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Biomedical subjects

A Zimran

Publications and source records attributed to A Zimran.

At least 91 records · Page 5Linked to original sources
PubMed1994

HCG contamination of alglucerase: clinical implications in low-dose regimen.

Alglucerase (Ceredase) is currently the treatment of choice for patients with symptomatic Gaucher disease. The contamination of this placental enzyme with human chorionic gonadotropin (hCG) has raised concern regarding possible endocrinological complications. We examined 32 patients treated with low-dose alglucerase and 27 untreated patients as controls, and found no significant clinical differences between the two groups: no prepubertal children were affected, no menstrual irregularities were reported, and all hCG levels were well within normal range. Conversely, our finding of a statistically significant difference between the groups underscores the importance of initiating parallel studies of hCG contamination in patients receiving high-dose protocol.

Adult↗
PubMed1994

Mutations causing Gaucher disease.

Glucocerebrosidase is a lysosomal enzyme responsible for hydrolysis of glucosylceramide to ceramide and glucose. Mutations disrupting the function of this enzyme cause autosomal recessive Gaucher disease. This disease is very heterogeneous. The clinical heterogeneity is due to a large number of mutations within the gene encoding glucocerebrosidase. To date 36 mutations have been described in Gaucher disease. In this part we present the mutations and review the more common ones. We also review the glucocerebrosidase natural activator, designated saposin C and mutations in its gene, associated with Gaucher disease.

Base Sequence↗
PubMed1994

Low-dose enzyme replacement therapy for Gaucher's disease: effects of age, sex, genotype, and clinical features on response to treatment.

Although alglucerase therapy has become the treatment of choice for symptomatic patients with Gaucher's disease, the low-dose/high-frequency regimen introduced as a means to reduce the high cost of treatment has raised major controversy. We evaluated the efficacy and safety of low-dose alglucerase in 29 patients with Gaucher's disease who completed 6 to 28 months of therapy. All received intravenous alglucerase at a monthly dose of 30 units/kg, given usually in equal doses 3 times a week. All patients responded well to treatment. The hematological improvement and the reduction in organomegaly were satisfactory. No correlation was found between age, sex, genotype, previous splenectomy, or severity score index and the response to treatment. Patients with a greater degree of hepatomegaly tended to have a more pronounced decrease in liver size, although this reduction did not reach statistical significance. We confirmed that a low-dose/high-frequency regimen of alglucerase was as effective as a high-dose/low-frequency protocol in the treatment of Gaucher's disease, even in the severely ill. Whenever cost is an issue, we recommend using this low-dose regimen.

Adolescent↗
PubMed1993

Home treatment with intravenous enzyme replacement therapy for Gaucher disease: an international collaborative study of 33 patients.

Intravenous enzyme replacement therapy (Alglucerase; Ceredase; Genzyme Corp, Boston, MA) is an effective and safe treatment for patients with type 1 Gaucher disease. In an attempt to reduce its high cost, a "low-dose high-frequency" protocol (30 U/kg/mo, 3 times a week) was introduced and found to be as effective as the original high-dose protocol (60 U/kg every 2 weeks). Because receiving frequent infusions creates a burden for many patients, we have implemented a program of home treatment for our patients. We now report the safety and feasibility of low-dose/high-frequency home intravenous enzyme-replacement therapy in 33 patients with Gaucher disease. The chronic nature of the treatment, its safety, lack of adverse effects, the stable condition of most patients, and the need to reduce the high cost make enzyme replacement for Gaucher disease a good candidate for intravenous home therapy.

Adolescent↗
PubMed1993

Correction of neutrophil chemotaxis defect in patients with Gaucher disease by low-dose enzyme replacement therapy.

We have recently described a chemotactic defect in severely afflicted Gaucher disease patients. Two of the patients were treated with low-dose intravenous enzyme replacement (Ceredase). Marked improvement in their hematological status, organomegaly, and growth was observed. In addition, their chemotactic defect and their tendency towards infections were corrected within 1 year of treatment.

