Search PubMed⌕ Search

Biomedical subjects

A Zimran

Publications and source records attributed to A Zimran.

At least 73 records · Page 4Linked to original sources
PubMed1996

Effect of low-dose enzyme replacement therapy on bones in Gaucher disease patients with severe skeletal involvement.

Gaucher disease, the most common glycolipid storage disorder, is characterized by hepatosplenomegaly and skeletal involvement. Enzyme replacement therapy in both the high- and low-dose regimens has been shown to be effective in reducing the organomegaly and improving the hematological parameters of symptomatic patients with type I disease. Herein we report subjective and objective responses of bone-related complications after 2 to 4 years of low-dose enzyme replacement therapy in 14 adult type I patients with severe skeletal involvement pre-treatment. We discuss our results relative to those reported in patients on the high-dose regimen, as well as with reference to a single patient who developed new avascular necrosis despite objective improvement in radiological studies.

Adolescent↗
PubMed1996

The glucocerebrosidase D409H mutation in Gaucher disease.

Gaucher disease, resulting from the decreased activity of the lysosomal enzyme glucocerebrosidase, is the most prevalent sphingolipid storage disease. Due to considerable heterogeneity of phenotypic expression, it has been subdivided into the nonneurological type 1 disease, and types 2 and 3, the neurological types. We describe homozygosity for the D409H mutation within the glucocerebrosidase gene associated with a unique form of type 3 Gaucher disease. Twelve patients, originating from three Arab sibships, were found to be homozygous for the D409H mutation. They all presented with oculomotor apraxia and a progressive cardiac valve defect with minimal organomegaly. When expressed in human cells in tissue culture, using the T7/EMC/vaccinia virus hybrid expression system, we were able to demonstrate that the mRNA carrying the D409H mutation was less stable than the normal counterpart. Pulse-chase experiments demonstrated that the mutated protein exhibited lower stability than the normal counterpart. Its activity toward the artificial substrate 4-methyl umbelliferyl glucopyranoside was similar to that of the mutated enzymes carrying the N370S or the L444P mutations. However, in loading experiments using lissamine-rhodamine conjugated glucosyl ceramide as a substrate, the recombinant mutated protein carrying the D409H mutation exhibited 28.63 +/- 6.05% of the activity exhibited by the normal enzyme. L444P and N370S mutations exhibited 51.90 +/- 7.16 and 115.75 +/- 12.64% of normal enzyme activity, respectively. Loading of cells homozygous for the D409H mutation demonstrated 10. 05% of the activity shown by normal cells. L444P and N370S homozygous cells demonstrated 25.3 and 98.5% of foreskin fibroblast glucocerebrosidase activity, respectively. We demonstrate that homozygosity for the D409H mutation is a unique case of a peculiar phenotype associated with a specific intracellular glucocerebrosidase activity.

DNA, Complementary↗
PubMed1996

Occurrence of Parkinson's syndrome in type I Gaucher disease.

Gaucher disease, the most prevalent glycolipid storage disorder, is classically subdivided into types according to the presence or absence of neurological involvement. Type I has hitherto been considered non-neuronopathic. We present six cases and a review of the literature of Parkinsonian symptoms in type I Gaucher disease patients. The hallmark of this atypical Parkinsonian syndrome is a relatively severe clinical course with early appearance of neurological signs in the 4th to 6th decade of life, aggressive progression of the signs and refractoriness to conventional anti-Parkinson therapy. We discuss the implications of these findings in the light of enzyme replacement therapy for Gaucher disease.

Adolescent↗
PubMed1996

Pulmonary function abnormalities in type I Gaucher disease.

The purpose of this study was to determine the prevalence of pulmonary function and radiographic abnormalities among patients with type I Gaucher's disease, and to analyse the relationship between the pulmonary involvement and genotype and clinical severity score. All patients attending the Gaucher clinic at the Shaare Zedek Medical Center, Jerusalem, Israel, during the years 1992-1993 were prospectively evaluated. Each patient had pulmonary function tests, chest radiography, clinical assessment in terms of degree of organ involvement, and genotype analysis. Of the 95 patients included in the study (mean +/- SD age 29 +/- 15 yrs), 68% had some pulmonary function abnormalities, most commonly a reduced FRC and transfer coefficient for carbon monoxide (Kco), found in 45% and in 42% of the patients respectively. Total lung capacity (TLC) was reduced in 22% of the patients and forced expiratory flows in approximately one third of the patients. Signs of airtrapping (elevated residual volume (RV) or RV/TLC) were seen in 18% of the patients. Males had a higher incidence of reduced expiratory flow than females, (forced expiratory volume in one second (FEV1) was reduced in 36% of males vs 5% of females). Chest radiographic abnormalities were found in 17% of the patients, although only 4% had severe changes. Patients with abnormal pulmonary function had a significantly higher severity score index than those with normal pulmonary function tests. There was no association between abnormal pulmonary function and genotype or age. In conclusion, abnormal pulmonary function is common among type I Gaucher patients. Pulmonary function tests show airways obstruction, with reduced expiratory flows, reduction in lung volumes and alveolar-capillary diffusion abnormality. The rate of progression and the clinical significance need to be determined.

