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Ari Zimran

Publications and source records attributed to Ari Zimran.

At least 19 recordsLinked to original sources
PubMed2007

Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease.

UNLABELLED: The effect of ERT with imiglucerase on BMD in type 1 GD was studied using BMD data from the International Collaborative Gaucher Group Gaucher Registry. Data were analyzed for 160 untreated patients and 342 ERT-treated patients. Imiglucerase significantly improves BMD in patients with GD, with 8 years of ERT leading to normal BMD. INTRODUCTION: The objective was to determine the effect of enzyme replacement therapy (ERT; Cerezyme, imiglucerase) on BMD in type 1 Gaucher disease (GD). MATERIALS AND METHODS: The study population included all adults (men, 18-70 years; women, 18-50 years) enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry for whom lumbar spine BMD measurements were available. BMD data with up to 8 years of follow-up were analyzed for 160 patients who received no ERT and 342 patients treated with ERT alone. BMD was assessed by DXA of the lumbar spine. Z scores for patients with GD were compared with a reference population. From the model's estimate, percent of patients by age and sex with osteoporosis (T score < or = -2.5) were calculated. RESULTS: DXA Z scores for patients with GD in the no ERT (untreated) group were significantly below normal (y intercept = -0.80 Z score units, p < 0.001) and remained approximately 1 SD below the reference population over time (slope = -0.010 Z score units per year, p = 0.68). The DXA Z scores for patients with GD who received ERT at a dose of 60 U/kg/2 weeks were significantly lower than the reference population at baseline (y-intercept = -1.17 Z score units, p < 0.001), but improved significantly over time (slope = +0.132 Z score units per year, p < 0.001). A significant dose-response relationship was noted for the ERT group, with the slopes for the three main dosing groups of 15, 30, and 60 U/kg/2 weeks of +0.064, +0.086, and +0.132 Z score units per year, respectively. The BMD of patients with GD treated with ERT increased to -0.12 (60 U/kg/2 weeks), -0.48 (30 U/kg/2 weeks), and -0.66 (15 U/kg/2 weeks) SD of the mean of the reference population after 8 years of ERT, approaching the reference population. Estimated risk of osteoporosis of this GD population, if left untreated, ranged from approximately 10 to 30% in women and 10% to 25% in men. CONCLUSIONS: ERT with imiglucerase (Cerezyme) may increase BMD in patients with GD. Response to treatment with imiglucerase is slower for BMD than for hematologic and visceral aspects of GD. A normal (age- and sex-adjusted) BMD should be a therapeutic goal for patients with type 1 GD.

Absorptiometry, Photon↗
PubMed2006

Outcome of ten years' echocardiographic follow-up in children with Gaucher disease.

The non-neuronopathic form Gaucher disease, the most prevalent lysosomal storage disorder, is marked by tremendous phenotypic heterogeneity; cardio-pulmonary involvement is distinctly rare except in the most severely affected patients. With the advent of enzyme replacement therapy, most symptomatic patients will not suffer from lung disease. However, because of concern about pulmonary hypertension among adult patients exposed to enzyme replacement therapy, echocardiography has been recommended as an early warning system for routine follow-up of all patients, including children. The purpose of this study was to review the results of more than a decade of echocardiographic findings in children followed semi-annually in a large referral clinic in order to ascertain whether echocardiography as an early signal of pulmonary hypertension in children is appropriate. 330 echocardiographic examinations were performed in 71 children (276 patient follow-up years). Only four patients receiving enzyme therapy each had a single abnormal examination that upon repeat examination six months later reverted to within normal limits. There were no abnormal results among the untreated patients. Therefore, we feel comfortable with rescinding our recommendation with regard to routine echocardiographic examinations in children. At the present time we believe that a baseline examination to rule out abnormalities would be sufficient.

Adolescent↗
PubMed2006

Aggregation of red blood cells in patients with Gaucher disease.

Gaucher disease is associated with increased red blood cell (RBC) aggregation, but the pathophysiological significance of this phenomenon and its correlation with disease manifestations are unclear. RBC aggregation was evaluated in 43 patients with Gaucher disease and 53 healthy controls. Dynamic RBC aggregation was examined in a narrow-gap flow chamber at varying shear stress. Compared with the controls, RBC aggregation in Gaucher disease was increased by 25%. Comparison of RBC aggregation in autologous plasma and in dextran (500 kDa) showed an increase both in plasma-dependent (extrinsic) and -independent (intrinsic) RBC aggregation. Subgroup analysis revealed that increased RBC aggregation was limited to patients with an intact spleen. RBC aggregation in patients did not correlate with plasma fibrinogen concentration, disease severity, enzyme replacement therapy or genotype. We conclude that RBC aggregation is increased in patients with Gaucher disease and an intact spleen, possibly reflecting the accumulation of glucocerebroside and other substances in the plasma and RBC membranes of these patients. Our results do not support a role for RBC aggregation in the pathogenesis of vascular complications of Gaucher disease.

