Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alglucerase is a mannose-terminated form of human placental glucocerebrosidase, developed to treat patients with Gaucher's disease. Functional glucocerebrosidase is deficient in Gaucher's disease, an autosomal recessive lipid storage disorder that affects people of all ethnic backgrounds, but has a higher incidence among East European Jews (Ashkenazim). Gaucher's disease manifests with hepatosplenomegaly, bleeding disorders and bone disease, with the more rare subtypes (types 2 and 3) featuring neurological dysfunction. Prior to the development of enzyme replacement therapy, treatment for Gaucher's disease was mainly symptomatic relief. Primary treatment with glucocerebrosidase focuses on removal of the lipid metabolite that causes the pathology. Because of the rarity of Gaucher's disease clinical trials are small, and much of the data investigating alglucerase therapy have been obtained from studies of patients with type 1 disease, the prevalent subtype. Nonetheless, after intravenous administration of alglucerase, improvements are evident within 6 months of therapy. Patients have increased haemoglobin levels and platelet counts, and decreased incidences of epistaxis and bruising. Spleen and liver size are reduced, and skeletal parameters improve. Children gain height and most patients receiving alglucerase therapy are able to resume work and daily activities. Alglucerase is well tolerated, with few mild adverse reactions reported. Although the pharmacokinetic and pharmacodynamic information for alglucerase is limited, its unequivocal efficacy justifies enzyme replacement therapy with this compound as first-line treatment for patients with Gaucher's disease, for whom treatment options are limited.
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PMID:Alglucerase. A review of its therapeutic use in Gaucher's disease. 137 12

Gaucher disease is a collection of related disorders of sphingolipid catabolism caused by the deficiency of a specific beta-glucosidase. The inefficiency of this enzyme, glucocerebrosidase, to degrade its natural substrate leads to the accumulation of the complex lipid glucocerebroside in tissue macrophages. The pathogenesis of the disease is, as yet, poorly understood. The manifestations of the disease are protean with hepatosplenomegaly and bone deterioration frequently the predominating signs. The disease most frequently causes disability because of its effects on the skeleton. This review seeks to summarize the current clinical understanding of these complications. Experience with 327 patients reveals that the bone disease in this disorder is extremely variable. The severity of the problems range from asymptomatic persons with neither radiographic, scintigraphic, nor histologic evidence of bone involvement to those whose skeleton is completely devastated by a process of osteopenia, osteonecrosis, and osteosclerosis. These severely affected individuals show the most bizarre deformities in their bones and are subject to pathologic fracture. Most patients fortunately, are less profoundly affected, but many are plagued by bone pain of an arthritic nature or by an acute prostrating bone crisis probably best described as a bone infarction. The accepted etiology that these crises are a result of vascular compromise produced by occlusion of vessels by Gaucher cells is not supported by scintigraphic or histologic studies. Moreover, the vascular hypothesis does not explain the variety of lesions of the skeleton seen in this multifocal bone disease. Preliminary metabolic and endocrinologic studies suggest that this is not a systemic disorder of metabolism which affects bone uniformly. On the contrary, the lesions are multiple and localized, and sometimes much of the skeleton is preserved. These observations suggest that bone is affected because of collections of Gaucher cells scattered throughout its substance and may be the result of a toxic process around these foci. Alternatively, the storage of glucocerebroside in tissue macrophages may disturb the generation of competent osteoclasts and thus result in a failure to maintain a healthy skeleton. Further research is needed to delineate the pathogenesis of this disorder before any effective therapy can be developed.
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PMID:Skeletal complications of Gaucher disease. 403 9

Modified placental human glucocerebrosidase (alglucerase) and recombinant glucocerebrosidase (imiglucerase) are effective means of treating Type 1 Gaucher's disease. Amelioration of hepatosplenomegaly and of haematological manifestations is usually apparent within 6 months. Bone disease responds more slowly but within several years improvement is evident in most patients. Analysis of a large body of data demonstrates that the rate of response of all manifestations of Gaucher's disease is independent of dose over the range of 30 to 260 U/kg body weight per month. Even the response to 15 U/kg per month appears to be equivalent under most circumstances; treatment failures are the same in patients treated with 15, 30 and 130 U/kg per month. Patients with severe manifestations respond more rapidly than those with mild disease, and this, too, is true at all but the 15 U/kg per month dosage level. All available data thus support the administration of no more than 15 to 30 U of alglucerase or imiglucerase per kg/month. Frequent dosing, i.e. three times weekly, appears to be the most effective means of administration.
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PMID:Enzyme replacement therapy for Gaucher's disease. 949 62

