Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enzyme replacement therapy (ERT) for Gaucher disease designed to target glucocerebrosidase (GC) to macrophages via mannose-specific endocytosis is very effective in reversing hepatosplenomegaly, and normalizing hematologic parameters but is less effective in improving bone and lung involvement and ineffective in brain. Recombinant GCs containing an in-frame fusion to the HIV-1 trans-activator protein transduction domain (TAT) were expressed in eukaryotic cells in order to obtain active, normally glycosylated GC fusion proteins for enzyme uptake studies. Despite the absence of mannose-specific endocytic receptors on the plasma membranes of various fibroblasts, the recombinant GCs with C-terminal TAT fusions were readily internalized by these cells. Immunofluorescent confocal microscopy demonstrated the recombinant TAT-fusion proteins with a mixed endosomal and lysosomal localization. Thus, TAT-modified GCs represent a novel strategy for a new generation of therapeutic enzymes for ERT for Gaucher disease.
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PMID:Improved intracellular delivery of glucocerebrosidase mediated by the HIV-1 TAT protein transduction domain. 1622 8

Type 1 Gaucher disease (GD) is a progressive lysosomal storage disorder due to an autosomal recessive deficiency of glucocerebrosidase. Clinical manifestations include anemia, thrombocytopenia, hepatosplenomegaly, and bone and pulmonary disease. Intravenous enzyme replacement (ERT) with imiglucerase is the accepted standard for treatment of symptomatic patients. More than 3,500 patients worldwide have received ERT with well-documented beneficial effects on the hematological, visceral, skeletal, and pulmonary manifestations, and with resultant improvement in health-related quality of life. Miglustat, an imino sugar that reversibly inhibits glucosylceramide synthase and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option. Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately. This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat.
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PMID:Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. 1624 43

The lysosomal hydrolase, glucocerebrosidase (GBA), catalyses the penultimate step in the breakdown of membrane glycosphingolipids. An inherited deficiency of this enzyme activity leads to the onset of Gaucher disease, the most common lysosomal storage disorder. Affected individuals range from adults with hepatosplenomegaly, haematological complications, and bone pain (type 1 disease) to children and neonates with severe neuronopathy leading to neurological degradation and premature death (type 2 and type 3 disease). Enzyme replacement therapy has become the standard of treatment for type I Gaucher disease but remains an expensive option, in part because of the cost of recombinant enzyme production using mammalian cell culture. Using a nonlytic integrative plasmid expression system, we have successfully produced active human GBA in stable transformed Sf9 (Spodoptera frugiperda) cells. Both the 39 and 19 amino acid native GBA signal sequences were capable of endoplasmic reticulum targeting, which led to secretion of the recombinant protein, although approximately 30% more enzyme was produced using the longer signal sequence. The secreted product was purified to apparent electrophoretic homogeneity using hydrophobic interaction chromatography and found to be produced in a fully glycosylated and a hypoglycosylated form, both of which cross-reacted with a human GBA-specific monoclonal antibody. The pH optimum (at pH 5.5) for activity of the recombinant enzyme was as expected for human GBA using the artificial substrate 4-methyl-umbelliferyl-beta-D-glycopyranoside. With initial nonoptimized expression levels estimated at 10-15 mg/L using small-scale batch cultures, stable transformed insect cells could provide a viable alternative system for the heterologous production of human GBA when grown under optimized perfusion culture conditions.
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PMID:Secretion of human glucocerebrosidase from stable transformed insect cells using native signal sequences. 1660 95