Adult↗
PubMed2006

Iliopsoas haematoma in Gaucher disease.

Extrapelvis or retroperitoneal haemorrhage has long been appreciated as having many causes and considerable variability in subsequent morbidity; however, to date only two cases have been reported in patients with Gaucher disease, the most common lysosomal storage disorder. It had been our assumption that these cases were unique and a consequence of severe disease in patients who had not been treated with enzyme (or other disease-specific) therapy. Herein we present three more cases (as well as our first patient), which allow one to make some generalizations. Ultrasound was used in one centre and computed tomography in the second centre to make the definitive diagnosis. The trigger for the bleeding in all cases was muscle strain after activity. All patients were young with massive hepatosplenomegaly, anaemia, thrombocytopenia, and bone pain with skeletal involvement; the last was the most obvious commonality among these patients. Differential diagnosis is complicated by exquisite groin pain that is common to both Gaucher disease and extrapelvis haemorrhage, but not necessarily.

Adolescent↗
PubMed2006

National health budgets for expensive orphan drugs: Gaucher disease in Israel as a model.

Drugs for orphan diseases are often disproportionately costly, although the patient population is by definition small. In Israel, with a high percentage of Ashkenazi Jews and therefore many patients with Gaucher disease, the expense of enzyme replacement therapy for all patients would be prohibitive. For this reason, with approval of enzyme replacement therapy in Israel, the low-dose regimen (30 U/kg/month), less than one quarter of the manufacturer's original recommended dosage, was instituted as the starting regimen. A Gaucher Committee of medical experts under the auspices of the Ministry of Health determines eligibility for enzyme replacement therapy based on criteria of disease severity. At the advent of 2006, 184 patients in Israel receive enzyme replacement therapy, about one third of all known Israeli patients with Gaucher disease. The national budget provides capitation for each patient to each Sick Fund via a health care basket for severe/expensive treatments. After nearly nine years, the benefits of these innovations include availability of budget for patients requiring enzyme replacement therapy, evidence-based data that low dose is safe and effective, and that untreated mildly affected patients generally continue a benign disease trajectory, but if necessary, have recourse to enzyme replacement therapy, that is, patient care is never compromised. Questionnaires of satisfaction with this system highlight good outcome scores. For countries with limited resources, the use of an impartial committee of experts is recommended, as is long-term surveillance of all patients; maintenance protocols or even drug vacations as enzyme-treated patients approach normalization of disease parameters should be considered.

Budgets↗
PubMed2006

Increased incidence of Parkinson disease among relatives of patients with Gaucher disease.

In a previous study of 99 Ashkenazi Jewish patients with Parkinson disease from Israel who were tested for the six most common mutations for Gaucher disease, 31.3% had at least one Gaucher disease mutation, implying that carrier status per se my be a risk for Parkinson disease. The purpose of this survey was to ascertain the presence of Parkinson disease among Ashkenazi Jewish obligate carriers of Gaucher disease relative to its incidence in a comparable cohort of Ashkenazi Jews who are putatively non-carriers. There was no statistically significant difference in gender or age between the groups (n>100). Among patients, 27.3% reported having a relative with Parkinson disease while among the controls there was a reported 12.3% which was statistically significant (P=0.05). While based completely on subjective reports in a paper-base questionnaire, the results of this survey implicate a high rate of Parkinson disease among individuals with Gaucher disease mutations.

Cohort Studies↗
PubMed2006

Serum levels of osteoprotegerin and osteoprotegerin polymorphisms in Gaucher disease.

Bone involvement in Gaucher disease causes disability and reduced quality of life; loss of function and pain are important indications for enzyme replacement therapy. The purpose of this study was to ascertain whether osteoprotegerin (OPG), which decreases osteoclast activity, is indicative of incipient bone involvement by comparing OPG serum levels to Gaucher disease severity (SSI) and bone mineral density (BMD), and to correlate bone and disease markers to OPG polymorphisms: OPG1-2(A163G), OPG3-4(T129C) and OPG5-6(C1217T). Of 554 patients, 173 Ashkenazi Jewish patients with non-neuronopathic Gaucher disease were enrolled and 32 healthy Ashkenazi Jews served as controls. Serum OPG levels were detected by enzyme-linked immunosorbent assay and BMD was obtained by dual X-ray absorptiometry. OPG polymorphisms were determined in 63 randomly chosen patients. Serum OPG values for patients were not greater than in controls, but showed a statistically significant trend to increase with age (P = 0.057). No correlation existed between OPG levels and BMD or with genotype or other disease markers. A significant correlation was noted between OPG5-6 genotype and SSI. A significant difference was found between the allele distributions of each OPG polymorphism when compared with Caucasians and Ashkenazi Jews. OPG levels probably do not predict BMD in Gaucher disease and hence are not indicative of osteoporosis in Gaucher disease.