Chemotaxis, Leukocyte↗
PubMed1993

Low-dose high-frequency enzyme replacement therapy for very young children with severe Gaucher disease.

Six children with a mean age of 4.6 years (range 2.5-7), suffering from severe Gaucher disease, were treated with low-dose high-frequency intravenous enzyme replacement (Ceredase, Genzyme, U.S.A.) for a period of 10-24 months. Although, in general, these patients were more severely affected than previously reported patients, the results of the treatment were as satisfactory as those obtained by using much higher doses at low frequency. In addition to regression of organomegaly and improvement of haematological abnormalities, we observed two unique clinical responses in three patients: two showed decreased tendency to bacterial infections, associated with improvement in neutrophil chemotaxis, and one patient, with type 3 Gaucher disease, showed some improvement in neurological findings. Several measures were taken to ameliorate the burden of the high-frequency treatment. These included implantation of venous access devices, establishment of a home-treatment programme and the application of effective local anaesthesia. Therefore the low-dose high-frequency protocol appears to be both an effective and feasible alternative to the costly high-dose low-frequency protocols even in very young children.

Child↗
PubMed1993

Abnormal neutrophil chemotaxis in Gaucher disease.

The tendency towards infection described in Gaucher disease patients has been attributed to their post-splenectomy state. We noticed that certain patients with intact spleen have also suffered from recurrent pyogenic infections, thus an attempt to study their neutrophil function has been made. Nine of 29 patients studied expressed significant decrease in neutrophil chemotaxis directed towards zymosan activated serum or N-formyl-methionyl-leucyl-phenylalanine. Random migration was significantly impaired in five of those nine patients. Adherence of neutrophils to nylon fibres and O2- production were intact. The patients with impaired chemotaxis were significantly afflicted by their disease (early onset of symptoms and severity score index > 10) and most of them had genotypes associated with severe disease (1448/1448 and 1226/84GG). No correlation was found with the spleen status. Three of the patients with impaired chemotaxis, and none of the patients with normal neutrophil function, suffered from recurrent pyogenic infections. It is suggested that the described neutrophil migration impairment may contribute to the tendency towards infection in certain patients with advanced Gaucher disease.

Adolescent↗
PubMed1993

Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients.

The frequency of nine different mutated alleles known to occur in the glucocerebrosidase gene was determined in 247 Gaucher patients, of whom 176 were of Jewish extraction, 2 were Jewish with one converted parent, and 69 were of non-Jewish origin. DNA was prepared from peripheral blood, active glucocerebrosidase sequences were amplified by using the PCR technique, and the mutations were identified by using the allele-specific oligonucleotide hybridization method. The N37OS mutation appeared in 69.77% of the mutated alleles in Jewish patients and in 22.86% of the mutated alleles in non-Jews. The 84GG mutation, which has not been found so far among non-Jewish patients, existed in 10.17% of the disease alleles among Jewish patients. The IVS + 1 mutation constituted 2.26% of the disease alleles among Jewish patients and 1.43% among the non-Jewish patients. RecTL, a complex allele containing four single-base-pair changes, occurred in 2.26% of the alleles in Jewish patients and was found in two (1.43%) of the patients of non-Jewish extraction. Another complex allele, designated "RecNciI" and containing three single-point mutations, appeared in 7.8% of alleles of non-Jewish patients and in only two (0.56%) of the Jewish families. The prevalence of the L444P mutation among non-Jewish Gaucher patients was 31.43%, while its prevalence among Jewish patients was only 4.24%. The prevalence of two other point mutations--D409H and R463C--was 5.00% and 3.57%, respectively, among non-Jewish patients and was not found among the Jewish Gaucher patient population. The prevalence of the R496H mutation, found so far only among Jewish patients, was 1.13%. The results presented demonstrate that seven mutations identify 90.40% of the mutations among Jewish patients and that these seven mutations allow diagnosis of only 73.52% of the non-Jewish patients. Identification of additional mutant alleles will enhance the accuracy of carrier detection.

