Uveitis and Fabry disease.
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Fabry Disease↗
Biomedical subjects
D Elstein
Publications and source records attributed to D Elstein.
Anaesthesia for total hip replacement in Gaucher's disease.
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Adolescent↗
Fibromyalgia and Gaucher's disease.
BACKGROUND: Patients with symptomatic Gaucher's disease sometimes have non-specific symptoms (such as general malaise with widespread musculoskeletal pains) that respond poorly to enzyme replacement treatment. These may indicate fibromyalgia syndrome; if so, other therapeutic options might be more appropriate. AIM: To identify patients with Gaucher's disease for whom fibromyalgia-specific therapy may be therapeutic. DESIGN: Questionnaire-based survey. METHODS: Adult patients (n = 109) with non-neuronopathic Gaucher's disease and adult healthy controls (n = 108) completed health-related questionnaires including the Fibromyalgia Impact Questionnaire, and underwent testing with a dolorimeter to ascertain sensitivity at 22 tender points. RESULTS: Six patients, but no controls, met the criteria for fibromyalgia. Patients with fibromyalgia had a significantly greater incidence of co-morbidities (p = 0.014) relative to other patients with Gaucher's disease; four suffered from bone involvement and were receiving enzyme therapy, but two were untreated. DISCUSSION: The presence of fibromyalgia-specific trigger points may result from multiple aetiologies, or may be an independently-sorting predisposition. Our findings cannot distinguish between these possibilities, but if fibromyalgia were the cause, enzyme replacement therapy would be expensive and inappropriate.
Adolescent↗
Anesthesia for obstetric patients with Gaucher disease: survey and review.
Pregnancy and delivery in patients with non-neuronopathic Gaucher disease, whether treated with enzyme replacement or untreated, are usually uncomplicated. Various factors may influence mode of delivery, vaginal or cesarean section, as well as type of anesthesia, general or regional, used during delivery. This retrospective review was intended to highlight some of the practical issues relating to obstetric anesthetic management, based on a review of the literature and experiences from a large referral clinic for Gaucher disease. In the past decade, there were 16 deliveries in 11 women in our institution. There were five normal vaginal deliveries, two vacuum extractions, one placental extraction, and eight cesarean sections. Platelet counts were 27-215 x 10(9)/L. Two spontaneous deliveries and one vacuum extraction were performed under epidural anesthesia; two other women having vaginal deliveries and one vacuum extraction were given i.v. analgesia; the fifth was given i.v. patient-controlled analgesia. The placental extraction was performed under general anesthesia. Seven of the women having cesarean deliveries received spinal anesthesia; the breech presentation required general anesthesia. There were no anesthesia-related side effects or complications, although there were some instances of post-partum bleeding irrespective of enzyme therapy. Gaucher disease affects multiple organs and can be a challenge to the anesthesiologist. Based on this survey we suggest that anesthetic management requires particular attention to hematological parameters before delivery. A multidisciplinary approach and extensive communication among obstetrician, hematologist and anesthesiologist is required to anticipate the possibility of post-partum hemorrhage, and preclude skeletal damage.
Adult↗
Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease.
It has been shown that treatment with miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer-term efficacy and safety data. Patients who had completed 12 months of treatment with open-label miglustat (100-300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p =0.007), and 1.30 g/dl at month 36 (p =0.013). The mean platelet count at month 36 increased from baseline by 22 x 10(9)/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12-month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.
1-Deoxynojirimycin↗
The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement.
N-Butyldeoxynojirimycin (NB-DNJ, miglustat 'Zavesca') is an orally active iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage-targetted enzyme replacement using intravenous mannose-terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease.
Clinical Trials as Topic↗
Decreased salivary output in patients with Gaucher disease.
BACKGROUND: Gaucher disease, the most common sphingolipid storage disease, results in accumulation of glucocerebroside in macrophages or "Gaucher cells". In a preliminary screening of 109 patients with type I disease, when asked specifically about dry mouth, approximately one quarter claimed to suffer from this symptom. AIM: To ascertain whether decreased salivary output is a feature of Gaucher disease. DESIGN: Prospective case-control study. METHODS: Salivary output was measured in 65 adult patients and 65 healthy controls using the Saxon test with Hochberg's modification. RESULTS: Mean salivary output was 1.91+/-1.19 g/min in the patient group vs. 2.74+/-1.17 g/min in the control group (p<0.001). This difference was greater among males. These results were not improved in the patients receiving enzyme replacement therapy, which is effective in ameliorating most Gaucher-related signs and symptoms. DISCUSSION: Recent studies have implicated an association between sicca syndrome and viral hepatitis C infection, which may imply an immunological trigger for these findings, but in this specific cohort, only three patients were reactive for hepatitis C. Follow-up of patients, both untreated and receiving enzyme therapy, is needed to delineate the association with salivary hypofunction, and ascertain whether enzyme therapy may induce sicca symptoms.
Adult↗
The interleukin-6 promoter polymorphism in Gaucher disease: a new modifier gene?