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by the deficient activity of glucocerebrosidase. Accumulation of glucosylceramide, primarily in the lysosomes of cells of the reticuloendothelial system, leads to hepatosplenomegaly, anemia and skeletal lesions in type I disease, and neurologic manifestations in types II and III disease. We report herein the identification of hydrophilic active-site-specific chaperones that are capable of increasing glucocerebrosidase activity in the cultured fibroblasts of Gaucher patients. Screening of a variety of natural and synthetic alkaloid compounds showed isofagomine, N-dodecyl deoxynojirimycin, calystegines A3, B1, B2 and C1, and 1,5-dideoxy-1,5-iminoxylitol to be potent inhibitors of glucocerebrosidase. Among them, isofagomine was the most potent inhibitor of glucocerebrosidase in vitro, and the most effective active-site-specific chaperone capable of increasing residual glucocerebrosidase activity in fibroblasts established from Gaucher patients with the most prevalent Gaucher disease-causing mutation (N370S). Intracellular enzyme activity increased approximately two-fold after cells had been incubated with isofagomine, and the increase in glucocerebrosidase activity was both dose-dependent and time-dependent. Western blotting demonstrated that there was a substantial increase in glucocerebrosidase protein in cells after isofagomine treatment. Immunocytochemistry revealed an improvement in the glucocerebrosidase trafficking pattern, which overlaps that of lysosome-associated membrane protein 2 in Gaucher fibroblasts cultivated with isofagomine, suggesting that the transport of mutant glucocerebrosidase is at least partially improved in the presence of isofagomine. The hydrophilic active-site-specific chaperones are less toxic to cultured cells. These results indicate that these hydrophilic small molecules are suitable candidates for further drug development for the treatment of Gaucher disease.
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PMID:Hydrophilic iminosugar active-site-specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients. 1693 36

Type 1 Gaucher disease, the most common lysosomal storage disorder, results from deficiency of glucocerebrosidase causing pathologic accumulation of glucocerebroside. The disease is characterized by marked variation in age of onset and degree of anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. Most published data on Gaucher disease come from populations with large proportions of Ashkenazi-Jewish patients, who tend to have less severe disease. We compared selected demographic, clinical, and genetic parameters for Brazilian (N = 221) and rest-of-world (N = 1477) type 1 Gaucher disease patients entered into the ICGG Gaucher Registry since 1991. We also compared Brazilian patients to non-Ashkenazi rest-of-world patients (N = 692) to determine if differences were the result of fewer Brazilian Ashkenazi-Jewish patients (0.5% vs 45.0%). The Brazilian cohort differed significantly (p < 0.05) from the rest-of-world and rest-of-world non-Ashkenazi cohort, respectively, in the following measures: higher proportion of females (59.7% vs 50.4% and 49.7%), lower mean age at diagnosis (17.1 vs 24.1 and 18.8), and higher proportions of patients with anemia (55.5% vs 29.9% and 35.7%), bone pain (57.7% vs 33.7% and 35%), bone crises (16.1% vs 6.5% and 7.4%), and lytic lesions (17.0% vs 7.6% and 7.4%). The most common genotype in Brazil was N370S/L444P (c1448T-->C/c1226A-->C) (46.8% versus 16.3% and 25.7%). These data highlight the genetic and phenotypic heterogeneity among geographic populations of type 1 Gaucher patients and suggest that as a group, Brazilian patients may have a more aggressive form of the disease than rest-of-world patients. The findings also emphasize the need for caution in making generalizations about Gaucher disease across demographic groups.
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PMID:Phenotypic and genotypic heterogeneity in Gaucher disease type 1: a comparison between Brazil and the rest of the world. 1699 65

Gaucher disease is a disorder of sphingolipid metabolism resulting from an inherited deficiency of the lysosomal hydrolase glucocerebrosidase. Affected individuals present with a spectrum of clinical symptoms ranging from hepatosplenomegaly, haematological abnormalities, and bone pain in type 1 disease, to severe neurodegeneration and premature death in types 2 and 3 disease. Although the basic biochemical defect is well characterized, there remains a poor understanding of the underlying pathophysiology of disease. In vitro studies suggest that macrophage glucocerebroside storage leads to tissue dysfunction through complex mechanisms involving altered intracellular calcium homeostasis and apoptosis. In order to study the pathogenic roles of these complex interactions, a viable animal model for Gaucher disease is needed. The complexity of this single gene disorder has been emphasized by the varied results of previous murine Gaucher models, ranging from perinatal lethality to phenotypically and biochemically asymptomatic animals. Recognizing the need to modulate the biochemical phenotype in mice to produce a relevant model, we have created a murine strain with key exons of the glucocerebrosidase gene flanked by loxP sites. We show that expression of Cre-recombinase in cells of hematopoietic and endothelial origin results in deficiency of glucocerebrosidase in the liver, spleen, bone marrow, and peripheral white cells. Glucocerebroside storage in this model leads to progressive splenomegaly with Gaucher cell infiltration and modest storage in the liver by 26 weeks of age. These results indicate the utility of this loxP GBA targeted murine strain for understanding the complex pathophysiology of Gaucher disease.
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PMID:Generation of a conditional knockout of murine glucocerebrosidase: utility for the study of Gaucher disease. 1707 75

