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

A 36-year-old woman was admitted for hepatosplenomegaly and anemia. Bone marrow cytology showed "sea-blue histiocytes", vacuolated macrophages and plasma cells. As primary liver disease, malignancy or hematologic disorders were excluded, and plasma chitotriosidase activity was increased 27-fold over control, the presence of a lysosomal storage disease was suspected. Biochemical analysis of skin fibroblasts revealed normal glucocerebrosidase and sphingomyelinase activity, but lipid analysis showed a more than 15-fold accumulation of cholesterol esters within the cells. The activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects. Mutational analysis of the patient's blood showed the homozygous G-->A mutation at position -1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD); the polymorphic background was that of the complex haplotype -6Thr, 2Gly, 894 G-->A. Based on clinical, laboratory, cytological and and biochemical findings, CESD can clearly be separated from other more frequent inherited lysosomal storage diseases, e.g. atypical forms of Gaucher disease.
 ...
PMID:Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation. 1055

Mucopolysaccharidosis type III A (MPS III A, Sanfilippo syndrome) is a rare, autosomal recessive, lysosomal storage disease characterized by accumulation of heparan sulfate secondary to defective function of the lysosomal enzyme heparan N- sulfatase (sulfamidase). Here we describe a spontaneous mouse mutant that replicates many of the features found in MPS III A in children. Brain sections revealed neurons with distended lysosomes filled with membranous and floccular materials with some having a classical zebra body morphology. Storage materials were also present in lysosomes of cells of many other tissues, and these often stained positively with periodic-acid Schiff reagent. Affected mice usually died at 7-10 months of age exhibiting a distended bladder and hepatosplenomegaly. Heparan sulfate isolated from urine and brain had nonreducing end glucosamine- N -sulfate residues that were digested with recombinant human sulfamidase. Enzyme assays of liver and brain extracts revealed a dramatic reduction in sulfamidase activity. Other lysosomal hydrolases that degrade heparan sulfate or other glycans and glycosaminoglycans were either normal, or were somewhat increased in specific activity. The MPS III A mouse provides an excellent model for evaluating pathogenic mechanisms of disease and for testing treatment strategies, including enzyme or cell replacement and gene therapy.
 ...
PMID:A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome). 1056 64

The mucopolysaccharidoses are a group of lysosomal storage diseases caused by deficiency of an enzyme required for the normal degradation of glycosaminoglycans. Patients with mucopolysaccharidosis typically have widespread lysosomal storage, skeletal and central nervous system disease, and hepatosplenomegaly. Some patients with mucopolysaccharidosis may benefit from enzyme replacement therapy or bone marrow transplantation. Animal models of mucopolysaccharidosis have proven valuable for the evaluation of the effectiveness of potential treatments for patients with lysosomal storage disease. A murine model of MPS VII (Sly syndrome) has proven particularly useful because of its well-defined genetics and its well-characterized clinical, pathologic, and biochemical alterations, which resemble those seen in patients with mucopolysaccharidosis. Correction of these alterations forms the basis for evaluation of the effectiveness of novel treatments. A wide range of therapies have been tested using this model, including enzyme replacement therapy, bone marrow, stem cell, and neural progenitor cell transplantation, and a variety of viral-mediated gene therapies. The inferences drawn from these therapeutic studies using the murine MPS VII model are likely generalizable to other lysosomal storage diseases.
 ...
PMID:Murine mucopolysaccharidosis VIL: impact of therapies on the phenotype, clinical course, and pathology in a model of a lysosomal storage disease. 1177 44

Gaucher's disease is an autosomal recessive lysosomal storage disease resulting from glucocerebrosidase deficiency. In this report, five patients with adult Gaucher's disease are described. The clinical course of these patients was characterized by progressive diffuse aseptic necrosis in the large bones, so-called Erlenmeyer's flask deformity, and hepatosplenomegaly. Splenomegaly was accompanied by hypersplenism with anemia and thrombocytopenia, therefore splenectomy was performed. The diagnosis of Gaucher's disease was based on the finding of Gaucher's cells on bone marrow biopsy. Tissue blocks were cut and routinely processed. Slides staining for iron (Peris' blue) and PAS (periodic acid--Schiff) including immunohistochemical staining for CD68 and HLA-DR was performed in all five cases. Gaucher's cells were seen as large cells with granular or fibrillar distended cytoplasm, with the characteristic 'wrinkled tissue paper' appearance, and eccentric nuclei. PAS staining showed strongly positive granular or fibrillar material in the cytoplasm. Immunohistochemical stain for CD68 and HLA-DR helped identify isolated Gaucher's cells, which are hystiocytic in nature. This stain accentuates their fine linear striations. Small pieces were ultrastructurally analyzed.
 ...
PMID:Immunohistochemical and ultrastructural features of Gaucher's cells--five case reports. 1185 32

