Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Deoxy-D-galactose, in a dose of 3 mmol/kg, was administered intraperitoneally twice daily to young rats for periods up to 12 weeks. This dosage schedule resulted in recurrent phosphate trapping predominantly in liver. UTP deficiency was excluded by simultaneous uridine injections. Phosphate trapping was caused by the rapid accumulation of 2-deoxy-D-galactose 1-phosphate and was most pronounced in liver but also demonstrated in small intestine, brain, spleen, and thymus. The marked, although transient, drop in the hepatic content of inorganic phosphate triggered the catabolism of adenine nucleotides and a loss of ATP. Other metabolic pathways affected by phosphate deficiency include glycogenolysis and glycolysis. Increasing with time, repeated doses of the galactose analog led to retardation and arrest of growth, hepatomegaly, and splenomegaly. The average relative liver and spleen weights were elevated 2.5- and 4.5-fold, respectively, after 12 weeks of treatment. Liver damage was indicated by hyperbilirubinaemia and a progressive rise in the activity in plasma of sorbitol dehydrogenase, alkaline phosphatase, and gamma-glutamyltransferase. Examination by light and electron microscopy showed increasing numbers of vacuoles, surrounded by a single membrane, in hepatocytes, sinusoidal endothelial cells, and Kupffer cells. Focal cytoplasmic degeneration in hepatocytes was occasionally indicated by formation of autophagic vacuoles and finger print lysosomes. Hepatocytes of 2-deoxy-D-galactose-treated rats showed a dissociation and fragmentation of the rough endoplasmic reticulum. Sinusoidal endothelial cells and Kupffer cells were markedly enlarged, the latter contained a PAS-positive but amylase resistant substance. Extrahepatic changes included an increased occurrence of vacuolated cells in thymus. Phosphate trapping and its metabolic consequences are common phenomena in the experimental injury induced b 2-deoxy-D-galactose and in some hereditary diseases such as uridylyltransferase deficiency galactosaemia, fructose intolerance and glucose-6-phosphatase deficiency.
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PMID:Consequences of recurrent phosphate trapping induced by repeated injections of 2-deoxy-D-galactose. Biochemical and morphological studies in rats. 4 10

Clinical and biochemical diagnostic studies concerned 17 cases of galactosemia coming from 15 not consauguineous families. Galactosemia was diagnosed between 1-st day and 11-th month of life. Tentative diagnosis based on clinical picture was made in 12 infants, others were detected through family history of galactosemia and/or biochemical newborn screening carried out at the National Research Institute of Mother and Child since 1969. Clinical symptoms of galactosemia occurred in most patients in the first week of life. They were the following (tab. II): hepatomegaly (in 94%), jaundice (81%), splenomegaly (79%), vomitus (62%) and diarrhoea in 56% of patients. Cataract was found in 6 infants (38%). Biochemical diagnosis was based on the results of enzymatic estimation of galactose-1-phosphate uridyl transferase activity in blood, galactose-1-phosphate in red blood cells and galactose in blood and urine. No activity of galactose-1-phosphate uridyl transferase was found in all patients, and the concentration of galactose-1-phosphate was higher than 25 mg/100 ml of red blood cells. High galactose level was observed in blood and urine in all patients with typical clinical course of galactosemia. In 2 patients however without clinical symptoms of the disease only trace amounts of galactose was detected in blood and urine. All these patients were treated with galactose free diet.
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PMID:[Clinical and biochemical diagnosis of galactosemia among our cases]. 26 27

Using rabbit erythrocyte-derived neutral glycosphingolipids enriched for a ceramide pentasaccharide as the antigen, we detected elevated anti-galactosyl-alpha(1-3)galactose (anti-G alpha G) antibody levels in 76% of children with active visceral leishmaniasis (kala-azar [KA]) and in 42% of clinically cured patients with KA who had been treated about 5 years previously with meglumine antimonate (30 mg/kg in a series of 15 daily injections). The long-term persistence of elevated G alpha G antibodies was also found in 56% of children living in the same geographic zone who, at the time of the initial clinical examination, had fever and evident splenomegaly with hyperglobulinemia but a negative bone marrow aspirate for leishmanial bodies. Five years after antimonate treatment, these clinically cured children with presumptive KA were studied serologically. Their mean G alpha G antibody values were slightly lower than those in patients with active KA but were still abnormal. Using different biochemical and immunological approaches, we found that elevated G alpha G antibodies present in patients with KA bound specifically to glycoconjugates with an alpha(1-3)-terminal galactose residue. G alpha G antibodies were mainly distributed between immunoglobulin classes G and M in patients with active KA and in antimonate-treated patients with clinically cured KA. The possibility of the existence of remnant living parasites or the persistence of inserted G alpha G epitopes in parasitized macrophages was proposed as a mechanism to explain the long-term persistence of abnormal G alpha G antibodies in patients apparently cured of KA.
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PMID:Persistence of elevated levels of galactosyl-alpha(1-3)galactose antibodies in sera from patients cured of visceral leishmaniasis. 246 Apr 98

