Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abetalipoproteinemia is an inherited disorder of lipoprotein metabolism. Affected individuals produce virtually no circulating apolipoprotein B-containing lipoproteins (chylomicrons, very low density lipoprotein, low density lipoprotein and lipoprotein (a)). Malabsorption of the antioxidant vitamin E occurs, leading to spinocerebellar and retinal degeneration. Biochemical and genetic studies show that abetalipoproteinemia is not a defect of lipid biosynthesis or of the apolipoprotein B gene. Instead a microsomal triglyceride transfer protein, which exists as a complex with protein disulphide isomerase in the endoplasmic reticulum, has been implicated. We have cloned and sequenced the human cDNA encoding microsomal triglyceride transfer protein. The predicted amino acid sequence shows extensive homology to vitellogenin, the precursor of the lipovitellin complex, which has been shown by X-ray crystallography to contain a large lipid storage cavity. Microsomal triglyceride transfer protein is expressed in ovary, testis and kidney, in addition to liver and small intestine. A homozygous mutation that disrupts splicing has been identified in affected siblings with classical abetalipoproteinemia. These results elucidate a key process in the packaging of apolipoprotein B with lipid, and should increase our understanding of the processes regulating the production of atherogenic lipoproteins.
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PMID:Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. 811 81

The fifth- and ninety-fifth-percentile concentrations of low-density lipoprotein (LDL) cholesterol in most Western populations are approximately 90 and 200 mg/dl, respectively. Persons with LDL cholesterol levels equal to or less than the fifth percentile are defined as having hypobetalipoproteinemia. Epidemiologic studies show that such individuals have lower-than-average risk for atherosclerotic cardiovascular disease but higher risk for a variety of cancers, pulmonary, and gastrointestinal diseases than persons with higher levels of cholesterol. The reasons for this are not known, nor are the causes of most cases of hypobetalipoproteinemia. However, in some well-studied kindreds the hypobetalipoproteinemia phenotype is inherited as an autosomal dominant trait. Heterozygotes in such kindreds are usually healthy and have no difficulty absorbing dietary fat. In most kindreds, the molecular variants responsible for the hypobetalipoproteinemia are unknown, but a subset of kindreds have strong genetic linkages between the low-cholesterol phenotype and truncation-producing mutations of the apolipoprotein (apo) B-100 gene. The truncations of apoB are named according to a centile nomenclature. The full-length 4536-amino acid protein is called apoB-100, and the 25 truncations identified to date have been named apoB-2 to apoB-89. The mutations introduce premature termination codons resulting from frameshift-producing base additions or deletions. The mutations produce slowed rates of secretion of the truncated apoBs relative to the apoB-100s present in the heterozygotes. In addition, the apoB-100 molecules of the heterozygotes are also secreted at rates slower than those observed in closely matched normolipidemic controls. These physiologic results account for the hypobetalipoproteinemia of these subjects. The response of the plasma lipoproteins of heterozygotes to the manipulation of various dietary components remains to be determined. Additional low-cholesterol syndromes are autosomal recessive forms of hypobetalipoproteinemia, chylomicron retention disease, and abetalipoproteinemia. The molecular causes of the first two are unknown. Abetalipoproteinemia is an autosomal recessive condition resulting from mutations of the microsomal triglyceride transfer protein. All three conditions are characterized by vanishingly small concentrations of LDL, dietary fat malabsorption, and failure to thrive in infancy.
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PMID:The hypobetalipoproteinemias. 852 19

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder that is characterized by defective assembly and secretion of plasma apolipoprotein (apo) B-containing lipoproteins. This disorder results from mutations in the MTP gene encoding the microsomal triglyceride transfer protein. We report a 58-year-old male homozygote for a missense mutation, S590I, in MTP. The patient had a lifelong history of fat malabsorption, but was only diagnosed with ABL at age 52, based upon such classic features as absence of apo B-containing lipoproteins, acanthocytosis, atypical retinitis pigmentosa and markedly depressed serum beta-carotene concentration. However, his presentation was notable not only by survival to the sixth decade of life without specific treatment, but also by the absence of neurological involvement and by normal serum vitamin E concentration. He subsequently developed adenocarcinoma of the ileum, which required ileal resection. Therefore, this missense mutation appears to be associated with a late-presenting and relatively mild ABL phenotype that lacks some classical features, particularly neuropathy, but appears to be associated with other atypical features, specifically small intestinal cancer.
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PMID:Ileal adenocarcinoma in a mild phenotype of abetalipoproteinemia. 1263 Sep 61