To better characterize skeletal complications in Japanese patients with type 1 Gaucher disease (GD), we performed genotyping and clinical and radiological analysis of 35 patients, the vast majority of this population, Skeletal complications tend to be very common, severe and rapidly progressive in Japanese patients with type 1 GD. Twenty (57%) of these patients manifested end points of severe bone disease including avascular necrosis, pathological fracture and/or bone crisis. Mean time from presentation/diagnosis of GD until presentation of this involvement was 3 years 6 months +/- 4 years 1 month. Prevalence of severe bone disease is significantly higher in splenectomized than in non-splenectomized patients--81% (17/21) versus 21% (3/14) (p = 0.0007, Fisher's exact test). Four (29%) of 14 patients receiving enzyme replacement therapy (ERT) or bone marrow transplantation (BMT) manifested severe bone involvement for the first time during or after treatment. All cases occurred in children in whom ERT doses had been lowered after only brief administration of higher starting doses (n = 3) or partial donor marrow engraftment resulted in low glucocerebrosidase (GCR) activity (n = 1). These observations suggest that splenectomy may correlate with accelerated skeletal deterioration with severe skeletal disease, at least in patients with severe phenotypic expression. They also suggest that it is important that sufficient GCR is available in paediatric patients with severe phenotypic expression. Hence ERT dosages should be based on disease severity and on age, with sustained administration of full doses in patients at greater risk of important skeletal complications.
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PMID:Severe skeletal complications in Japanese patients with type 1 Gaucher disease. 1007 Jun 19

Patients with type I Gaucher disease often present as adults with a mild disease and with less severe genetic mutations, especially 1226G/1226G (N370S/N370S). Patients presenting as children have an excess of compound heterozygotes of N370S and other mutations, such as 84GG, 1448C (L444P) and IVS2 + 1 in whom bone disease is common. We report our experience with low-dose high-frequency enzyme replacement therapy in such severely affected children. Ten patients (with severe juvenile onset type I Gaucher disease) were treated. Alglucerase (Ceredase) was infused at 30 units/kg/month in 13 fractions/month for more than one year. Bone disease was used as the main criterion for evaluating treatment results. No fractures occurred in spite of the fact that bone crises occurred in four patients after 12 to 24 months of treatment, in two during the third year, and in one during the fifth year. Nonosseous manifestations improved with treatment. The ability of low-dose high frequency alglucerase to prevent fractures in the presence of continuing bone crises was demonstrated.
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PMID:Low-dose high-frequency enzyme replacement therapy prevents fractures without complete suppression of painful bone crises in patients with severe juvenile onset type I Gaucher disease. 1008 88

Alglucerase is a modified form of human placental glucocerebrosidase used as enzyme replacement therapy for patients with Gaucher's disease, in whom functional glucocerebrosidase is deficient. Alglucerase has provided a breakthrough in treatment for patients with this relatively rare disease. With alglucerase infusions typical disease manifestations are ameliorated or normalised: hepatosplenomegaly is reduced, haematological parameters improve, and patients experience an increased quality of life usually within 4 to 6 months of treatment. Parameters of bone disease also respond, but generally over a longer period of treatment. Alglucerase is well tolerated by children and adults, with few adverse effects reported. Seroconversion occurs in approximately 15% of patients on high-dose therapy, but does not appear to affect the efficacy of treatment. Several dosage regimens have been used to deliver alglucerase, and the comparative benefits of these remain controversial. High-dose regimens of 60 IU/kg bodyweight administered every 2 weeks are clearly effective; however, smaller dosages given more frequently are also effective and incur a greatly reduced acquisition cost. Patient responses are variable, and the dosage regimen should be tailored to individual needs. Dosage regimens may be considerably reduced for the maintenance phase of treatment, but clinical experience is as yet insufficient to establish the minimum dosages required in the long term. Acquisition cost of alglucerase is $US3.70 per unit (1994 US dollars); thus, a dosage regimen of 60 IU/kg bodyweight administered every 2 weeks for a patient weighing 70kg costs $US404,040 per year. The minimal costs per quality-adjusted life year saved (QALY) have been estimated for 3 dosage regimens over a 10-year period. Cost per QALY was $US147,000 for 60 IU/kg bodyweight administered every 2 weeks, $US75,000 for 30 IU/kg every 2 weeks, and $US49,000 for 2.3 IU/kg administered 3 times per week. These costs were calculated assuming immediate death with no treatment, which suggests that the actual costs per QALY for most patients with type 1 or 3 disease are likely to be much higher. Drug administration costs may become a significant part of the cost during maintenance therapy; in addition, possible cost savings due to increased patient productivity and reduced palliative treatments remain unresolved. Although some patients may obtain increased benefit from high-dosage regimens, the very high cost may preclude general use of these regimens. Healthcare resources consumed by alglucerase therapy represent a large opportunity cost for other therapeutic areas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alglucerase. A pharmacoeconomic appraisal of its use in the treatment of Gaucher's disease. 1015 4

