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)

A Japanese patient with Gaucher disease type 2 was treated with enzyme therapy, alglucerase, from 7 to 22 months of age. Whereas hematologic parameters were normalized and hepatosplenomegaly was alleviated, no improvement in neurologic symptoms occurred, and the patient died of respiratory failure at age 22 months. Postmortem examination revealed massive intra-alveolar infiltration of Gaucher cells in lungs and in the central nervous system, i.e., the presence of Gaucher cells in the perivascular Virchow-Robins spaces in the cortex and deep white matter and extensive lamilar necrosis with reactive proliferation of blood vessels and macrophage infiltration of the cerebral cortex. It is suggested that enzyme therapy, with thus far recommended dose, does not prevent long-term respiratory and central nervous system involvement in severe varients of Gaucher disease.
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PMID:Enzyme therapy in Gaucher disease type 2: an autopsy case. 1022 17

The finding of extensive lytic lesions in the mandible of a 19-year-old Ashkenazi Jewish woman led to the diagnosis of Type 1 Gaucher disease. She had extensive skeletal involvement, marked hepatosplenomegaly, and deficient acid beta-glucosidase activity. Mutation analysis identified heteroallelism for acid beta-glucosidase mutations N370S and P401L, the latter being a novel missense mutation in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced catalytic activity (specific activity based on cross-reacting immunological material approximately 0.21), which was similar to that of the mild N370S mutant enzyme. The expression studies predicted a mild phenotype for the proposita's N370S/P401L genotype which was inconsistent with her severe diffuse skeletal disease and organ involvement. Since lytic mandibular lesions may be complicated by osteomyelitis, pathologic fracture, and tooth loss, regular dental assessments in Type 1 Gaucher patients should be performed.
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PMID:Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: identification and expression of a novel acid beta-glucosidase mutation. 1034 Jun 47

Imiglucerase, the recombinantly produced enzyme, is gradually replacing the human placental derived alglucerase in the treatment of gaucher patients. We describe the first case, to the best of our knowledge, of an anaphylactoid reaction to imiglucerase in a patient who tolerated alglucerase. The patient was diagnosed at the age of 2 4/12 years with anemia and hepatosplenomegaly. Over the years he had suffered from marked splenomegaly, thrombocytopenia and recurrent bleeding episodes. At the age of 24 he started treatment with imiglucerase. After 3 months of treatment, immediately after starting an infusion, he experienced flushing, cough, tachycardia, palpitation, chest pain and excessive sweating, which reoccurred on a consecutive administration. Substitution with alglucerase was tolerated well, with only mild rash when he was premedicated with benadryl. Immediate skin tests to alglucerase, imiglucerase and gelatin were negative. IgG against alglucerase was undetectable. The in vitro mast cell degranulation test was positive for alglucerase, imiglucerase heamaccel (a gelatin based plasma substitute, which is a component of imiglucerase). This sensitivity to imiglucerase but not to alglucerase, raises the question of future treatment for this patient, since the production of alglucerase may cease, once imiglucerase production will cover the need for replacement enzyme.
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PMID:Anaphylactoid reaction to imiglucerase, but not to alglucerase, in a type I Gaucher patient. 1038 90

Gaucher's disease is characterized by increased incidence of several autoantibodies, but autoimmune phenomena are rare in Gaucher patients. We report the first occurrence of Gaucher's disease and antiphospholipid syndrome in the same patient. A 27-year-old woman with hepatosplenomegaly and thrombocytopenia who was diagnosed as having Gaucher's disease with the genotype 1226G/1226G developed Coombs'-positive hemolytic anemia, recurrent abortions, and a high titer of IgG and IgM anticardiolipin antibodies constituting the diagnosis of antiphospholipid syndrome. A successful pregnancy outcome was achieved by combined therapy with aspirin, low-molecular-weight heparin, prednisone, and enzyme replacement therapy with imiglucerase. The possible pathogenicity of antiphospholipid antibodies found in the sera of many asymptomatic Gaucher patients should be further clarified.
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PMID:Successful pregnancy outcome in a patient with Gaucher's disease and antiphospholipid syndrome. 1190 43

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

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

Gaucher disease (GD) is a progressive macrophage lipidosis capable of causing disabling and life-threatening complications. Anecdotal experiences suggest that GD may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy (ERT) with imiglucerase. We conducted surveys of patients and Hematology-Oncology specialists to assess the frequency of diagnostic delays. Additionally, we report a series of patients who suffered diagnostic delays and as a result developed disabilities including potentially life-threatening manifestations of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 48.7 +/- 123.6 months. More than two-thirds were evaluated and managed by a hematologist-oncologist (Hem-Onc). A global survey of 406 Hem-Oncs found that only 20% considered GD in the differential diagnosis for all of its classic symptoms (cytopenia, hepatosplenomegaly, bone pain); the diagnosis considered most likely included leukemia, lymphoma, and multiple myeloma. To illustrate actual consequences of diagnostic delays, we describe 14 patients with GD who suffered from symptoms for up to 10 years before correct diagnosis. Diagnostic delays led to complications that are preventable or reversible with ERT (i.e., avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, liver pathology). Patients homozygous for N370S mutation in this series were vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur in GD and may result in severe disease manifestations. Our findings suggest that physician education will increase the likelihood of prompt detection of GD and improve its management with ERT with imiglucerase when indicated.
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PMID:Consequences of diagnostic delays in type 1 Gaucher disease: the need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention. 1880 77

Enzyme replacement therapy (ERT) with imiglucerase reduces hepatosplenomegaly and improves hematologic parameters in Gaucher disease type 1 within 6-24 months. Miglustat reduces organomegaly, improves hematologic parameters, and reverses bone marrow infiltration. This trial evaluates miglustat in patients clinically stable on ERT. Tolerability of miglustat and imiglucerase, alone and in combination, pharmacokinetic profile, organ reduction, and chitotriosidase activity were assessed. Thirty-six patients stable on imiglucerase were randomized into this phase II, open-label trial. Statistically significant changes from baseline were assessed (paired t test) on primary objectives with secondary analyses on biochemical and safety parameters. Liver and spleen volume were unchanged in switched patients. No significant differences were seen between groups regarding mean change in hemoglobin. Mean change in platelet counts was only significant between miglustat and imiglucerase groups (P = .035). Chitotriosidase activity remained stable. In trial extension, clinical endpoints were generally maintained. Miglustat was well tolerated alone or in combination. Miglustat's safety profile was consistent with previous trials; moreover, no new cases of peripheral neuropathy were observed. Gaucher disease type 1 (GD1) parameters were stable in most switched patients. Combination therapy did not show benefit. Findings suggest miglustat could be an effective maintenance therapy in stabilized patients with GD1.
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PMID:Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. 1760 29

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


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