Adolescent↗
PubMed2005

TNF-alpha levels and TNF-alpha gene polymorphism in type I Gaucher disease.

The objective of this pilot study was to determine the levels of Tumor Necrosis Factor (TNF)-alpha and TNF-alpha gene polymorphism as a marker of inflammation among patients with type I Gaucher disease as well as to ascertain the relationship between this cytokine and parameters of disease severity and other measures of inflammation. Levels of TNF-alpha and genotyping for the -308 G-->A polymorphism in the promoter of the TNF-alpha gene were performed in 17 patients with type I Gaucher disease. TNF-alpha levels were compared with the promoter gene polymorphism, and with hematological and other clinical parameters of Gaucher disease. Eight patients (47.1%) were homozygotes (A/A) for the TNF-alpha polymorphism, six patients (35.3%) had the wild type (G/G), and three patients (17.6%) were heterozygotes (G/A). A significant correlation was found between serum TNF-alpha levels and TNF-alpha genotypes for homozygotes versus heterozygotes patients (p = 0.02), with patients homozygous for the polymorphism having the lower levels of serum TNF-alpha relative to heterozygotes with the highest levels. No correlation was found between TNF-alpha genotypes and chitotriosidase levels, a putative biochemical marker for Gaucher disease severity. Because a significant correlation was found between homozygosity for a common promoter polymorphism of TNF-alpha and milder expression i.e. non-neuronopathic form, of Gaucher disease (versus the neuronopathic forms), this may be suggestive of an association between genetic variability in TNF-alpha and phenotypic expression in Gaucher disease. Larger studies will be required.

Adolescent↗
PubMed2005

Gaucher disease and cancer incidence: a study from the Gaucher Registry.

Patients with Gaucher disease (GD) are alleged to be at an increased risk of malignant disorders, possibly due to potential chronic stimulation of the immune system and lymphoproliferation associated with storage of glucocerebroside in tissue macrophages. Because previous reports of increased risk of malignancy in GD may have been affected by small patient numbers and ascertainment bias, 2742 patients with GD from the International Gaucher Registry were studied. The number of cancers identified among patients in the registry was compared with that expected in the US population of similar attained age and sex. The majority of patients were young or middle-aged adults at the time of last follow-up, with only 14% older than age 60. There were 10 patients with multiple myeloma, yielding an estimated relative risk of 5.9 (95% confidence interval [95% CI]: 2.8, 10.8). The relative risk of cancer overall was 0.79 (95% CI: 0.67, 0.94), and the subgroups for cancers of the breast, prostate, colon and rectum, lung, and hematologic malignancies other than myeloma did not yield statistically significant higher risks. This study suggests that, in general, patients with Gaucher disease are not at highly increased risk of cancer, at least during early and middle age. However, there appears to be a significantly higher risk of multiple myeloma of which physicians should be aware when caring for these patients.

Adolescent↗
PubMed2005

Uncomplicated outcome after anesthesia for pediatric patients with Gaucher disease.

PURPOSE: The purpose of this retrospective review was to highlight clinical issues relating to anesthetic management in children who present with Gaucher disease-specific features that may impact on anesthetic management and surgical outcome. Previous reports have dealt primarily with neuronopathic forms where neurological dysfunction determined the mode of anesthesia. To date, no series of routine surgeries in pediatric patients with non-neuronopathic Gaucher disease has been published. METHODS: All surgeries performed in children with Gaucher retrospectively analyzed. RESULTS: There were 31 procedures under anesthesia in 15 pediatric patients. Twenty-seven of these (87%) involved either insertion or removal of a central venous catheter. There was no correlation between disease severity and the need for blood transfusion postoperatively [required in only eight cases (25.8%), including a total hip replacement]. No difficult intubations or other airway problems were recorded. Positioning of two patients, because of gibbus and prior to hip replacement, respectively, required special attention. CONCLUSIONS: We record our experience in surgeries in children with mild, non-neuronopathic type I and severe neuronopathic type III Gaucher disease, who had relatively short surgeries under general anesthesia. Attention to hematological parameters in particular can minimize postoperative bleeding, the most serious complication.

Adolescent↗
PubMed2005

Uveitis in Gaucher disease.

PURPOSE: Chronic uveitis has been previously reported in a patient with Gaucher's disease and improved with enzyme replacement therapy. This report describes the course of uveitis in two other patients with type I Gaucher's disease. DESIGN: Observational case reports. METHODS: Review of all patients in a large referral clinic for Gaucher's disease for incidence of uveitis. RESULTS: Two patients with uveitis among 527 patients (0.4%) were found. Each had a different clinical outcome from the other and from the patient cited in the literature. CONCLUSIONS: Both patients have mild Gaucher's disease, but one patient has uveitis well controlled for 10 years solely by local corticosteroids, whereas the other has suffered progression of uveitis despite enzyme replacement therapy.

