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)

Tangier disease is a rare autosomal recessive lipid transport disease characterized by the absence of the usual high density lipoproteins from plasma and cholesteryl ester storage in many organs. 25 cases of Tangier disease have been described so long. The predominant clinical symptoms include tonsilar hypertrophy, splenomegaly and peripheral neuropathy. The cholesteryl ester storage is limited to macrophages, Schwann's cells and intestinal smooth muscle cells. Hypocholest erolemia (less than 80mg/dl), hypertriglyceridemia (greater than 200 mg/dl), and the absence of high density lipoproteins in agarose electrophoresis are the major plasma abnormalities. The protein moiety of normal high density lipoprotein consists of apoprotein A-I and apoprotein A-II. In Tangier disease, serum concentrations of these apoproteins are reduced to less than 1% and 5-10%, respectively. Theories concerning the pathogenesis of Tangier disease are only incomplete and unproved up to now; however, a structural abnormality of apoprotein A-I causing an inability to bind to lipid or other proteins (apoprotein A-II) is consistent with several of the recent biochemical findings. The imbalance of cellular cholesterol metabolism caused by the absence of high density lipoproteins as well as the presumed role of these lipoproteins in cholesterol removal from cells are discussed in this article.
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PMID:[Tangier-disease (author's transl)]. 21 46

We present a six-year follow-up of a boy with a novel type of hypolipoproteinemia, with clinical and biochemical features distinct from classical hypoalphalipoproteinemias. There were abnormally low concentrations of total and high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) B, apo A-I, and apo A-II, and the phospholipids were decreased. The most striking abnormality was an extra fraction containing mainly phospholipids and apo A-I in the HDL3 subfraction. This fraction is reminiscent of concentric 20- to 50-nm-diameter lamellar phospholipid liposomes. Plasma lecithin:cholesterol acyltransferase activity was strongly decreased. We noted a persisting polyclonal hypergammaglobulinemia, hematological abnormalities (hemolytic anemia and thrombocytopenia), and a progressive splenomegaly. After the five-year follow-up, the patient had recurrent severe infections; moderate hematuria and proteinuria developed gradually. Treatment with corticosteroids and immunoglobulins improved thrombocytopenia and hypolipoproteinemia. These clinical and biochemical findings differ from those in the known primary and secondary hypo-alpha-lipoproteinemia syndromes. Although investigation of the relatives suggests a familial predisposition for hypo-alpha-lipoproteinemia, the subject's condition can be regarded as acquired.
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PMID:Acquired hypolipoproteinemia. 158 35

A new case of C-II anapolipoproteinemia (complete apolipoprotein C-II deficiency) as the cause of severe hypertriglyceridemia with chylomicronemia (type I lipoprotein phenotype) is described. The patient was a five-year-old boy living in Connecticut. He had splenomegaly, episodic abdominal pain, and bloody stools. Absence of apolipoprotein C-II (and its isoforms C-II1 and C-II2) was documented by a sensitive and specific radioimmunoassay, analytical isoelectric focusing, and in vitro lipolytic assay. Decreased levels of high- and low-density lipoprotein cholesterol and apolipoproteins A-I and A-II and increased levels of plasma triglycerides and apolipoprotein E were found. Post-heparin extra-hepatic lipoprotein lipase activity was within normal range. Incorporation of exogenous purified human apolipoprotein C-II to an incubation mixture of purified lipoprotein lipase and the patient's triglyceride-rich lipoproteins resulted in a dramatic increase in the catabolic rate of the defective triglyceride-rich lipoproteins. The absence of the isoforms of apolipoprotein C-II in this patient indicates that a common gene exists for the C-II isoproteins, which appear to be necessary for normal triglyceride transport in humans. A literature review of 23 reported cases indicates that xanthomas and hepatosplenomegaly are less common in C-II anapolipoproteinemia than in lipoprotein lipase deficiency, the other major etiologic cause of genetic chylomicronemia.
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PMID:C-II anapolipoproteinemia and severe hypertriglyceridemia. Report of a rare case with absence of C-II apolipoprotein isoforms and review of the literature. 647 85