Base Sequence↗
PubMed1993

Adult-type Gaucher disease in children: genetics, clinical features and enzyme replacement therapy.

Clinical manifestations of type 1 (Adult) Gaucher disease usually start in childhood. However, most of the previously published data describe the features of this disorder in adults. We present the clinical and genetic characteristics of 34 children and adolescents with type 1 Gaucher disease evaluated in our clinic during the past two years. Patients were aged 2-18 years; 18 were boys and 16 girls. The majority presented before the age of 10. Growth retardation appeared as a prominent feature, with 26% in or below the third percentile in weight, and 30% so in height, especially in the youngest age group (2-5 years). Anaemia and thrombocytopenia occurred in 80% and 60% of the children, respectively. Hepatosplenomegaly was noted in all the children; only 3 were splenectomized. Skeletal involvement was evident on X-rays in 90% of the patients, but only 50% complained of bone pains. Three patients had severe bone disease, with avascular necrosis of the hip joint. Mutation analysis at the DNA level revealed the 1226/1226 genotype in 12 (35%) patients and 1226/84GG in 13 (38%). Correlation was found between the genotypes and the severity of the disease, including growth retardation. A positive response was documented in all 9 patients who completed 12 months of the recently-introduced enzyme replacement therapy for Gaucher disease.

Adolescent↗
PubMed1992

Mutations in Jewish patients with Gaucher disease.

DNA from 100 unrelated patients, 97 of whom were Jewish and three half-Jewish, was analyzed for 22 mutations known to cause Gaucher disease. All but seven of the alleles were identified as having previously described mutations. Five of the unidentified mutations proved to be a previously undescribed nucleotide substitution in a splice junction (IVS2+1) that causes skipping of exon 2. Thus, only 2 of 197 alleles remained unidentified. Homozygotes for the most common mutation, that a nucleotide (nt) 1226, manifested, on average, the mildest disease and the latest age of onset. The mutation at nt 84 and the newly described IVS2+1 mutation, which do not produce any enzyme, were associated with earlier onset and more severe disease. Five of the mutations were considered to be "public," in the sense that they were found in more than one unrelated individual. Screening for these five mutations permitted detection of 97.5% of all Gaucher alleles in this patient population. Because the mutation at nt 1226 is underrepresented in the patient population and because not all homozygotes come to medical attention, screening the Ashkenazi population using DNA analysis should detect approximately 99% of all heterozygotes.

Alleles↗
PubMed1992

Gaucher disease. Clinical, laboratory, radiologic, and genetic features of 53 patients.

We have reviewed our experiences with the clinical, laboratory, radiologic, and genetic features of 53 patients with Gaucher disease. Most were evaluated during early adult life, with a mean age of 33 years. Our patients were evaluated in a referral center, and therefore the data need to be interpreted with caution when applied to the general patient population, which includes a greater proportion of very mild cases. Thirty-nine patients were Ashkenazi Jews, 13 were non-Jewish and 1 was half-Jewish. The most common presenting symptom was bleeding related to splenomegaly and thrombocytopenia. The chronic symptoms, evaluated an average of 20 years after the diagnosis had been established, were mainly skeletal. Splenectomy had been performed in 43% of our patients and there was no evidence that this procedure accelerated the progression of liver and bone involvement. DNA from the patients was examined for 20 different mutations. The association between the 1226G/1226G genotype and a milder clinical course, and between the 1226G/84GG and 1226/1448C genotypes with more severe clinical manifestations, was confirmed. Repeated follow-up examinations in 29 patients revealed that in the majority of the patients, progression of the disease occurs during childhood, adolescence, or early adulthood with a marked tendency for stabilization thereafter. This observation suggests that Gaucher disease in most of the patients is not a relentless progressive disorder but a rather stable disorder during adulthood. The indications for the newly introduced intravenous enzyme replacement therapy as well as of future experimental treatments should be examined in the light of the natural history of the disease.