BACKGROUND: Individuals with Gaucher disease vary significantly with regard to degree of bone disease, but there are no predictive markers for severity of skeletal involvement. AIM: To determine the frequency of polymorphisms of interleukin-6 (IL-6) among patients with Gaucher disease, and the relationship to bone mineral density (BMD) and other markers of disease severity. DESIGN: Case-control study. METHODS: Genotyping for the 174G --> C promoter polymorphism of IL-6 was performed in adult patients with Gaucher disease for whom there was concurrent bone mineral density (BMD) data and in healthy Ashkenazi Jewish controls. RESULTS: The prevalence of allelic variants (58% G/G, 36% G/C, and 6% C/C) was similar in Ashkenazi Jewish adults with Gaucher disease as in Ashkenazi Jewish controls, but significantly different (p < 0.05) from that reported among Caucasians. No statistically significant correlation was found between IL-6 genotypes and BMD or markers of severity of Gaucher disease. Patients with the C/C genotype had relatively mild Gaucher disease. DISCUSSION: The IL-6 polymorphisms appear to be distributed differently in Ashkenazi Jews than among other Caucasians. In Gaucher disease, the C/C genotype may be associated with a milder Gaucher phenotype, and may serve as a mitigating genetic modifier.
Adolescent↗
Plasma chitotriosidase activity in patients with beta-thalassemia.
Variable increases in chitotriosidase levels have been reported in Italian patients with beta-thalassemia major and intermedia. We measured plasma chitotriosidase levels in Israeli patients with beta-thalassemia to ascertain its use as a universal marker of disease and/or response to therapy. Chitotriosidase levels in 39 adults (16-53 years; 30 with beta-thalassemia major, 9 with intermedia), and in 14 children (0.7-15 years; 12 with beta-thalassemia major, 2 with intermedia) were compared with other measures of disease, such as ferritin, hemoglobin, liver function tests, and genotype. Plasma chitotriosidase levels were normal (0.37 +/- 0.04 mU/mL) in all children. Twelve adults (31%) had elevated levels (>1.33 mU/mL): 11 patients (37%) with thalassemia major and 1 patient (11%) with thalassemia intermedia. A significant correlation was only found between plasma chitotriosidase levels and ferritin levels, and with mean number of transfusions per year. The patient with the highest chitotriosidase (1,440 nmol/mL/hr) had the highest ferritin (5,175 microg/L), required the most transfusions per year (40), and had abnormal liver tests. Normal chitotriosidase levels in the pediatric cohort and increased levels in only some adults may reflect status of iron overload in macrophages; thus there may be a role for monitoring chitotriosidase in patients with beta-thalassemia. Our results confirm results of the Italian cohort; however, in the latter, a more universal correlation was noted and chitotriosidase levels were much higher.
Adolescent↗
High prevalence of complement C7 deficiency among healthy blood donors of Moroccan Jewish ancestry.
The incidence of the specific component deficiencies in various ethnic groups is not known, although there appears to be an ethnic predilection for C6 and C8alpha-gamma deficiencies in blacks, whereas C7 and C8beta deficiencies are predominantly noted in Caucasians. Infectious diseases, particularly recurrent meningococcal infections, are observed more commonly with late component deficiencies. In the current study, we have simplified the PCR technique by using site-directed mutagenesis and designer primers in a cohort of Israeli Moroccan Jewish blood donors to ascertain allele frequency in this ethnic group, which, based on earlier studies, was considered to be at risk for C7 deficiency. The total mutant allele frequency in this ethnic cohort was 1.1% of a total of 365 healthy Israeli Moroccan Jews, including one homozygote. The identification of mutant alleles was efficient and inexpensive, and hence a large cohort was studied. The finding of complement deficiency identifies individuals at risk for Neisserial infections, which are known to be potentially life-threatening. Conversely, when a patient of Moroccan ancestry is diagnosed with a Neisserial infection, it is important to determine the complement status.
Blood Coagulation Disorders↗
Inhibition of substrate synthesis as a strategy for glycolipid lysosomal storage disease therapy.
The glycosphingolipid (GSL) lysosomal storage diseases are caused by mutations in the genes encoding the glycohydrolases that catabolize GSLs within lysosomes. In these diseases the substrate for the defective enzyme accumulates in the lysosome and the stored GSL leads to cellular dysfunction and disease. The diseases frequently have a progressive neurodegenerative course. The therapeutic options for treating these diseases are relatively limited, and for the majority there are no effective therapies. The problem is further compounded by difficulties in delivering therapeutic agents to the brain. Most research effort to date has focused on strategies for augmenting enzyme levels to compensate for the underlying defect. These include bone marrow transplantation (BMT), enzyme replacement and gene therapy. An alternative strategy that we have been exploring is substrate deprivation. This approach aims to balance the rate of GSL synthesis with the impaired rate of GSL breakdown. The imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits the first step in GSL biosynthesis and has been used to evaluate this approach. Studies in an asymptomatic mouse model of Tay-Sachs disease have shown that substrate deprivation prevents GSL storage in the CNS. In a severe neurodegenerative mouse model of Sandhoff disease, substrate deprivation delayed the onset of symptoms and disease progression and significantly increased life expectancy. Combining NB-DNJ and BMT was found to be synergistic in the Sandhoff mouse model. A clinical trial in type I Gaucher disease has been undertaken and has shown beneficial effects. Efficacy was demonstrated on the basis of significant decreases in liver and spleen volumes, gradual but significant improvement in haematological parameters and disease activity markers, together with diminished GSL biosynthesis and storage as determined by independent biochemical assays. Further trials in type I Gaucher disease are in progress; studies are planned in patients with GSL storage in the CNS.