Adolescent↗
PubMed1996

Epidermal abnormalities may distinguish type 2 from type 1 and type 3 of Gaucher disease.

A major clinical challenge in Gaucher disease is the early and presymptomatic discrimination of type 2 (acute neuronopathic) from milder type 1 and type 3 Gaucher patients to enable appropriate management and counseling. Although most patients with Gaucher disease do not have skin abnormalities, a subset of patients with severe type 2 Gaucher disease display ichthyosiform skin. Analogous findings occur in the skin of type 2 (null allele) Gaucher mice. Ultrastructural and functional studies of epidermis from these mice reveal that glucocerebrosidase is required to generate functionally competent membranes for normal epidermal barrier function. We have extended our studies by examining the epidermal lipid content and ultrastructure in all three types of Gaucher patients. Only the type 2 Gaucher patients, some of whom had clinical ichthyosis, demonstrated an increased ratio of epidermal glucosylceramide to ceramide as well as extensive ultrastructural abnormalities, including the persistence of incompletely processed lamellar body-derived contents throughout the stratum corneum interstices. These epidermal alterations may provide a means for early differentiation of type 2 Gaucher disease.

Animals↗
PubMed1995

Gaucher's disease variant characterised by progressive calcification of heart valves and unique genotype.

Gaucher's disease is the most prevalent sphingolipid storage disease, characterised by substantial genetic and phenotypic variability. Cardiac manifestations are rare. We report 12 Arab Gaucher's disease patients, 2-20 years of age, who presented with oculomotor apraxia but only slight classic signs of the disease. All but the youngest had calcifications of the aortic or mitral valves or both. All these patients were homozygous for the rare point mutation D409H (1342C). Valvular calcifications increased with age and showed progression during 2 years of follow-up. Two of the oldest patients underwent aortic valve replacement, and one sibling had died suddenly at age 16, before this study, Corneal opacities were another common feature. The potentially fatal course of this Gaucher's disease variant, and the availability of a reliable PCR-based method for heterozygote detection, mean that population screening and genetic counselling in the geographic area at risk are important. Affected individuals should be closely monitored by echocardiography to gauge the need for valve replacement. The potential of enzyme replacement to prevent these cardiac complications cannot be ascertained at present, because of the high cost of therapy.

Adolescent↗
PubMed1995

[Frequency of the Gaucher mutation among recent Russian immigrants].

Gaucher's disease is frequent in the Ashkenazi Jewish population of Israel, with a gene frequency by molecular analysis of approximately 0.032, corresponding to a birth rate of 1:850. The recent immigration from the former Soviet Union brought more than 400,000 Jews, mostly of Ashkenazi descent. However, only a few cases of Gaucher's disease have been diagnosed. Possible explanations are lack of awareness of the signs of Gaucher's disease among Russian health workers and family practitioners in Israel, and a significantly lesser frequency of the Gaucher gene among Russian immigrants than among other Ashkenazi Jews in Israel and the US. We studied the frequency of the 1226G (N370S) mutation in a cohort of 202 recent immigrants from the former Soviet Union. We found 10 carriers (4.95%), indicating a decreased frequency of the Gaucher gene, but by extension, the probability of unidentified cases in need of treatment. Family practitioners should be aware of the possibility that heretofore misdiagnosed symptoms may be those of Gaucher's disease.

Emigration and Immigration↗
PubMed1995

Replacement therapy with imiglucerase for type 1 Gaucher's disease.

Gaucher's disease, the most common sphingolipidosis, is caused by deficiency of the lysosomal enzyme glucocerebrosidase. Therapy with alglucerase (the placental enzyme) is safe and effective at various dosing regimens. We report the use of low-dose imiglucerase (the recombinant enzyme) at two dosing schedules: 15 u/kg once fortnightly or 2.5 u/kg thrice weekly. Mean reductions in spleen and liver volumes achieved (in all ten patients) by imiglucerase at 12 months were 36.4% and 14.5%, respectively; mean increase in haemoglobin and platelet counts were 13.4% and 25.7%. There were no serious side-effects. No significant differences were observed between the two schedules. Low-dose low-frequency imiglucerase may be an alternative cost-effective approach with satisfactory clinical response and uncompromised quality of life.

Adolescent↗
PubMed1995

Prenatal molecular diagnosis of Gaucher disease.

