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)

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

Systemic findings such as hepatosplenomegaly and typical Gaucher storage cells in a bone marrow aspirate led to the clinical diagnosis of Gaucher's disease in the seven-year old patient described in this report. On the basis of the lack of neurologic involvement the child was classified as having the Type 1, nonneurologic form of Gaucher's disease. After splenectomy glucocerebrosidase was extracted from her spleen for biochemical analysis. As expected, a marked deficiency of glucocerebrosidase activity was evident in the splenic extract, however her enzyme displayed anomalous behavior compared to other identical splenic preparations from documented Type 1 Gaucher's disease patients in that it failed to reconstitute with the acidic lipid phosphatidylserine. Using the polymerase chain reaction (PCR)-based color complementation assay and restriction endonuclease analysis, we compared the mutation genotype of this child with that of five other classical Type 1 patients. This analysis revealed that our patient alone was homoallelic for a T----C transition at position 1448 in the glucocerebrosidase cDNA that results in a 444Leu----Pro substitution in the glucocerebrosidase protein. The latter mutation genotype is normally associated with the neurologic phenotype, namely, the Types 2 and 3 forms of the disease. The relevance of the nature of polarity in clinical and biochemical analyses is discussed with regard to the phenotypic classification and the future clinical course of disease in the child.
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PMID:A case of nonneurologic Gaucher's disease that biochemically resembles the neurologic types. 167 7

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

Autopsy samples were obtained from a 12.5-year-old girl who died with a neurologic disorder consisting of myoclonus, myoclonic epilepsy, spasticity, strabismus, and mild mental retardation but no hepatosplenomegaly. Studies in leukocytes, cultured skin fibroblasts, brain, liver, and spleen of this patient revealed glucosylceramide beta-glucosidase (EC 3.2.1.45, glucocerebrosidase) activity about 10% of controls, and well in the range found in samples from Gaucher disease patients. Extraction of the lipids from liver and spleen with chloroform-methanol (2:1) did not show accumulation of glucosylceramide or other lipid. Examination of the lipids in brain by high performance liquid chromatography revealed the presence of glucosylceramide, which is not found in brain samples from controls. Pathologic examination of the liver and spleen revealed no evidence of Gaucher disease. The brain showed many degenerative lesions and loss of neurons. There was no complementation of glucocerebrosidase activity when the cells from this patient were hybridized with cells from patients with Type 1 or Type 2 Gaucher disease. The reason for the lack of glucosylceramide storage in the liver and spleen has not been determined.
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PMID:Biochemical studies in a patient with subacute neuropathic Gaucher disease without visceral glucosylceramide storage. 685 96

Gaucher disease is a sphingolipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GC) and the consequent deposition of glucocerebrosides into the cells of the macrophagic system. Among the three types of clinical disease, type 1 leads to hepatosplenomegaly, hypersplenism and skeletal abnormalities including bone pain, osteopenia and fractures. Two pediatric female patients with moderately severe type 1 Gaucher disease were treated with commercially available GC, mannose terminated to be macrophage-targeted. GC was given by intravenous infusion (30 to 60 units per kilogram of body weight every two weeks) for 8 and 18 months. The hemoglobin concentration increased and the serum acid phosphatase decreased in both patients. In the most affected child, hepatic volume decreased significantly and bony symptoms disappeared. Infusions were uneventful except for an episode of anaphylaxis that subsided rapidly, allowed resumption and did not affect efficacy. These observations are in agreement with the international experience in approximately 800 cases, with good tolerance in all type 1 patients who show objective clinical improvement; patterns of response are variable from patient to patient, independent from previous splenectomy, and dose-dependent; the dose can be tapered after a period of time. Antibodies anti-GC are seen in 13% of the patients, but their presence does not have clinical consequences. The cost of the enzyme makes it crucial to define precise indications, optimal dosing schedules, duration of treatment and cost-benefit ratio.
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PMID:[Enzyme replacement therapy in type 1 Gaucher's disease]. 799 30

Gaucher disease is the most prevalent hereditary metabolic storage disorder, and the most common genetic disease in individuals of Ashkenazic Jewish ancestry. Patients with Gaucher disease have been classified into three clinical phenotypes. Patients with type 1 disease exhibit markedly variable hepatosplenomegaly, anemia, thrombocytopenia, skeletal, and, to a lesser extent, pulmonary and kidney involvement. The central nervous system does not appear to be involved. In patients with type 2 Gaucher disease, hepatosplenomegaly and extensive central nervous system damage are apparent in infancy. These patients usually die between 1 and 2 years of age. Patients with type 3 Gaucher disease have been subclassified into types 3a and 3b. Type 3a patients exhibit mild-to-moderate hepatosplenomegaly and slowly progressive neurologic deterioration. Recurrent myoclonic seizures are common. Patients with type 3b Gaucher disease exhibit splenomegaly along with extensive hepatomegaly that is frequently accompanied by esophageal varices. Horizontal supranuclear gaze paresis is the major neurologic sign. Excessive quantities of glucocerebroside accumulate in the organs of patients with Gaucher disease because of a deficiency of the enzyme glucocerebrosidase. In the vast majority of patients, the reduction of glucocerebrosidase activity is caused by mutations in the gene that codes for glucocerebrosidase. In a few instances, glucocerebroside accumulates due to a lack of saposin C, a cohydrolase that is required in addition to glucocerebrosidase for the catabolism of glucocerebroside. Mutations in the glucocerebrosidase gene are discussed in the context of the severity of disease and the presence or absence of nervous system involvement. Enzyme replacement therapy is highly beneficial for patients with type 1 Gaucher disease. Enzyme replacement is also being investigated for patients with type 3b Gaucher disease. Novel procedures must be developed to deliver glucocerebrosidase to the nervous system so that patients with type 2 and type 3a Gaucher disease can be helped. Exploration of gene therapy for Gaucher disease is under way.
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PMID:The role of neurogenetics in Gaucher disease. 821 80