A 48-yr-old Caucasian female of central European origin (subject IM) with low plasma cholesterol and normal plasma triglyceride (TG) had extremely low apo A-I (6 mg/dl), A-II (5 mg/dl), and HDL cholesterol (2 mg/dl) levels. She had most of the clinical symptoms typically associated with Tangier disease, including early corneal opacities, yellow-streaked tonsils, hepatomegaly, and variable degrees of peripheral neuropathy, but had no splenomegaly. She had a myocardial infarction at age 46. Since HDL are postulated to be involved in the transport of excess cholesterol from peripheral tissues to the liver for degradation, and the ability of an HDL particle to promote cellular cholesterol efflux appears to be related to its density, size, and apo A-I and A-II contents, we isolated and characterized the HDL particles of this patient and all her first degree relatives (mother, a brother, and two children). The plasma A-I, A-II, and HDL cholesterol levels of all five relatives were either normal or high. Using anti-A-I and anti-A-II immunosorbents, we found three populations of particles in IM: one contained both apo A-I and A-II, Lp(AI w AII); one contained apo A-I but no A-II, Lp(AI w/o AII); and the third (an unusual one) contained apo A-II but no A-I, Lp(AII). Two-thirds of her plasma A-I and A-II existed in separate HDL particles, i.e., in Lp(AI w/o AII) and Lp(AII), respectively. Only Lp(AI w AII) and Lp(AI w/o AII) were present in the plasma of the relatives. All three populations of the patient's HDL particles had a normal core/surface lipid ratio, but the cores were enriched with TG. The apo A-I-containing particles, however, were considerably smaller and contained much less lipid than Lp(AII). Despite these unusual physicochemical characteristics, the apo A-I-containing particles and Lp(AII) were effective suppressors of intracellular cholesterol esterification in cholesterol-loaded human skin fibroblast. The patient's plasma apo D and lecithin cholesterol acyltransferase levels were reduced, with an increased proportion located in non-HDL plasma fractions. These findings are discussed in light of Tangier disease and other known HDL-deficiency cases, and the role of HDL in the maintenance of cell cholesterol homeostasis.
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PMID:Characterization of apolipoprotein A-I- and A-II-containing lipoproteins in a new case of high density lipoprotein deficiency resembling Tangier disease and their effects on intracellular cholesterol efflux. 843 61

Tangier disease is a rare, autosomally-inherited disorder of lipoprotein metabolism characterized by absence or marked deficiency of normal high density lipoprotein (HDL) cholesterol in plasma resulting in the accumulation of cholesteryl esters in various organs. The patient was a 55-yr-old male diagnosed as Tangier disease 16 years before. He had angina on exercise and his coronary angiogram revealed triple vessel disease including left main trunk (LMT) lesion. Stenosis of the right coronary artery was treated by percutaneous transluminal coronary angioplasty (PTCA). He was scheduled for a MIDCAB for further PTCA to be performed to relieve the stenosis of LMT. Preoperative laboratory data and physical examination showed total cholesterol 36 mg.dl-1, HDL-cholesterol 2 mg.dl-1, apoprotein A-I not-detected, pancytopenia, hyperplastic orange tonsils, splenomegaly and hepatomegaly. Clonidine 0.225 mg was orally given as a preanesthetic medication. Anesthesia was induced with fentanyl and midazolam and maintained with propofol, sevoflurane and supplemental fentanyl. Nitroglycerin and diltiazem were infused continuously. ST segment was elevated transiently during the clamping of the left anterior descending branch. Hemodynamic parameters were stable during the operation. He was extubated 2 hours after the end of the operation. No significant changes were found in postoperative EKG, total cholesterol, HDL-cholesterol and triglyceride. Perioperative course was uneventful.
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PMID:[Anesthesia for MIDCAB (minimally invasive direct coronary bypass) in a patient with Tangier disease: a case report]. 1079 27