Animals↗
High prevalence of low serum vitamin B12 in a multi-ethnic Israeli population.
This study ascertained serum vitamin B12 levels among patients with Gaucher disease and among healthy Israelis. Serum B12 and metabolites' levels were studied in consecutive adult patients with Gaucher disease not treated with enzyme plus Ashkenazi Jewish neighbour-controls, together with healthy blood-donor volunteers of various ethnicities. Each group showed a high incidence of low serum B12 concentrations, with a 22.3% incidence among Ashkenazi Jews and 40% among patients with Gaucher disease. These findings raise questions on the individual and community levels of serum B12. We recommend evaluation of B12 levels among geographically contingent peoples.
Adult↗
Effect of ozone on neutrophil function in vitro.
The application of ozone is widely practised as a form of alternative medicine, particularly in Germany and Eastern Europe. Ozone major autohemotherapy (the return of a small amount of a patient's blood to the circulation after ex vivo exposure to ozone) has been reported to have a therapeutic effect in various pathological conditions, including ischemic, infectious, autoimmune and neoplastic disorders. Ozone has an effect on the expression of cytokines, adhesion molecules and acute phase reactants, which are responsible in part for the respiratory inflammatory response observed after exposure to this gas. The purpose of the present study was to investigate the effect of ozone administration ex vivo, at a concentration commonly used in major autohemotherapy, on peripheral blood neutrophil function in vitro. Blood drawn from healthy volunteers was studied for neutrophil adhesion, chemotaxis and O-2 production before and after exposure to 30 microg/ml ozone. There was no significant difference in adhesion and chemotaxis of neutrophils exposed to ozone versus unexposed cells. O-2 production was minimally decreased (20.3 +/- 5.0 vs. 22.1 +/- 5.5 nmol/106 cells/10 min, respectively; P=0.01), a reduction of no clinical significance. This study confirms that major autohemotherapy with ozone is safe as far as neutrophil function is concerned. Combined with previous data, it seems that well-designed clinical trials to assess the efficacy of major autohemotherapy would pose no danger to blood cell populations, and should be encouraged.
Adult↗
Outcome of total hip arthroplasty in patients with Gaucher disease.
This retrospective survey includes 29 total hip arthroplasties (THAs) in 23 patients with Gaucher disease, with heterogeneous techniques, with various prostheses, and performed by 9 different surgical teams. THA was discouraged in patients with Gaucher disease because of a tendency toward infection, poor bone matrix because of Gaucher cell infiltration, and deterioration of matrix with disease progression. Subjective assessment of pain and function, objective examination of outcome, and radiologic signs of loosening after THA were evaluated. In primary THAs, there was enhancement of quality of life, allowing restoration of full participation in normal activities; function was improved; radiologic evidence of loosening was low; and there were no infections. In revisions, the results were not as good. THA is recommended in this population using criteria comparable to those in other patients, with equally good results.
Activities of Daily Living↗
Lung involvement and enzyme replacement therapy in Gaucher's disease.
Symptomatic lung involvement in Gaucher's disease is relatively rare, being restricted to patients with other severe manifestations. We describe our experience in eight of 411 patients in our referral clinic, who presented with prominent pulmonary signs or symptoms. There were four adults and four children; all have been successfully treated with enzyme replacement therapy. Routine means of monitoring pulmonary status including clinical assessment, chest X-ray, pulmonary function tests, and high-resolution CT (HRCT) were used. Enzyme treatment resulted in decreased hepatosplenomegaly, improved haematological parameters, and increased well-being; There was decreased clubbing and decreased dyspnoea in some of the patients, although on radiology, lung pathology had not normalized. All four children showed improved respiratory compliance, with significant improvement of the radiological findings in one and unchanged disease in the others. Two adults showed improvement in oxygen saturation but worsening of pulmonary hypertension. On chest X-ray, both had increased interstitial markings; one had gradual progression of pulmonary artery accentuation and fine interstitial stable pattern on HRCT. The other two adults had no change in lung function or on chest X-ray, but on HRCT there was apparent improvement in one patient. There is great heterogeneity in presentation and response to enzyme therapy in patients with Gaucher's disease and symptomatic lung involvement. Clinically, some benefited significantly from enzyme therapy, but in contrast to the dramatic reduction in organomegaly, there was no normalization in pulmonary function or lung architecture.
Adolescent↗
Wandering spleen in a young girl with Gaucher disease.
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Child↗
How B12 deficiency can impact on the individual and how society can impact on B12 deficiency.
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Anemia, Macrocytic↗