A 5-month-old boy had respiratory problems and gastroesophageal reflux. Electron microscopy of a tracheal biopsy specimen showed accumulation of lamellar bodies in the columnar cells indicative of lysosomal storage disease. Subsequently, the child had neurologic symptoms and hepatosplenomegaly, and the diagnosis of Gaucher's disease type 2 was made.
 ...
PMID:A patient with type 2 Gaucher's disease with respiratory disease. 1258 49

Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. No clear correlation exists between the approximately 200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with non- neuronopathic and neuronopathic disease, respectively. We report the X-ray structure of GlcCerase at 2.0 A resolution. The catalytic domain consists of a (beta/alpha)(8) TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest alpha-helix (helix 7), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase.
 ...
PMID:X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease. 1279 54

Gaucher disease is a lysosomal storage disease caused by glucocerebrosidase deficiency. Although purely visceral in most cases, some Gaucher disease patients have neurological signs. Signs of Gaucher disease appear after a symptom-free period, except in rare cases with fetal onset. The description of such cases was based mainly on single reports and siblings. We report here a series of perinatal-lethal Gaucher disease cases highlighting the specificity of this phenotype. We retrospectively studied eight original cases of proven Gaucher disease with fetal onset. Non-immune hydrops fetalis was present in all cases but one, and associated with hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphy. The similarities between our cases and 33 previously described cases allow us to better delineate the perinatal-lethal Gaucher disease phenotype. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurological involvement begins in the first week and leads to death within three months. Hepatosplenomegaly is a major sign, and associated with ichthyosis, arthrogryposis, and facial dysmorphy in some 35-43% of cases. Perinatal-lethal Gaucher disease is a specific entity defined by its particular course and signs that are absent in classical type 2 Gaucher disease. Our study provides clues to the diagnosis of this likely underdiagnosed condition, which must be biochemically confirmed in order to propose appropriate genetic counselling.
 ...
PMID:Perinatal-lethal Gaucher disease. 1283 52

alpha-Mannosidosis is a rare lysosomal storage disease that is caused by an inherited deficiency of the lysosomal alpha-mannosidase. Clinical symptoms include coarse facial features, skeletal involvement (dysostosis multiplex), hearing disabilities, mental retardation and hepatosplenomegaly. Only few cases with ocular symptoms have been reported, mainly with lenticular opacities. We report on two brothers with complex neurological symptoms who presented with late-onset retinal dystrophy and were followed up for 6 years.
 ...
PMID:Late-onset retinal dystrophy in alpha-mannosidosis. 1607 19

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.
 ...
PMID:Gaucher disease: review of the literature. 1846 35

Niemann-Pick type C (NP-C) disease is a neurovisceral lysosomal storage disease characterized by neurologic dysfunction, hepatosplenomegaly, and early death. Natural history studies are very difficult to perform due to the low incidence and high heterogeneity of disease in the human population. Sixteen cats with a spontaneously occurring missense mutation in NPC1 were evaluated over time to define the progression of neurologic and hepatic disease. Affected cats had remarkably regular onsets of specific signs of cerebellar and vestibular system dysfunction with progressive severity of dysfunction quantified by postrotatory nystagmus and brain stem auditory evoked response measures. NP-C disease cats also showed increasing serum activity of alanine aminotransferase, asparate aminotransferase, and cholesterol with advancing age. Affected cats lived to a mean age of 20.5 +/- 4.8 wk. CNS and hepatic lesions were similar to those described in human patients. These data are the first to document progressive hepatic disease in the feline model and demonstrate the importance of liver disease as part of the NP-C disease phenotype. Both neurologic and hepatic measures of disease onset and severity can be used as a baseline with which to assess the efficacy of experimental therapies of NP-C disease in the feline model.
 ...
PMID:Clinical, electrophysiological, and serum biochemical measures of progressive neurological and hepatic dysfunction in feline Niemann-Pick type C disease. 1861 65


<< Previous 1 2 3 4 5 Next >>