CSA1M tumor-bearing mice exhibited a severe immune dysfunction but the underlying mechanism remained unclear. In this study, we demonstrated that the myeloid suppressor cell (Mac-1(+)Gr-1(+) cells)-(MSC) related T cell immunosuppression in this tumor-bearing model. In mice at the late stage of CSA1M tumor-bearing (Late TB [8-10 weeks after cell inoculation in male BALB/c mice]), the percentages for CD4(+) and CD8(+) T cells decreased but Mac-1(+) cells increased in spleens with severe splenomegaly. There was no deficit for concanavalin A-induced CD4(+) and CD8(+) T cell proliferation, interferon-gamma (IFN-gamma) and interleukin (IL)-4 production, but delayed-type hypersensitivity reaction were attenuated. Analysis of cytokine production in unfractionated spleen cells showed a significant reduction of IFN-gamma and a marked increase of IL-10 and IL-4. In Late-TB mice, splenic MSC number intensively accumulated; the mRNA expressions of the signal transducer and activator of transcription 1, interferon regulatory factor 1 (IRF-1), and inducible nitric-oxide synthase (iNOS) were enhanced in MSC; the nitric oxide production and arginase enzyme activity increased in MSC as well. Furthermore, the concanavalin A-induced T cell proliferation was inhibited in the presence of lipopolysaccharide- or IFN-gamma-activated MSC from Late-TB mice, which could be reversed by the iNOS specific inhibitor L-NMMA. iNOS seemed to be required more than arginase for the suppressive activity of MSC. Taken together, our results suggest that the immune dysfunction in tumor-bearing mice might be causally associated with the accumulation of MSC and its tumor-favoring property.
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PMID:Myeloid suppressor cell-associated immune dysfunction in CSA1M fibrosarcoma tumor-bearing mice. 1743 38

Hb Dhofar is a variant haemoglobin (beta(29 (GGC-GGT) gly-gly), beta(58 (CCT-CGT) pro-arg)) associated with a thalassaemic phenotype and unique to the Sultanate of Oman. We report clinical and haematological data on 54 subjects with Hb Dhofar (37 heterozygotes, 14 homozygotes and three compound heterozygotes with a different beta-thalassaemia mutation). In heterozygotes, the level of Hb Dhofar ranged from 8.8% to 21.5%. All heterozygotes had Hb A2 > 3.5%, consistent with beta-thalassaemia trait. Hb Dhofar in homozygotes and compound heterozygotes ranged from 26% to 59.7%, with a peripheral film consistent with homozygous beta-thalassaemia. Age at presentation in homozygotes ranged between 6 months and 8 yr, with a majority presenting before 5 yr of age. All had splenomegaly and six (43%) had undergone splenectomy. All had some degree of frontal bossing and in particular, two patients with infrequent transfusions had marked thalassaemic facies and stunting of growth. Hb Dhofar can be mistaken for Hb D as the electrophoretic mobility is similar, but differs from it by a variable and reduced quantity of variant Hb in both heterozygotes and homozygotes. Clinical and haematological data suggest that this mutation behaves like a moderately severe beta(+) thalassaemia allele resulting in a thalassaemia intermedia phenotype.
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PMID:Haematological and clinical features of beta-thalassaemia associated with Hb Dhofar. 1817 41

Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels <10 mg/dL in the absence of severe hypertriglyceridemia or liver disease) and to provide information about coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If apolipoprotein (Apo) A-I is not present in plasma, then three forms of ApoA-I deficiency, all with premature CHD,and normal low-density lipoprotein (LDL) cholesterol levels have been described: ApoA-I/C-III/A-IV deficiency with fat malabsorption, ApoA-I/C-III deficiency with planar xanthomas, and ApoA-I deficiency with planar and tubero-eruptive xanthomas (pictured in this review for the first time). If ApoA-I is present in plasma at a concentration <10 mg/dL, with LDL cholesterol that is about 50% of normal and mild hypertriglyceridemia, a possible diagnosis is Tangier disease due to mutations at the adenosine triphosphate binding cassette protein A1 (ABCA1) gene locus. These patients may develop premature CHD and peripheral neuropathy, and have evidence of cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma ApoA-I levels <40 mg/dL, moderate hypertriglyceridemia, and decreased LDL cholesterol, and the finding that most of the cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and splenomegaly, and are at increased risk of developing renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk.
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PMID:Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. 2129 40

