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Type 1 Gaucher Disease (type 1 + gaucher_disease)

Distribution by Scientific Domains

Medical Sciences	90%

Selected Abstracts

The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2009
Tamar H. Taddei
Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross-sectional study. In addition, the relative risk (RR) of cancer in patients compared with age-, sex-, and ethnic-group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% CI 9.17,54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% CI 1.49,6.79), and overall cancer risk (RR 1.80, 95% CI 1.32,2.40) was increased. Homozygous N370S GD leads to adult-onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source]

Long-Term Outcomes of Liver Transplantation in Type 1 Gaucher Disease

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010
R. M. Ayto
Gaucher disease (GD) is the most prevalent lysosomal storage disorder. Enzyme replacement therapy (ERT) has demonstrable efficacy in reversing clinical and pathological manifestations of GD. We report four patients with GD and severe hepatic impairment who were successfully treated by orthotopic liver transplantation. Liver failure resulted from GD in two patients and due to a comorbidity in two others (HCV and autoimmune chronic active hepatitis). Following successful liver transplantation, patients received long-term ERT. Liver transplantation is a life-saving treatment for end-stage liver disease in patients with Gaucher disease. All four patients have had excellent outcomes from liver transplantation for up to 10 years postprocedure with no evidence of Gaucher-related pathology in the graft. [source]

Hyperferritinemia and iron overload in type 1 Gaucher disease,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2010
Philip Stein
Hyperferritinemia occurs in Gaucher disease but its clinical spectrum or its association with systemic iron overload and HFE mutations are not known. In 114 patients with Type 1 Gaucher disease, we determined serum ferritin, transferrin saturation and HFE genotype. The results were correlated with the extent of hepatosplenomegaly, overall Gaucher disease severity score index, and response to enzyme replacement therapy. In a subset of patients with radiological and/or laboratory evidence of systemic iron overload, liver biopsy was performed. There was a mean 3.7-fold elevation of serum ferritin over the upper limit of normal (ULN). Prior splenectomy was associated with most severe hyperferritinemia compared to patients with intact spleen (6.53 × ULN vs. 2.69 × ULN, P = 0.003). HFE genotyping revealed two patients homozygous for H63D mutation and 30% of patients heterozygote carriers of H63D mutation; no patients harbored C282Y mutation; there was no correlation of ferritin with HFE genotype. Ferritin level correlated with liver volume (Pearson correlation coefficient = 0.254, P = 0.035) and it was negatively correlated with hemoglobin (r = ,0.315, P = 0.004); there was no relationship with other indicators of Gaucher disease activity. Enzyme replacement therapy (ERT) resulted in amelioration of hyperferritinemia: 707 ± 898 ng/ml vs. 301 ± 310 ng/ml (P = 0.001), transferrin saturation remained normal. Three patients were suspected of clinical iron overload, confirmed on liver biopsy. Iron accumulation was variably noted in hepatocytes and Kupffer cells. There is a high prevalence of hyperferritinemia in Type 1 Gaucher disease that is associated with indicators of disease severity, reversed by ERT and is not related to HFE mutations. Am. J. Hematol. 2010. © 2010 Wiley-Liss, Inc. [source]

Expanding spectrum of the association between Type 1 Gaucher disease and cancers: A series of patients with up to 3 sequential cancers of multiple types,Correlation with genotype and phenotype,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2010
Sarah M. Lo
In Gaucher disease (GD), inherited deficiency of lysosomal glucocerebrosidase due to mutations in GBA1 gene results in accumulation of glucosylceramide in tissue macrophages, systemic macrophage activation, and a complex multisystemic phenotype. We and others have reported an increased risk of multiple myeloma and other malignancies in non-neuronopathic Type 1 GD (GD1). Here, we describe a subset of GD1 patients with multiple malignancies. In our cohort of 403 patients with GD1, nine patients (2.2%) developed two or three different types of cancers either consecutively or simultaneously. Patients were characterized by age at diagnosis of GD1, GBA1 genotype, disease severity, age at cancer diagnosis, enzyme replacement therapy (ERT) status, and splenectomy status. Of the nine patients, six developed two types of malignancies and three had three cancers each. Overall, the hematologic malignancies comprised lymphoma/leukemia (4) and multiple myeloma (4). Nonhematologic malignancies included colon (2), lung (2), thyroid (2), and prostate cancer (1). Of the seven patients who received ERT, the first cancer was diagnosed before initiation of ERT in all but one. Asplenic patients were more likely to have single or multiple cancers compared with patients with intact spleens (P < 0.0072 and P < 0.0203, respectively). Our data strengthen the association of GD1 and cancer and suggest that patients may be at risk of developing multiple malignancies. We found an association between splenectomy and multiple cancers in GD1. It will be of interest to determine whether timely ERT and declining rates of splenectomy will translate into declining rates of multiple and single cancers. Am. J. Hematol. 2010. © 2010 Wiley-Liss, Inc. [source]

