Aim. The aim of this study is to evaluate the in vitro erythroid status at baseline (T0) and the response to Enzyme Replacement Therapy (ERT) after 6 months (T1) and 1 year (T2). We evaluated the expansion and differentiation in erythroid cultures of CD34+ cells obtained from peripheral blood of GD type 1 patients at diagnosis before starting ERT (T0), at 6 months (T1) and at 1 year (T2) of ERT.Methods. CD34+ cells were obtained by immunomagnetic separation from peripheral blood mononuclear cells of GD patients (n=3) and controls (n=5). Isolated CD34+ were evaluated by in vitro clonogenic capacity assays using the methylcellulose semisolid culture medium after 14-16 days of culture. Hematopoietic colonies (burst-forming unit-erythroid (BFU-E) and colony-forming unit-macrophage (CFU-M)) were scored with an inverted microscope. CD34+ cells were expanded in StemSpan medium, 1% StemSpan CC100 cytokine cocktail, 2 U/ml Erythropoietin (EPO) and 1 μM dexamethasone. Differentiation was induced in StemSpan medium with 10 ng/ml SCF and 10 U/ml EPO. Proliferation and surface marker expression (CD34, CD45, Glycophorine A, CD71) were examined by flow cytometry. Cell morphology was analyzed on cytocentrifuged smears stained with May-Grunwald-Giemsa.Results. At T0 we observed a higher number of BFU-E in GD samples (126±23 BFU-E/105 cells) compared to controls (49±12 BFU-E/105 cells) (Tab.1). Similarly, higher macrophage CFU-M were observed in GD samples (29±12 CFU-M/105 cells) compared to controls (10±1 CFU-M/105 cells) (Tab.1). The BFU-E and CFU-M morphology showed no difference between GD patients and controls. The increased proliferation of erythroid precursors of GD patients was associated to impaired ability to differentiate in liquid cultures after 14 days (45,9% proerythroblasts and only 4% polichromatophilic erythroblasts) compared to controls (27% and 19%, respectively) (Tab.1). Flow cytometry confirmed an impaired differentiation of GD erythroblasts compared to controls at day 14 of the erythroid liquid cultures, as shown by high percentage of CD71high/GlyAlow early erythroid precursor cells and low percentage of CD71high/GlyAhigh mature erythroblasts (GD: 73,9 and 4,9%, respectively; controls: 67,2 and 22.4%, respectively) (Fig.1). In samples from GD patients, after 1-year treatment with ERT (T2), we observed a reduction in the number of BFU-E compared to T0, reaching values similar to controls (GD T0: 126±23 BFU-E/105 cells, T2: 41±11 BFU-E/105 cells; controls: 49±12 BFU-E/105 cells) and an increased number of mature erythroid cells generated in GD liquid cultures (Tab. 1). Also CFU-M were reduced at T2 compared to T0 (GD T0: 29±12 CFU-M/105 cells, T2: 8±5 CFU-M/105 cells; controls: 10±1 CFU-M/105 cells) (Tab.1). An increased percentage of more differentiated erythroid cells at T2 compared to T0 was confirmed by flow cytometry in cultures from GD patients, as shown by low percentage of the CD71high/GlyAlow early erythroid precursor cells and high percentage of CD71high/GlyAhigh mature erythroblasts on day 14 (GD: 44,7 and 45,6%, respectively; controls: 67,2 and 22.4%, respectively) (Fig.1).Conclusions. These preliminary data suggest that anemia in GD might partly be related to a delay in erythroid differentiation. ERT treatment seems to correct the dyserythropoiesis by improving erythroid differentiation. Since glucosylceramide accumulates in macrophages, that are key elements in the erythroid niche, impaired erythroid differentiation might be related to the pathological micro-environment, rather than intrinsic hematopoietic stem cell defect. More extensive studies are needed to better understand the pathophysiology of anemia and pancytopenia of this rare disease.This study was partially supported by Sanofi Genzyme. [Display omitted] DisclosuresCappellini:Celgene: Honoraria; Novartis: Speakers Bureau; Vifor: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding, Speakers Bureau.

Diffusion tensor imaging of vertebral bone marrow in children with Gaucher's disease type I and III: Pre- and post-therapy

PurposeTo assess diffusion tensor imaging (DTI) of the vertebral bone marrow (BM) in children with Gaucher's disease (GD) types I and III before and after therapy. MethodsProspective study was conducted upon 25 children with GD type I (n = 17) and III (n = 8) and 13 age and sex-matched controls underwent DTI of vertebral BM. Mean diffusivity (MD) and fractional anisotropy (FA) of vertebral BM was calculated and correlated with genotyping, chitotriosidase, hemoglobin (HB) and, platelet count. ResultsThere was a statistically significant difference in MD and FA of BM between patients and controls (P = 0.001 and 0.02). The area under the curve (AUC) of MD and FA used to differentiate untreated patients from controls was 0.902 and 0.68 with sensitivity, specificity, and, accuracy 92%, 84.6%, and, 89.5% respectively. There was a significant difference in MD and FA of BM between untreated and treated patients (P = 0.001 and 0.02). AUC of MD and FA used to differentiate untreated from treated patients was 0.93 and 0.649 with sensitivity, specificity, and accuracy of 92%, 80%, and 86% respectively. There was a significant difference in MD and FA (P = 0.03, 0.001 respectively) of BM in GD with homozygous L444P mutation (n = 9) and other mutations (n = 14). Chiotriptase, HB and platelet count of patients was correlated with MD (r = −0.36, 0.42, −0.41) and FA (r = −0.47, −0.37, −0.46) respectively. ConclusionDTI of vertebral BM can help in diagnosis and monitoring patients with GD after therapy and correlated with genotyping, and hematological biomarkers of GD.