Prenatal diagnosis of Gaucher disease, the most prevalent glycolipid storage disease, is based on a reliable enzyme assay of cells from amniocentesis or chorionic villous samples. However, this method cannot differentiate among the various forms of the disease. This report details four cases of prenatal diagnosis of Gaucher disease, three of which predate the use of molecular diagnosis. DNA mutation analysis to determine the genotype was predictive of the phenotypic status of the fetus and conformed to the genotype of an affected proband where available.

Adult↗
PubMed1995

Five new Gaucher disease mutations.

DNA from 17 individuals with 20 unidentified alleles was subjected to single-stranded conformation polymorphism analysis and/or sequencing and 5 previously undescribed mutations have been identified: 245T, 259T, 635G, 914C del, and IVS10(+2). Two of these mutations, 914C del and IVS10(+2), are null, or "lethal" mutations. Because the other mutation each of these two patients carried was "mild", the phenotype was type I disease. In addition to the new mutations we describe, the second example of the rare 1448G mutation has been documented in one of the patients. This mutation is particularly interesting because in samples studied by restriction analysis with NciI it can readily be confused with the common 1448C mutation. Reexamination of 28 patients who had previously been diagnosed as carrying the 1448C mutation were confirmed to be 1448C.

Adult↗
PubMed1995

Natural autoantibodies in sera of patients with Gaucher's disease.

Gaucher's disease (GD) is associated with hyperactivity of the immune system, which manifests by polyclonal hypergamma-globulinemia and an increased incidence of monoclonal gammopathies in GD patients. We analyzed sera of 43 patients with GD for the presence of autoantibodies against 14 autoantigens. The results demonstrated a significant increase in the incidence of all autoantibodies tested, ranging from 11% for anti-RNP, pyruvate dehydrogenase (PDH), and DNA antibodies to 57% for rheumatoid factor. The autoantibodies were of all three isotypes, namely, IgG, IgM, and IgA. There was no correlation between the levels of immunoglobulins in the serum and the titer of autoantibodies found. Immunization of naive mice with a pool of purified anti-DNA antibodies form GD patients did not result in induction of experimental systemic lupus erythematosus (SLE), suggesting that they may represent natural autoantibodies that are not pathogenic. In conclusion, we found high titers of natural, polyspecific, nonpathogenic autoantibodies in the sera of GD patients.

Adolescent↗
PubMed1995

Gynecologic and obstetric aspects of Gaucher's disease: a survey of 53 patients.

OBJECTIVE: We report our experience on the gynecologic and obstetric features of 53 female patients with Gaucher's disease. STUDY DESIGN: Each patient was interviewed for a detailed medical history, and all underwent a complete physical examination and laboratory work-up. RESULTS: Delay of puberty onset was encountered in two thirds of the patients without subsequent infertility. Heavy menstrual bleeding was a major problem and was best treated with low-dose oral contraceptives. Of the 102 spontaneous pregnancies' 25 (24.5%) ended in spontaneous first-trimesters abortions; 72 continued beyond the twenty-second week. Nine patients (27.7%) were diagnosed as having Gaucher's disease during their first pregnancies. Aggravation of thrombocytopenia and anemia were prominent features, but antepartum blood transfusion was not required. Early postpartum hemorrhage and fever were increased after both cesarean and vaginal deliveries. Development of bone crisis in seven women during the third trimester and early postpartum periods recurred in subsequent pregnancies. Genotypes had not influenced the gynecologic or obstetric manifestations. CONCLUSIONS: Gynecologic and obstetric complications play a significant role in this patient population, representing an additional burden to female patients with Gaucher's disease.

Abortion, Spontaneous↗
PubMed1995

Outcome of partial splenectomy for type I Gaucher disease.

Partial splenectomy was introduced to achieve the benefits of splenectomy and to avoid the risk of overwhelming infection in patients with symptomatic Gaucher disease. We observed regrowth of the splenic remnant, reemergence of preoperative symptoms, and new bone involvement among most of our patients who had undergone partial splenectomy. Enzyme replacement therapy has markedly limited indications for splenectomy, partial or total, for Gaucher disease.

Adolescent↗
PubMed1994

RecTL: a complex allele of the glucocerebrosidase gene associated with a mild clinical course of Gaucher disease.

We describe 4 Jewish patients with type 1 Gaucher disease and the genotype N370S/recTL. They present either asymptomatic or mild Gaucher disease. RecTL is a complex allele that contains 4 single point mutations in the glucocerebrosidase gene: D409H, L444P, A456P, and V460V. Since patients who have the genotype N370S/L444P usually develop a moderate to severe course of Gaucher disease, and those who are homozygous for the D409H or the L444P mutations develop aggressive disease accompanied by neurological signs, it is of great importance to distinguish between the severe single base pair mutations and the mild complex recTL allele. This distinction should prove useful in assessing the natural history of Gaucher disease and in considering the indications for early enzyme replacement therapy.

Adult↗