Adolescent↗
PubMed1991

Molecular aspects of Gaucher disease.

Gaucher disease is the most common sphingolipid storage disorder. Due to its high prevalence it may appear with a nonrelated neurological disease and be misinterpreted as Gaucher type 3. A family is described in which 2 Gaucher brothers presented different clinical signs. Molecular analysis has shown that both carried two mutated alleles. One allele had a G to C transversion at nucleotide 3119 of the active gene (Asp140-His) while the other presented two base pair changes, an A to C transversion at nucleotide number 3170 (Lys157-Gly), and a G-A transition at nucleotide number 5309 (Glu324-Lys). Therefore, both presented the same type of Gaucher disease which was accompanied with a nonrelated neurological disease in one of them. Molecular diagnosis of 161 patients has provided a relative abundance of different mutations among Jewish and non-Jewish patients and allowed some genotype-phenotype correlation. Differential expression of the murine glucocerebrosidase activator gene (the prosaposine) has been demonstrated using Northern technique and in situ hybridization. High expression levels were observed in the brain and testes. In the testes the prosaposine expression was confined to the supporting cells. In the female gonad prosaposine expression has also been shown, in the corpus luteum. In a 12 1/2-day-old embryo, prosaposine gene expression was detected mainly in brain stem, in dorsal ganglia and in the genital ridge.

Adolescent↗
PubMed1991

High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews.

Reliable estimates of the frequency of Gaucher disease-producing mutations are not available. The high frequency of Gaucher disease in the Ashkenazi Jewish population is due to the occurrence of a mutation at nucleotide (nt) 1226. We have screened 593 DNA samples from normal Ashkenazi Jews, as well as 62 DNA samples from all our Ashkenazi Jewish patients with Gaucher disease, for the presence of the 1226 mutation. In the 593 presumed normal Ashkenazi Jewish individuals the 1226 mutation was identified in the heterozygous state in 37 and in the homozygous state in two, giving a gene frequency of .035 for the mutation. This 1226 mutation represented 73% of the 124 Gaucher disease alleles in Jewish Gaucher disease patients. Accordingly we estimate that the gene frequency for Gaucher disease among the Ashkenazi Jewish population is .047, which is equivalent to a carrier frequency of 8.9% and a birth incidence of 1:450.

Adolescent↗
PubMed1990

[Pneumatosis cystoides intestinalis of the splenic flexure].

We describe a case of pneumatosis cystoides intestinalis with unusual localization and radiologic features. Barium enema showed multiple, rounded, submucosal masses, which were polypoid and airless and were localized to a 20 cm segment of the splenic flexure. There was no extraluminal gas on X-ray. Puncture of these formations via colonoscopic biopsy did not result in deflation of air. Surgical resection was performed and the classical features of pneumatosis cystoides intestinalis were found. Isolated splenic flexure involvement in conjunction with atherosclerotic cardiovascular disease may suggest that pneumatosis cystoides intestinalis is a reparative process after ischemic injury.

Aged↗
PubMed1990

In vivo aging of red cell enzymes: study of biotinylated red blood cells in rabbits.

It is generally recognized that the activities of some of the red cell enzymes decline as the cell ages. However, there is still a controversy regarding the rate at which this aging occurs. In the present study we applied newly developed technology for the specific isolation of maturing reticulocytes/erythrocytes for a more comprehensive study of in vivo aging of red cell enzymes in rabbits. Anemia was induced by repeated phlebotomy, and reticulocyte-rich erythrocytes were labeled with N-hydroxy succinimido-biotin and then transfused into a normal rabbit. These biotinylated cells were isolated at various time points by their affinity for an avidin support, and the enzymatic activity of 19 red cell enzymes was measured. We observed a biphasic pattern of decay for the activity of six age-dependent enzymes--aldolase, glutamate-oxaloacetate transaminase, glucose 6-phosphate dehydrogenase, hexokinase, pyrimidine 5'-nucleotidase, and pyruvate kinase.

Animals↗