Cases reported "Gaucher Disease"

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1/135. Massive splenomegaly and Epstein-Barr virus-associated infectious mononucleosis in a patient with gaucher disease.

    PURPOSE: gaucher disease should be considered in the differential diagnosis of a patient with Epstein-Barr virus (EBV) infection who has unexplained or disproportionate splenomegaly. patients AND methods: A previously asymptomatic adolescent with EBV-associated infectious mononucleosis and massive splenomegaly is described. He was found to have gaucher disease on bone marrow biopsy, which was performed to exclude a hematologic malignancy. The diagnosis was confirmed by assay of beta-glucosidase enzyme activity. RESULTS: Regression of splenomegaly and improving hematologic indices. CONCLUSION: patients with infectious mononucleosis and disproportionate organomegaly should be investigated to exclude a hematologic malignancy or an underlying storage disorder such as gaucher disease.
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ranking = 1
keywords = enzyme
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2/135. Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease.

    gaucher disease is an autosomal recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal hydrolase, acid beta-glucosidase. Three phenotypically distinct subtypes result from different acid beta-glucosidase mutations encoding enzymes with absent or low activity. A severe neonatal type 2 variant who presented with collodion skin, ichthyosis, and a rapid neurodegenerative course had two novel acid beta-glucosidase alleles: a complex, maternally derived allele, E326K L444P, and a paternally inherited nonsense mutation, E233X. Because the only other non-pseudogene-derived complex allele, D140H E326K, also had the E326K lesion and was reported in a mild type 1 patient with a D140H E326K/K157Q genotype, these complex alleles and their individual mutations were expressed and characterized. Because the E233X mutation expressed no activity and the K157Q allele had approximately 1% normal specific activity based on cross-reacting immunologic material (CRIM SA) in the baculovirus system, the residual activity in both patients was primarily from their complex alleles. In the type 1 patient, the D140H E326K allele was neuroprotective, encoding an enzyme with a catalytic efficiency similar to that of the N370S enzyme. In contrast, the E326K L444P allele did not have sufficient activity to protect against the neurologic manifestations and, in combination with the inactive E233X lesion, resulted in the severe neonatal type 2 variant. Thus, characterization of these novel genotypes with non-pseudogene-derived complex mutations provided the pathogenic basis for their diverse phenotypes.
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ranking = 3
keywords = enzyme
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3/135. enzyme therapy in gaucher disease type 2: an autopsy case.

    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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ranking = 2
keywords = enzyme
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4/135. Type 1 gaucher disease presenting with extensive mandibular lytic lesions: identification and expression of a novel acid beta-glucosidase mutation.

    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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keywords = enzyme
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5/135. Anaphylactoid reaction to imiglucerase, but not to alglucerase, in a type I Gaucher patient.

    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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ranking = 2.5471760814901
keywords = enzyme, replacement
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6/135. Intracellular transport of acid beta-glucosidase and lysosome-associated membrane proteins is affected in Gaucher's disease (G202R mutation).

    Gaucher's disease (GD) is caused by an inherited deficiency of acid beta-glucosidase with storage of glucosylceramides in the lysosomes of macrophages. This study identifies a G202R mutation in the acid beta-glucosidase gene in an infant with severe neuronopathic (type 2) GD and only slightly reduced acid beta-glucosidase activity. Western blot analysis, pulse chase experiments, and the thin frozen section immunogold method were used to analyse the implications of this mutation on the pathogenesis, clinical heterogeneity and diagnostic evaluation of GD. The results show that acid beta-glucosidase persists in the patient's fibroblasts as a mannose-rich polypeptide in the endoplasmic reticulum and is not transported to the lysosomes. By contrast, high expression of the lysosome-associated membrane proteins LAMP-1 and LAMP-2, saposin C, and cathepsin d was observed in the patient's lysosomes. Immunogold labelling of the integral membrane proteins LAMP-1 and LAMP-2 increases significantly at the cell surface of kupffer cells and fibroblasts as well as at the apical membrane of hepatocytes. In addition, LAMP-1 and LAMP-2 associate with the bilayer of stored glucosylceramide. It is concluded that defective intracellular transport of mutant acid beta-glucosidase from the endoplasmic reticulum to lysosomes leads to a more severe clinical phenotype than the residual enzyme activity may indicate. Furthermore, the detection of LAMP in the tubular bundles of undigested glucosylceramides, as well as their increased concentration at the surfaces of the affected cells, suggests that these proteins play a role in the storage or removal of substrate in GD. Intracellular targeting of acid beta-glucosidase and LAMP contributes to the broad phenotypic heterogeneity of GD.
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ranking = 1
keywords = enzyme
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7/135. Metaphyseal undertubulation in gaucher disease: resolution at MRI in a patient undergoing enzyme replacement therapy.