Cardiac Manifestations in a Group of Romanian Patients with Gaucher Disease Type 1 (a Monocentric Study).

Gaucher disease (GD), one of the most common lysosomal disorders, is characterised by clinical heterogeneity. Cardiac involvement is rare and refers to pulmonary hypertension (PH), valvular abnormalities and myocardial infiltrative damage. The aim of this study was to evaluate cardiac involvement in a group of Romanian GD patients. Phenotypic and genotypic characterisation was carried out in 69 patients with GD type 1. Annual echocardiography and electrocardiography were performed to assess pulmonary pressure, morphology and function of the valves and electrocardiographic changes. Nine patients (13%) exhibited baseline echocardiographic signs suggesting PH. Mitral regurgitation was present in 33 patients (48%) and aortic regurgitation in 11 patients (16%). One patient presented aortic stenosis. Significant valvular dysfunction was diagnosed in 10% of patients. PH was associated with greater age (p < 0.001), longer time since splenectomy (p = 0.045) and longer time between clinical onset and the start of enzyme replacing therapy (p < 0.001). Electrocardiographic changes were present in five patients (7%).

Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Gaucher Disease: Case Report

Gaucher disease is the most common lysosomal storage disease. It is marked by deficient glucocerebrosidase enzyme activity, leading to elective accumulation of its substrate in the lysosomes of macrophages. Macrophages are most often deposited in the liver, spleen and bone marrow, creating typical symptomatology in these organs. It is a genetic disorder with autosomal recessive inheritance pattern. The extent of the damage and severity of the symptoms increase in proportion to the genetic damage in the culprit gene, GBA1. As a result, the symptoms and course of the disease may range from mild to quite acute, with potential death of the patient at a young age. Case: Patient, 29, was diagnosed with Gaucher disease type 1 and underwent enzyme replacement therapy, with satisfactory response. Along with the common symptoms of the disease, he had also developed the rare Erlenmeyer flask deformity.

The International Collaborative Gaucher Group GRAF (Gaucher Risk Assessment for Fracture) score: a composite risk score for assessing adult fracture risk in imiglucerase-treated Gaucher disease type 1 patients

BackgroundFractures in Gaucher disease type 1 (GD1) patients cause significant morbidity. Fracture risk may be decreased by enzyme replacement therapy (ERT) but not eliminated. When considering initiation of treatment, it is useful to know to what extent fixed patient-specific factors determine risk for future fractures beyond standard risk factors that change with time and treatment, such as decreased bone mineral density. We developed a tool called the GRAF score (Gaucher Risk Assessment for Fracture) that applies 5 widely available characteristics (sex, age at treatment initiation [ATI], time interval between diagnosis and treatment initiation, splenectomy status, history of pre-treatment bone crisis) and provides a practical method to assess future fracture risk when imiglucerase ERT is initiated.MethodsInclusion criteria: GD1 patients in the International Collaborative Gaucher Group Gaucher Registry as of September 2019 initially treated with alglucerase/imiglucerase; known splenectomy status; at least one skeletal assessment on treatment (3216 of 6422 patients). Data were analyzed by ATI group (< 18, ≥ 18 to < 50, or ≥ 50 years of age) using Cox proportional hazards regression with all 5 risk factors included in the multivariable model. A composite risk score was calculated by summing the contribution of each parameter weighted by the strength of its association (regression coefficient) with fracture risk.ResultsPatients were followed from the date of treatment initiation (or age 18 years for patients if treatment started earlier) to the date of first adult fracture (n = 288 first fracture endpoints), death, or end of follow-up. The GRAF score for each ATI group was associated with a 2.7-fold increased risk of adult fracture for each one-point increase (p < 0.02 for < 18 ATI, p < 0.0001 for ≥ 18 to < 50 ATI and ≥ 50 ATI).ConclusionsThe GRAF score is a tool to be used with bone density and other modifiable, non-GD-specific risk factors (e.g. smoking, alcohol intake, frailty) to inform physicians and previously untreated GD1 patients about risk for a future fracture after starting imiglucerase regardless of whether there is an eventual switch to an alternative ERT or to substrate reduction therapy. GRAF can also help predict the extent that fracture risk increases if initiation of treatment is further delayed.

A qualitative study of the experience of venglustat for patients with Gaucher disease type 3 (GD3) in LEAP: A phase II open-label, multicenter, multinational study

A qualitative study of the experience of venglustat for patients with Gaucher disease type 3 (GD3) in LEAP: A phase II open-label, multicenter, multinational study

Lyso-Gb1 levels in sisters with Gaucher disease type 1: A case report

Lyso-Gb1 levels in sisters with Gaucher disease type 1: A case report

Venglustat combined with imiglucerase positively affects neurological features and brain connectivity in adults with Gaucher disease type 3

Venglustat combined with imiglucerase positively affects neurological features and brain connectivity in adults with Gaucher disease type 3

Transition to eliglustat in an individual with Gaucher disease type 1 on antipsychotic medication

Transition to eliglustat in an individual with Gaucher disease type 1 on antipsychotic medication

Hematologic malignancies and monoclonal gammopathy of undetermined significance in Gaucher disease type 1 patients in the International Collaborative Gaucher Group Gaucher Registry

Hematologic malignancies and monoclonal gammopathy of undetermined significance in Gaucher disease type 1 patients in the International Collaborative Gaucher Group Gaucher Registry

Uncovering the burden of Gaucher disease type 1: Patient perspectives on unaddressed symptoms, impact of disease, and the future of treatment

Uncovering the burden of Gaucher disease type 1: Patient perspectives on unaddressed symptoms, impact of disease, and the future of treatment