The aim of this study was to characterize the spectrum of 13-glucocerebrosidase gene mutations in Czech and Slovak Gaucher patients and to study genotype/phenotype associations. We have analyzed fifty-eight chromosomes from twenty-six type I, two type 2, and one type 3 13-glucocerebrosidase deficient subjects by direct sequencing of PCR products. Fifty-eight mutant alleles were identified. Seventy-eight percent of mutant alleles carried common mutations (N370S 28/58, L444P 11/58, recNciI 5/58, and IVS2(+1)A 1/58), the remaining twenty-two percent carried rare and private mutations (1263del55, l326insT, S196P, rec(g4889-6506), 2O3delC, G202E, F216Y, R257X, R12OW, R359Q, S1O7L, L444P + V460V, and D409H + T369M). Six of these alleles have not been previously described (rec(g4889-6506), 1326insT, SI96P. G202E, D409H + T369M, and L444P + V460V). The most common genotypes were N370S/L444P (8/29). N370S/recNciI (5/29), and N370S/N370S (2/29). The spectrum of the mutations is characteristic for a Caucasian (non-Jewish) population, with N370S, L444P and recNciI being the most prevalent mutations. The absence of the mutation 84insG that is frequently associated with severe bone disease may have contributed to the low incidence of severe bone disease in Czech and Slovak Gaucher subjects.
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PMID:Analysis of the beta-glucocerebrosidase gene in Czech and Slovak Gaucher patients: mutation profile and description of six novel mutant alleles. 1074 24

Legg-Calve-Perthes disease (LCPD) is an avascular necrosis of the femoral head with an annual incidence of 5-15/100,000. The estimated incidence of Gaucher disease, a lysosomal recessive storage disease, is 1:850, with a carrier rate of 1:17.5 for the 1226G (N370S) mutation among Ashkenazi Jews in whom there is a predilection. Since clinical and radiological findings of avascular hip necrosis due to either Gaucher disease or LCPD may be indistinguishable, misdiagnosis may occur. The purpose of this study was to evaluate the incidence of 1226G Gaucher mutation in a cohort of radiologically confirmed LCPD patients (diagnosed 1986-2000) in Israel. Enzyme assay was performed for confirmation of affected versus carrier status in patients with the 1226G mutation. In all, 78 LCPD patients, 86% males, 51% with severe bone disease, were studied. Family history was negative for Gaucher disease. Ethnic origin was 39% Ashkenazi Jewish, 6% Arab, and 55% other ethnicities. One Ashkenazi Jewish LCPD patient was homozygous for the 1226G mutation, and 4 LCPD patients were carriers: 3 Ashkenazi Jewish and 1 Arab patient. The frequency of the 1226G mutation among the LCPD patients was increased relative to historical Ashkenazi Jewish Israeli controls (P = 0.01). Since Gaucher disease may be misdiagnosed as LCPD, glucocerebrosidase enzyme testing is recommended among Ashkenazi Jewish children diagnosed with LCPD.
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PMID:The 1226G (N370S) Gaucher mutation among patients with Legg-Calve-Perthes disease. 1285 Apr 87

Gaucher's disease (GD) is one of the most prevalent lysosomal storage disorders (LSDs) and a rare genetic disease for which specific therapy is now available. GD is an autosomal, recessive, inborn error of glycosphingolipid metabolism, due to a deficiency in the enzyme acid beta-glucosidase. Partial deficiency of acid beta-glucosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomitant anemia and thrombocytopenia in non-neuronopathic, type 1 GD. Severe deficiency of glucocerebrosidase caused by severe mutations is additionally associated with neurological manifestations in the less common type 2 and type 3 GD subtypes. Outside of the Ashkenazi Jewish community, a high molecular diversity is observed. Clarification of genotype/phenotype relationship and the identification of modifier loci that impact on GD phenotypes remains a critical area for research. Enzyme replacement therapy (ERT) is proven to be safe and effective in the treatment of type 1 GD, establishing imiglucerase as the current standard of care. Amelioration of hepatosplenomegaly and of hematological manifestations is usually apparent within 6-12 months, whereas the bone disease responds more slowly. ERT cannot reverse the neurological deficits in type 2 or type 3 GD. Small molecule inhibitors of glucosylceramide synthase are being developed for substrate reduction therapy. Other potential therapeutic options such as chaperon-mediated enzyme enhancement therapy and gene therapy are being explored.
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PMID:Gaucher's disease: a paradigm for interventional genetics. 1498 63

Gaucher disease (GD) is one of the most prevalent lysosomal storage disorders and one of the rare genetic diseases for which therapy is now available. Partial deficiency of glucocerebrosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomitant anaemia and thrombocytopenia in non-neuronopathic, type 1, Gaucher disease. Severe deficiency of glucocerebrosidase caused by disabling mutation is additionally associated with neurological manifestations in the less common type 2 and type 3 Gaucher diseases. Outside of the Ashkenazi Jewish community, a high molecular diversity is observed. Clarification of genotype-phenotype relationship and the identification of modifier loci that impact on Gaucher disease phenotypes remain a critical area for research. Recombinant glucocerebrosidase (imiglucerase) is an effective mean of treating type 1 Gaucher disease and should be initiated early on in life. Amelioration of hepatosplenomegaly and of haematological manifestations is usually apparent within six months. Bone disease responds more slowly. Imiglucerase has recently been approved for the treatment of type 3 Gaucher disease. Enzyme replacement therapy cannot reverse the neurological deficits in type 2 or type 3 Gaucher disease. This should prompt further research on substrate deprivation and gene therapy.
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PMID:[Gaucher disease: clinical, genetic and therapeutic aspects]. 1526 78


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