    gaucher disease is a sphingolipid storage disorder that results in the accumulation of Gaucher cells within the reticuloendothelial system. The life span can be near normal in the most common form. Our case illustrates the resolution of the skeletal findings in gaucher disease following enzyme replacement therapy. We also report the correlation of these findings with clinical improvement.
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ranking = 77080.23210972
keywords = enzyme replacement therapy, enzyme replacement, replacement therapy, enzyme, replacement
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8/135. Type 2 gaucher disease: the collodion baby phenotype revisited.

    The association of gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45), and congenital ichthyosis was first noted a decade ago. Subsequently, a null allele type 2 Gaucher mouse was generated that also exhibited ichthyotic skin, confirming that the skin disorder and enzyme deficiency were directly related. This paper details the clinical and molecular characterisation of 6 cases of type 2 gaucher disease presenting with the collodion baby phenotype. The identified mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q), as well as alleles resulting from recombination with the nearby glucocerebrosidase pseudogene. There is significant genotypic heterogeneity in this rare subset of patients with type 2 gaucher disease. gaucher disease should be considered in the differential diagnosis of congenital ichthyosis in the newborn period.
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ranking = 1
keywords = enzyme
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9/135. Massive hepatic fibrosis in Gaucher's disease: clinico-pathological and radiological features.

    hepatomegaly is frequent in patients with type 1 Gaucher's disease and is associated with infiltration of the liver with pathological macrophages. Most patients suffer no significant clinical consequences, but a few develop portal hypertension which may progress to parenchymal liver failure. We describe four patients with Gaucher's disease who have developed portal hypertension. We have reviewed their clinical histories and all available histological and radiological material. All had severe Gaucher's disease with multi-organ involvement, and had undergone splenectomy in childhood. Histologically, this advanced liver disease was characterized by a picture of extreme and advanced confluent fibrosis occupying the central region of the liver. This massive fibrosis is associated with characteristic radiological appearances. The liver histology in these cases is highly unusual and virtually unknown in other conditions. Our studies indicate that without specific treatment the liver disease is progressive and rapidly fatal. However, institution of enzyme replacement therapy with imiglucerase may have beneficial effects even when the condition is far advanced.
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ranking = 15416.046421944
keywords = enzyme replacement therapy, enzyme replacement, replacement therapy, enzyme, replacement
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10/135. Perinatal lethal form of Gaucher's disease presenting with hemosiderosis.

    A term infant with hydrops fetalis presented with hypotonia, massive splenomegaly, renal failure, and severe hyperferritinemia. multiple organ failure, myoclonus, and opisthotonus ensued and she died at 15 days of age. High rounded forehead, large open fontanel, and a small recessed chin led to initial premortem diagnosis of zellweger syndrome, but her plasma profile of long chain fatty acid was normal. Her subsequent clinical course and findings of postmortem examinations were consistent with perinatal lethal form of Gaucher's disease (PLGD). The diagnosis was confirmed by deficiency of enzyme beta-glucocerebrosidase in white blood cells and in cultured fibroblasts. In addition to the crossover features of Zellweger phenotype, this infant exhibited a number of unusual features including, severe hyperferritinemia, rapid progression of splenomegaly, and absence of icthyosis.
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ranking = 1
keywords = enzyme
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