A common feature of cystic fibrosis (CF) is the functional derangement of the exocrine pancreas, which affects output of pancreatic lipase. This condition results in severe dietary malabsorption due to the poor hydrolysis of triacylglycerol (TG) in the lumen of the small intestine. Despite the benefits of pancreatic enzyme supplements, patients with CF present with persistent intestinal fat malabsorption. The aim of the present investigation was to determine whether defects in the intracellular phase of lipid transport occur in this pathophysiology in addition to the known disturbed digestive processes. Our hypothesis was tested by incubating intestinal biopsies from six CF and six healthy subjects with radiolabeled lipid and protein precursors. Lipid esterification and secretion were markedly decreased by 22-31% and 38-42%, respectively, in CF samples, as noted by the low incorporation of [(14)C]palmitic acid into TGs, phospholipids, and cholesteryl esters in patients' duodenal explants and culture media compared with controls (100%). Accordingly, the output of TG-rich lipoproteins was substantially reduced (P < 0.05), and a similar trend was observed for high-density lipoproteins. Because intestinal lipoprotein assembly/secretion shows an absolute requirement for apolipoprotein (apo) B-48, radioactive labeling experiments were performed; these experiments demonstrated a significantly (P < 0.05) diminished synthesis of apoB-48 (40%) and apoA-I (30%). Given the critical role of microsomal triglyceride transfer protein in the formation of apoB-containing lipoproteins, its activity was determined and not found to be altered in CF intestinal tissue. Together, these results suggest that CF malabsorption may also be caused by defects in mucosal mechanisms leading to abnormal lipoprotein delivery into the blood circulation.
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PMID:Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients. 1622 44

Abetalipoproteinaemia (ABL), an extremely rare recessive disorder, is characterized by exceptionally low or undetectable concentrations of apolipoprotein (apo) B-containing lipoproteins. ABL results from mutations in the gene encoding microsomal triglyceride transfer protein (MTP), a chaperone that facilitates the transfer of lipids onto apoB. Patients with ABL often present in childhood with a range of symptoms including fat malabsorption and manifestations of fat-soluble vitamin deficiencies. We describe a patient with sub-clinical hypothyroidism and ABL found to be compound heterozygous for a novel splice site mutation of intron 1 (c.61 + 2T > C) and a single adenine insertion in MTP exon 4 (c.419-420insA) that results in a frameshift and a protein truncated at 140 amino acids.
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PMID:A mild case of abetalipoproteinaemia in association with subclinical hypothyroidism. 1713 87

In the present study, we investigated the potential toxic effects of 2-week oral treatment with T-0126, a novel microsomal triglyceride transfer protein (MTP) inhibitor, on the liver and intestine in male and female rats. Administration of T-0126 decreased serum lipids and resulted in fat accumulation in the liver and the small intestine. In addition, slight changes in the liver, including an increase in serum aminotransferase (AST and ALT) activity, presence of focal inflammatory lesions, and prolongation of PT and APTT were observed after treatment with T-0126. These changes may be related to a mechanism based on malabsorption of fat, fat-soluble antioxidants, and vitamin K, although we cannot exclude other potential mechanisms such as direct cytotoxicity of T-0126.
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PMID:Hepatic and intestinal changes in rats treated with T-0126, a microsomal triglyceride transfer protein (mtp) inhibitor. 1753 40