It was recently shown in this laboratory that treatment of newborn animals with certain enzymic inducers causes stable changes in the activities of the inducible enzymes at a later adult stage. Cataracts, hepato-splenomegaly and other galactosemia symptoms in galactosemic W/SSM rats develop spontaneously. The increased uptake of galactose by erythrocytes, but not the decreased level of galactose-1-phosphate uridyl transferase (Gal-1-PUT) activity was assumed to be the major cause of the disease. The administration of galactose to the newborn W/SSM rats (2 mg/g of body weight for 14 days) resulted in a sustained decline in the uptake of 14C-galactose by erythrocytes at least for five months, in an increase of glucoso-6-phosphate dehydrogenase activity and in a continuous fall of Gal-1-PUT activity. The neonatal treatment of the galactosemic rats with galactose abolished the main symptoms of galactosemia (cararacts, hepato-splenomegally) in adult animals, perhaps ar a consequence of the stable changes in the galactose metabolism.
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PMID:[Correction of the symptoms of hereditary galactosemia in W/SSM strain rats by enzymatic imprinting]. 720 Apr 39

Two cases of red cell aldolase deficiency associated with congenital nonspherocytic hemolytic anemia are reported. The proband is a fourteen-month-old Japanese boy. Consanguineous marriage was not proven but probable in this family, as the parents were born in the same small island. The proband had moderate to mild anemia aggravated by upper respiratory infections, 1 cm hepatomegaly and 2.5 cm splenomegaly, but was unremarkable in other respects and has thus far not shown mental or growth retardation. He did not have dysmorphic features. The red cell aldolase activity was 6% of the normal mean. The enzyme was unstable with respect to heat, and Km for fructose 1,6-diphosphate (F-1,6-DP) was high. The parents and other heterozygotes showed intermediate activity between that of the proband and that of normal subjects. Red cell F-1,6-DP concentration in this case was remarkably increased. Red cell glucose consumption, and lactate formation, as well as hexose monophosphate shunt activity, were decreased as compared with a comparable reticulocyte-rich hereditary spherocytosis patient. Hexose monophosphate dehydrogenase by a high concentration of F-1,6-DP in his red cells. As a result of family study, another homozygous aldolase deficiency case associated with hemolytic anemia was found. He is 13 years old and a nephew of the proband's paternal grandmother. His hemolytic anemia also is moderate to mild and aggravated by upper respiratory infections. He does not seem to have mental or growth retardation, nor does he possess dysmorphic features.
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PMID:Two cases of red cell aldolase deficiency associated with hereditary hemolytic anemia in a Japanese family. 733 96

Gaucher's disease is a genetically determined inborn error of metabolism in which acid beta-glucosidase or one of its cofactors is absent or diminished in macrophage cells and cause an accumulation of glucosylceramide in these cells. These Gaucher cells accumulate in the organs of the reticuloendothelial system and cause varying degrees of splenomegaly, hepatomegaly, and encroachment of the marrow cavity of bones. Dental radiographs often reveal consistent bony changes that result from this encroachment. In cases where visceral signs are not apparent, dental radiographs can detect the presence of the disease. Because therapy is available, early recognition of this disorder may reduce overall morbidity. A review of the dental radiographic changes over as many as 60 years shows the effects of oral surgery procedures on bone degeneration and regeneration. The effects of mannose lectin acid beta-glucosidase, alglucerase on bone deposition are discussed. Finally, a literature review shows that the changes in the dental radiograph of patients with Gaucher's disease are very specific. Currently, this disorder and its associated molecular genetics are a prototype for research of new treatments such as allogenic bone marrow transplantation and molecularly engineered enzymes.
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PMID:Dental observations in Gaucher's disease: review of the literature and two case reports with 13- and 60-year follow-ups. 897 38