Hyperferritinemia and iron overload in type 1 Gaucher disease,

Miglustat (Zavesca®) in type 1 Gaucher disease: 5-year results of a post-authorisation safety surveillance programme

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 9 2009
Carla E. M. Hollak MD
Abstract Purpose Miglustat (Zavesca®) is an orally-available substrate reduction therapy (SRT) for treatment of mild-to-moderate type 1 Gaucher disease (GD1) in adult patients unsuitable for enzyme replacement therapy (ERT). Miglustat has not been evaluated in children with GD1, and is not used during pregnancy and breast-feeding. A non-interventional, prospective, web-based safety surveillance programme was initiated at the time of the European launch of miglustat in 2003, and is ongoing. We report the first 5 years of collected data, focusing on neurological manifestations. Methods Data were collected on 122 GD1 patients between March 2003 and April 2008, representing 244 patient-years cumulative miglustat post-authorisation experience. The electronically-captured data collected from participating physicians includes patient demographics, prior and current therapies, baseline disease manifestations and concurrent conditions, disease severity, duration of miglustat exposure, and safety-relevant information. Results Mean (SD) age at baseline was 46.1 (16.5) years. At baseline, bone disease and neurological manifestations were reported in 55.6 and 28.6% of patients, respectively; the latter included peripheral neuropathy (7.2%) and a wide variety of neurological symptoms and signs. In addition, 23.2% had other health conditions relevant to neurological status. During the reporting period, new neurological manifestations were reported in 23 (18.9%) patients, principally tremor. Thirty-five (28.7%) patients discontinued treatment, predominantly for gastrointestinal (GI) disturbances (11.5%), two-thirds of which occurred during the first 6 months. Conclusion The safety profile of miglustat in GD1 patients included in the safety surveillance programme is overall consistent with that reported in the registration and other clinical trials, and no new safety finding was identified. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis

BRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2009
Pramod K. Mistry
Summary Data from the International Collaborative Gaucher Group Gaucher Registry were analysed to assess the relationship between enzyme replacement therapy with imiglucerase (ERT) and incidence of avascular necrosis (AVN) in type 1 Gaucher disease (GD1), and to determine whether the time interval between diagnosis and initiation of ERT influences the incidence rate of AVN. All patients with GD1 enrolled in the Gaucher Registry who received ERT and did not report AVN prior to starting therapy (n = 2700) were included. The incidence rate of AVN following initiation of ERT was determined. An incidence rate of AVN of 13·8 per 1000 person-years was observed in patients receiving ERT. Patients who initiated ERT within 2 years of diagnosis had an incidence rate of 8·1 per 1000 person-years; patients who started ERT ,2 years after diagnosis had an incidence rate of 16·6 per 1000 person-years. The adjusted incidence rate ratio was 0·59 [95% confidence interval (CI) 0·36,0·96, P = 0·0343]. Splenectomy was an independent risk factor for AVN (adjusted incidence rate ratio 2·23, 95% CI 1·61,3·08, P < 0·0001). In conclusion, the risk of AVN was reduced among patients who initiated ERT within 2 years of diagnosis, compared to initiating treatment ,2 years after diagnosis. A higher risk of AVN was observed among patients who had previously undergone splenectomy. [source]

The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease

CLINICAL GENETICS, Issue 3 2007
J Charrow
The effect of enzyme replacement therapy (ERT) on bone crisis and bone pain was investigated in patients with Gaucher disease (GD) type 1 followed over 4 years. Data from the International Collaborative Gaucher Group Gaucher Registry were used. Only patients with bone crisis and/or bone pain data for 1 year prior to ERT, and for each of 3 years after the start of ERT, were included. Bone crises were reported in 17% of patients during the year before starting ERT. The frequencies of bone crises decreased to 5%, <1% and 3% for 1, 2, and 3 years after initiation of treatment, respectively (p < 0.0001). Bone pain followed a similar pattern of response. Bone pain was reported in 49% of patients the year before treatment and decreased to 30% in the first year, 29% in the second year, and 30% in the third year of ERT (p < 0.0001). ERT is associated with a reduction in bone crisis and bone pain in patients with GD type 1 . This study shows that significant improvements in symptoms of skeletal disease are achievable clinical outcomes and treatment goals in GD type 1. [source]