Abetalipoproteinaemia (ABL) and homozygous familial hypobetalipoproteinaemia (FHBL) are rare inherited disorders associated with low or undetectable levels of apolipoprotein B (apoB)-containing lipoproteins. Patients present with the symptoms and sequelae of fat malabsorption, including fat-soluble vitamin deficiencies. We describe two novel mutations: one an APOB gene mutation causing FHBL and the other a microsomal triglyceride transfer protein (MTP) gene mutation causing ABL. Two siblings of consanguineous parents were homozygous for an apoB mutation 4339delT causing an apoB-30.9 truncation. In another family, a boy born to consanguineous parents was homozygous for a 319 bp in-frame deletion of MTP exon 15 (c.2076-39_2303 + 52del319). All three children presented with malabsorption and liver dysfunction and had similar very low serum lipid, apoB, and fat-soluble vitamin levels. The FHBL parents had low serum lipid and apoB profiles distinguishing the disorder from the normal levels in ABL parents. Future patients presenting with FHBL or ABL should be genotyped to provide further insight into the varying clinical severity related to molecular heterogenicity in these two conditions.
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PMID:Novel mutations in abetalipoproteinaemia and homozygous familial hypobetalipoproteinaemia. 1802 3

Abetalipoproteinemia (ABL, OMIM 200100) is a rare, autosomal recessive disorder, characterized by fat malabsorption, acanthocytosis and hypocholesterolemia in infancy. Later in life, deficiency of fat-soluble vitamins is associated with development of atypical retinitis pigmentosa, coagulopathy, posterior column neuropathy and myopathy. ABL results from mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein (MTP; OMIM 157147). To date at least 33 MTP mutations have been identified in 43 ABL patients. We describe the clinical progress of two patients, both currently in the fifth decade of life, who were diagnosed with ABL as children and were treated with high oral doses of fat soluble vitamins, including vitamin E over the last three decades. Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients. Because pharmacologic inhibition of MTP is being developed as a novel approach to reduce plasma cholesterol for prevention of cardiovascular disease, defining the long-term clinical features of patients with a natural deficiency in MTP might provide some insight into the possible effects of such treatments. We review the range of clinical, biochemical and molecular perturbations in ABL.
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PMID:Abetalipoproteinemia: two case reports and literature review. 1861 Dec 56

Abetalipoproteinemia (ABL; OMIM 200100) is an inherited disorder resulting from mutations in the microsomal triglyceride transfer protein gene and characterized by a major lipid malabsorption leading to extremely low plasma cholesterol and triglyceride levels and fat-soluble vitamins deficiencies. We report two novel mutations (c.59del17 and c.582C>A) and the long-term follow-up of four ABL subjects treated with vitamin E. The good outcome of the early-treated patients contrasts with severe ataxia and retinopathy observed in the patient with delayed treatment. In conclusion, early diagnosis and early management are essential to prevent the manifestations following the fat-soluble vitamin deficiencies.
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PMID:Identification of two novel mutations and long-term follow-up in abetalipoproteinemia: a report of four cases. 1906 57

Abetalipoproteinemia (ABL; OMIM 200100) and homozygous hypobetalipoproteinemia (HHBL; OMIM 107730) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein (apo) B-containing lipoprotein particles due to mutations either in both alleles of the MTP (alias MTTP) gene encoding microsomal triglyceride transfer protein (MTP) or both alleles of the APOB gene itself in the case of ABL and HHBL, respectively. Clinical diagnosis is based on signs and symptoms, acanthocytosis on blood smear, and virtually absent apo B-containing lipoproteins, including chylomicrons, very low density lipoprotein and low density lipoprotein. Obligate heterozygote parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, while heterozygous parents of HHBL patients typically have half normal levels of apo B-containing lipoproteins consistent with autosomal co-dominant inheritance. Definitive diagnosis involves sequencing the MTP and APOB genes, for which >30 and >60 mutations have been described for ABL and HHBL, respectively. Follow-up includes monitoring for ophthalmologic, neurologic, hematologic, and hepatic complications, as well as compliance with treatment. Investigations include lipid profile, serum transaminases, markers for lipid-soluble vitamins, and periodic instrumental assessment of ocular and neurological function. Mainstays of treatment include adherence to a low-fat diet, and supplementation with essential fatty acids and high oral doses of fat soluble vitamins. Prognosis is variable, but early diagnosis and strict adherence to treatment can recover normal neurological function and halt disease progression.
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PMID:Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. 2428 38


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