A kindred affected with fish eye disease (FED) from Oklahoma is reported. Two probands with corneal opacification had mean levels of high-density lipoprotein (HDL) cholesterol (C), apolipoprotein (apo) A-I, and apoA-I in very large alpha-1 HDL particles that were 9%, 17%, and 5% of normal, whereas their parents and 1 sibling had values that were 61%, 77%, and 72% of normal. The probands had no detectable lipoprotein-X, and had mean low-density lipoprotein cholesterol (LDL-C) and triglyceride levels that were elevated. Their mean lecithin cholesterol acyltransferase (LCAT) activities, cholesterol esterification rates, and free cholesterol levels were 8%, 42%, and 258% of normal, whereas their parents and 1 sibling had values that were 55%, 49%, and 114% of normal. The defect was due to 1 common variant in the LCAT gene in exon 1: c101t causing a proline34leucine substitution and a novel mutation c1177t causing a threonine37methionine substitution, with the former variant being found in the father and 1 sibling, and the latter mutation being found in the mother, and both mutations being present in the 2 probands. FED is distinguished from familial LCAT deficiency (FLD) by the lack of anemia, splenomegaly, and renal insufficiency as well as normal or increased LDL-C. Both FLD and FED cases have marked HDL deficiency and corneal opacification, and FED cases may have premature coronary heart disease in contrast to FLD cases. Therapy, using presently available agents, in FED should be to optimize LDL-C levels, and 1 proband responded well to statin therapy. The investigational use of human recombinant LCAT as an enzyme source is ongoing.
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PMID:A kindred with fish eye disease, corneal opacities, marked high-density lipoprotein deficiency, and statin therapy. 2463 83

Although BCR-ABL negative myeloproliferative neoplasms (MPN)--and especially myelofibrosis (MF)--are recognized to be associated with autoimmune phenomena, immune derangements in MPN have been much less studied. Myeloid-derived suppressor cells (MDSC) are one type of important immune modulator cell. Therefore, we studied MDSCs in MPN disease. MDSCs were studied in two cohorts: the first cohort was 55 patients including 16 primary myelofibrosis (PMF), 7 post-polycythemia vera (PV)-MF, 2 post-essential thrombocythemia (ET)-MF, 11 ET, 17 PV, 2 undefined MPN disorder, and 23 normal controls; the second cohort included 38 patients: 17 ET, 7 PMF, 3 ET-MF, 2 PV-MF, 9 PV patients, and 20 normal volunteers. The second cohort was studied using freshly collected specimens and a comparable age group as controls. CD11b(+), CD14(-), and CD33(+) cells were defined as MDSCs in both cohorts by flow cytometry. Since there are no differences in MDSC levels among different MPN categories, they were grouped as MPNs. The results showed that MDSCs were significantly elevated in MPNs compared with controls in both cohorts. We also performed RT-PCR and found that MPN patients have significantly elevated arginase-1 mRNA compared with controls, and sorted MDSCs were found to have suppressor T cell activity in MPNs, substantiating the hypothesis that levels of MDSCs are, in fact, deranged in MPNs. MDSC levels were not correlated with JAK2 status, white blood cells, Hb levels, platelet counts, splenomegaly, or the degree of bone marrow fibrosis (in MF). Further studies in immune therapy involving MDSC inhibitors or differentiation may be developed to treat MPN disease.
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PMID:Myeloid-derived suppressor cells in patients with myeloproliferative neoplasm. 2694 2


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