Adult↗
PubMed2005

A comprehensive assessment of renal function in patients with Gaucher disease.

BACKGROUND: Gaucher disease (GD) is caused by deficiency of acid beta-glucocerebrosidase and is the most common lysosomal storage disease. Patients may have massive hepatosplenomegaly, severe bone disease, and, occasionally, pulmonary or neurological involvement. Although other storage diseases, such as Fabry disease, frequently affect the kidneys, reports of renal abnormalities in patients with GD are limited to case reports. Our aim was to perform a comprehensive evaluation of renal function in patients with GD. METHODS: Evaluation was performed at routine clinic visits and included blood pressure recording and renal ultrasound. Serum chemistries, urinalysis, urine electrolytes, total protein, and tubular proteinuria were assessed, and estimated glomerular filtration rate (GFR) was calculated. RESULTS: One hundred sixty-one patients underwent evaluation, including 26 children. GFR was significantly greater in patients with GD than in age- and sex-matched healthy controls (P = 0.01 in men, P < 0.001 in women, P = 0.003 in children). Subgroups of patients with markers of more severe disease had a greater GFR than other patients. No patient had decreased renal function. Significant proteinuria was found only in patients with such comorbidities as diabetes mellitus or multiple myeloma. No evidence of renal tubular abnormalities was found, and kidney sonographic appearance and size were normal. CONCLUSION: Despite the multiorgan nature of the disease, a systematic evaluation did not find renal abnormalities in patients with GD. Glomerular hyperfiltration was observed in a proportion of patients, particularly those with markers of more severe disease. This phenomenon does not seem to be associated with a subsequent decline in renal function.

Adolescent↗
PubMed2005

Survey of hematological aspects of Gaucher disease.

Hematologists have classically been the treating physicians of patients with Gaucher disease, and today, despite both specific and symptomatic therapeutic advances, they remain at the forefront of specialists to whom patients with Gaucher disease present. It is therefore appropriate to review that has changed and what has remained the same in hematological signs and symptoms of the disease in the decade and a half since therapy has become available.

Anemia↗
PubMed2005

Phenotypic heterogeneity in patients with Gaucher disease and the N370S/V394L genotype.

Correlation between genotype and phenotype in Gaucher disease is limited. It is known that the most common mutation N370S is protective of neurological involvement, but for the V394L mutation, described as the fifth most common among Ashkenazi Jews, little data are available. This study reports all known patients from a large referral clinic and from the international registry with Gaucher disease who are documented to have the N370S/V394L genotype. Of 476 patients in the Gaucher Clinic, 7 patients (2.0%) had the N370S/V394L genotype; of 2,836 patients in the registry, there were 14 patients (0.8%) with this genotype. There was an overlap of 3 patients, making a total of 18 patients, reflecting the rarity of this genotype among the studied cohorts. Most of these patients had mild disease; only 8 patients required specific enzyme therapy, none was splenectomized. Only 3 patients had skeletal involvement, but other baseline parameters were very diverse. Although genotype-phenotype correlation in this case may be difficult, because the V394L mutation when seen in a compound heterozygote with a null allele results in neuronopathic disease, one cannot conclude that this mutation is protective of neuronopathic disease and hence this is important for counseling of at-risk populations.

Adolescent↗
PubMed2005

Menetrier's disease presenting as an acute protein-losing gastroenteropathy in a 27-year-old man with Gaucher disease.

OBJECTIVES: To describe a unique case of a young man with Gaucher disease who was diagnosed with Menetrier's disease. BACKGROUND: After an acute episode of severe gastritis, the patient developed hypoalbuminemia and protein-losing gastroenteropathy, and became unwell. STUDY: Endoscopy revealed an abnormal stomach, with rigid, thickened folds covered with viscous greyish exudates. Superficial biopsies revealed foveolar hyperplasia, acute and severe gastritis with massive inflammatory infiltrate of neutrophils in the lamina propria with pit abscess formation. Tissue cultures for Helicobacter pylori were negative. RESULTS: Snare deep particle biopsy revealed the typical features of Menetrier's disease. Enzyme replacement therapy for Gaucher disease was started. CONCLUSION: This case poses a dilemma because the patient improved spontaneously, and as such is dissimilar to other adults who develop Menetrier's disease because of an infection; it is hoped that he may also not be at risk of the potential malignancies that are correlated with adult Menetrier's disease. The value of enzyme treatment is considered.

Acute Disease↗
PubMed2005

Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.

1-Deoxynojirimycin↗