Gaucher disease is the most prevalent hereditary metabolic storage disorder. The metabolic defect in Gaucher disease is a deficiency of the lysosomal enzyme glucocerebrosidase. Patients with Gaucher disease may present with the following symptoms: hepatosplenomegaly, anemia, thrombocytopenia, bone involvement (pathologic fractures and bone pain), and, more rarely pulmonary, renal, cardiac, and central nervous system involvement. Since 1991, Ceredase (Genzyme Corporation, Cambridge, MA) (alglucerase) and since 1994, Cerezyme (Genzyme Corporation, Cambridge, MA) (imiglucerase for injection), have provided long-term successful treatment for more than 1400 patients with Gaucher disease.
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PMID:Gaucher disease: an overview of clinical characteristics and therapy. 885 67

Gaucher's disease is an autosomal recessive lysosomal storage disease, resulting from a deficiency of the enzyme glucocerebrosidase, important for the physiologic recycling of cell membrane lipids. The clinical symptoms and disease presentations of Gaucher's disease are heterogeneous, including hepatosplenomegaly, bone "crisis" and fracture, anemia, thrombocytopenia and in some forms, rapid neurological decompensation. Similarly, the genetic variability of Gaucher's disease is diverse, and in some aspects affects phenotypic expression. Type 1 Gaucher's disease, however, usually present with less severe symptoms, at more advanced age, and is particularly amenable to enzyme replacement therapy with alglucerase. In type 1 patients with Gaucher's disease reproductive age is commonly reached and childbearing frequently desired with need for appropriate prenatal diagnosis, counseling and careful obstetrical surveillance. Although pregnancy concurrent with Gaucher's disease has been reported in the medical literature, only one small series of alglucerase treated Gaucher's disease during pregnancy exists. Without treatment, pregnancy concurrent with Gaucher's disease has several risks including an increased severity of anemia and thrombocytopenia that can potentiate postpartum bleeding, significant increases in organomegaly and possibly an increased spontaneous abortion rate. It is yet to be shown whether alglucerase reduces the risk of these complications during pregnancy and whether its use has any adverse effect on fetal development.
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PMID:Gaucher's disease in pregnancy. 887 55

In type 1 Gaucher disease, decreased activity of glucocerebrosidase results in accumulation of glucosylceramide in macrophages. Infiltration of liver, spleen and bone marrow by lipid-laden macrophages leads to hepatosplenomegaly, bone lesions and cytopenia. These abnormal macrophages may produce and release macrophage derived factors and cytokines, which could contribute to the pathophysiology of the disease. Whether these cytokines and factors are elevated in Gaucher disease is currently unknown. In 29 type 1 Gaucher disease patients we measured serum levels of the macrophage derived cytokines IL8, IL6, TNFalpha, M-CSF and the monocyte/macrophage activation marker sCD14. These factors were studied in relation to disease severity and during treatment with enzyme supplementation therapy. Most patients showed remarkably elevated levels of M-CSF (2-8 fold) and sCD14 (2-5 fold) as compared to normal controls. Levels of IL8 were elevated in all patients (2-20 fold), whereas levels of IL6 and TNFalpha were normal. There was a significant correlation between severity of the disease as determined by the severity score index (SSI), and M-CSF, sCD14 and IL8 levels. M-CSF and sCD14 levels also correlated with the excess liver and spleen volumes. During treatment with alglucerase, levels of M-CSF and sCD14 declined, but IL8 remained unchanged. The relative reduction in excess liver and spleen volume did not correlate with the relative reduction in M-CSF or sCD14 levels. We conclude that serum levels of M-CSF, sCD14 and IL8 are increased in type 1 Gaucher disease. The biological activities of M-CSF and IL8 may add to the pathophysiology of the disease.
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PMID:Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. 923 58

The complete spectrum of clinical phenotypes resulting from glucocerebrosidase deficiency continues to evolve. While most patients with Gaucher disease have residual glucocerebrosidase activity, we describe a fetus with severe prenatal lethal type 2 (acute neuronopathic) Gaucher disease lacking glucocerebrosidase activity. This 22-week fetus was the result of a first cousin marriage and had hydrops, external abnormalities, hepatosplenomegaly, and Gaucher cells in several organs. Fetal fibroblast DNA was screened for common Gaucher mutations, none of which was detected. Southern blot analysis using the restriction enzymes SstII and SspI ruled out a fusion gene, deletion, or duplication of either allele, and quantitative studies of SspI digested genomic DNA indicated that both alleles were present. Northern blot analysis of total RNA from fetal fibroblasts demonstrated no detectable transcription, although RT-PCR successfully amplified several exons, suggesting the presence of a very unstable mRNA. Direct PCR sequencing of all exons demonstrated a homozygous frameshift mutation (deletion of a C) on codon 139 in exon 5, thereby introducing a premature termination codon in exon 6. The absence of glucocerebrosidase protein was confirmed by Western analysis. This unique case confirms the essential role of glucocerebrosidase in human development and, like the null allele Gaucher mouse, demonstrates the lethality of a homozygous null mutation. The presence of this novel mutation and the resulting unstable mRNA accounts for the severity of the phenotype observed in this fetus, and contributes to the understanding of genotype/phenotype correlation in Gaucher disease.
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PMID:Prenatal lethality of a homozygous null mutation in the human glucocerebrosidase gene. 937 21


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