Type I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T(3), elevated rT(3), normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24 h) was not correlated with circulating levels of T(3), rT(3) or fT(4). Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT(4) levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT(4) and T(3).
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PMID:Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels. 1791 12

Gaucher disease is a recessively inherited lysosomal storage disorder, caused by deficiency of glucocerebrosidase activity. Affected individuals usually present with hepatosplenomegaly, anaemia, thrombocytopenia, and skeletal diseases. A wide range of neurological manifestations have also been recognized in Gaucher patients including acute neurological deterioration in infancy, mental retardation, ocular motor apraxia, seizure, and parkinsonism. Although muscle weakness is not an uncommon finding in patients with Gaucher disease, the aetiology of weakness is not well understood. We prospectively investigated seven Gaucher patients and found that four of them (patients 1-4) had mild to moderate degree of proximal-predominant symmetrical muscle weakness in four limbs. By history, three patients (patients 1-3) developed insidious onset of nonprogressive muscle weakness in four limbs with easy muscle fatigue from adolescence. A needle electromyographic study detected some small, brief polyphasic waves in these four patients. Muscle biopsy in one patient (patient 1) showed a few atrophic type II muscle fibres without infiltration of Gaucher cells. Three patients (patients 1-3) continuously received enzyme replacement therapy with imiglucerase and their muscle strength seemed improved after two years. We concluded that Gaucher disease may be associated with myopathy.
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PMID:Myopathy in Gaucher disease. 1819 73

We present a brief review of Gaucher disease, the most common lysosomal storage disease. Gaucher disease is a rare autosomal recessive disorder characterized by defective function of the catabolic enzyme beta-glucocerebrosidase, leading to an accumulation of its substrate, glucocerebroside, in the mononuclear phagocyte system, especially histiocytes in the spleen, lymph nodes, and bone marrow; Kupffer cells in the liver; osteoclasts in bone; microglia in the central nervous system; alveolar macrophages in the lungs; and histiocytes in the gastrointestinal tracts, genitourinary tracts, and the peritoneum. Clinical signs and symptoms include neurologic dysfunctions, bone infarcts and malformations, hepatosplenomegaly and hypersplenism leading to anemia, neutropenia, and thrombocytopenia. Enzyme replacement therapy with recombinant glucocerebrosidase is the mainstay of treatment for Gaucher disease, which became the first successfully managed lipid storage disease. Future treatments may include oral enzyme replacement and/or gene therapy interventions.
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PMID:Gaucher disease: review of the literature. 1846 35

Gaucher disease is an autosomal recessive disorder. It is characterized by the accumulation of glucosylceramide in lysosomes of mononuclear phagocyte system, attributable to acid beta-glucosidase deficiency. The main consequences of this disease are hepatosplenomegaly, skeletal lesions and, sometimes, neurological manifestations. At sub-inhibitory concentrations, several competitive inhibitors act as chemical chaperones by inducing protein stabilization and increasing enzymatic activity. Here we tested two iminosugars (NB-DNJ and NN-DNJ) and four aminocyclitols with distinct degrees of lipophilicity as pharmacological chaperones for glucocerebrosidase (GBA). We report an increase in the activity of GBA using NN-DNJ, NB-DNJ and aminocyclitol 1 in stably transfected cell lines, and an increment with NN-DNJ and aminocyclitol 4 in patient fibroblasts. These results on specific mutations validate the use of chemical chaperones as a therapeutic approach for Gaucher disease. However, the development and analysis of new compounds is required in order to find more effective therapeutic agents that are active on a broader range of mutations.
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PMID:Promising results of the chaperone effect caused by imino sugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease. 1916 50


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