The prevalence of anti-Leishmania donovani antibodies was investigated in 1,500 Brazilian blood donors and multiply transfused hemodialysis patients. Sera were tested using the fucose-mannose ligand (FML) ELISA, which was shown to have 100% sensitivity and 96% specificity for kala-azar. Among 1,194 volunteer blood donors, seroreactivity was 9%, increasing to 25% in a periurban kala-azar focus. However, higher positivity (37%) was found in multiply transfused hemodialysis patients from Natal, where kala-azar is constantly present in low numbers (endemic), with sporadic outbreaks in localized regions (endemic and epidemic). Risk factors included blood transfusion, which was significantly associated with the presence of anti-Leishmania antibodies (chi2 = 8.567, P < 0.005), but did not include potential exposure to sandfly bites (chi2 = 0.033, P > 0.1). The prevalence significantly decreased to 7% in hemodialysis patients from Rio de Janeiro, where kala-azar is only occasionally seen, and was 0% in patients undergoing continuous ambulatorial peritoneal dialysis. The prospective analysis of 27 FML-seroreactive donors from Natal revealed amastigotes of Leishmania in the bone marrow of one subject while four had clinical complaints, including splenomegaly and hepatosplenomegaly. Our results point to the need for control of blood transfusion as a possible route for transmission of kala-azar in endemic areas.
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PMID:Prevalence of anti-Leishmania donovani antibody among Brazilian blood donors and multiply transfused hemodialysis patients. 928 10

In neonates, inborn errors of metabolism can produce all the major signs of liver dysfunction - jaundice, coagulopathy, hepatomegaly, splenomegaly, ascites and encephalopathy. The significance of encephalopathy in the neonate is different from that in older patients; it is usually due to a specific abnormality such as hypoglycaemia rather than being a non-specific indicator of liver failure. Attention is focused on five neonatal presentations: unconjugated hyperbilirubinaemia, cholestatic jaundice with otherwise good liver function, severe liver dysfunction (jaundice, coagulopathy persisting after vitamin K, and ascites), hepatomegaly with hypotonia+/- cardiomyopathy; and hepatosplenomegaly. The metabolic disorders presenting in these ways are listed alongside specific clinical features that can aid differential diagnosis and tests that can be used to confirm or refute the diagnosis. Diagnosis is important because treatment can be dramatically effective, e.g. withdrawal of galactose in galactosaemia. Even when treatment is not effective it is often possible to offer prenatal diagnosis for future pregnancies.
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PMID:Inborn errors presenting with liver dysfunction. 1206 38

The maturation of N-glycans to complex type structures on cellular and secreted proteins is essential for the roles that these structures play in cell adhesion and recognition events in metazoan organisms. Critical steps in the biosynthetic pathway leading from high mannose to complex structures include the trimming of mannose residues by processing mannosidases in the endoplasmic reticulum (ER) and Golgi complex. These exo-mannosidases comprise two separate families of enzymes that are distinguished by enzymatic characteristics and sequence similarity. Members of the Class 2 mannosidase family (glycosylhydrolase family 38) include enzymes involved in trimming reactions in N-glycan maturation in the Golgi complex (Golgi mannosidase II) as well as catabolic enzymes in lysosomes and cytosol. Studies on the biological roles of complex type N-glycans have employed a variety of strategies including the treatment of cells with glycosidase inhibitors, characterization of human patients with enzymatic defects in processing enzymes, and generation of mouse models for the enzyme deficiency by selective gene disruption approaches. Corresponding studies on Golgi mannosidase II have employed swainsonine, an alkaloid natural plant product that causes "locoism", a phenocopy of the lysosomal storage disease, alpha-mannosidosis, as a result of the additional targeting of the broad-specificity lysosomal mannosidase by this compound. The human deficiency in Golgi mannosidase II is characterized by congenital dyserythropoietic anemia with splenomegaly and various additional abnormalities and complications. Mouse models for Golgi mannosidase II deficiency recapitulate many of the pathological features of the human disease and confirm that the unexpectedly mild effects of the enzyme deficiency result from a tissue-specific and glycoprotein substrate-specific alternate pathway for synthesis of complex N-glycans. In addition, the mutant mice develop symptoms of a systemic autoimmune disorder as a consequence of the altered glycosylation. This review will discuss the biochemical features of Golgi mannosidase II and the consequences of its deficiency in mammalian systems as a model for the effects of alterations in vertebrate N-glycan maturation during development.
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PMID:Golgi alpha-mannosidase II deficiency in vertebrate systems: implications for asparagine-linked oligosaccharide processing in mammals. 1241 4

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous multisystem condition. Patients with non-neuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase reverses or ameliorates many of the manifestations of type 1 Gaucher disease. However, the variable disease pattern and severity, and the uncertain manner of progression, render the decision to initiate ERT difficult. Thus, implementation of treatment and evaluation of the therapeutic response must be tailored to the individual patient. To obtain an evidence-based consensus on contemporary therapeutic goals, an international panel of physicians with extensive clinical experience in Gaucher disease met to review the extant literature on its treatment. The panel adopted an integrated system-based approach to arrive at a comprehensive guide to individualized management. Here we establish goals of treatment in Gaucher disease and propose a comprehensive schedule of monitoring of all relevant aspects to confirm the achievement, maintenance, and continuity of the therapeutic response.
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PMID:Therapeutic goals in the treatment of Gaucher disease. 1546 45


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