Tangier disease: Difference between revisions
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==Reverse cholesterol transport== | ==Reverse cholesterol transport== | ||
HDL C cycle of formation and recycling:<ref name="pmid21537175">{{cite journal| author=Asztalos BF, Tani M, Schaefer EJ| title=Metabolic and functional relevance of HDL subspecies. | journal=Curr Opin Lipidol | year= 2011 | volume= 22 | issue= 3 | pages= 176-85 | pmid=21537175 | doi=10.1097/MOL.0b013e3283468061 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21537175 }} </ref> | |||
{{Family tree/start}} | {{Family tree/start}} | ||
{{Family tree | | | | A01 | | | |A01= Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease causing to have only pre beta HDL on 2D electrophoresis.}} | {{Family tree | | | | A01 | | | |A01= Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease causing to have only pre beta HDL on 2D electrophoresis.}} | ||
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{{Family tree | | | | |!| | | | | }} | {{Family tree | | | | |!| | | | | }} | ||
{{Family tree | | | | D01 | | | |D01= Very large α-1 HDL particles are preferential donors of cholesterol to the liver, and the constituents of these particles can recycle back to form very small discoidal particles and can re-enter the HDL cycle, or be catabolized directly by the kidney or liver}} | {{Family tree | | | | D01 | | | |D01= Very large α-1 HDL particles are preferential donors of cholesterol to the liver, and the constituents of these particles can recycle back to form very small discoidal particles and can re-enter the HDL cycle, or be catabolized directly by the kidney or liver}} | ||
{{Family tree/end}} | {{Family tree/end}} | ||
==Demographics, Natural History and Complications== | ==Demographics, Natural History and Complications== | ||
Revision as of 22:08, 8 November 2016
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2], Twinkle Singh, M.B.B.S. [3] Aravind Kuchkuntla, M.B.B.S[4]
Synonyms and keywords: Familial alphalipoprotein deficiency, HDL deficiency - familial, high density lipoprotein deficiency, analphalipoproteinaemia, high density lipoprotein deficiency - type 1, high density lipoprotein deficiency - Tangier type, A-alphalipoprotein Neuropathy, alpha High Density Lipoprotein Deficiency Disease, Cholesterol thesaurismosis, Familial Hypoalphalipoproteinemia, Tangier Disease Neuropathy, Tangier Hereditary Neuropathy
Overview
Tangier is a disease due to a mutation in ABCA gene and is characterized by low or absent HDL, Apo A1. Accumalation of cholesterol esters in tonsil, peripheral nerves, liver, skin and cornea cause the symptoms of yellow-orange tonsillar enlargement, peripheral neuropathy and corneal opacities. These patients are at an increased risk of pre-mature coronary artery disease as low HDL is an independent cardiovascular risk factor.
Historical perspective
- In 1960, Fredricson and colleagues described the disease in two young siblings from Tangier Island in the Chesapeake Bay. They described the condition to have very low plasma levels of HDL C, moderately elevated triglycerides and decreased LDL cholesterol levels. The patients presented with mild corneal opacification, hepatosplenomegaly and orange coloured tonsils. Cholesterol- laden macrophages were found in their tonsils, bone marrow, nerves and smooth muscle cells.
- In 1985, Francis and Oram and also Schmitz and Assmann, noted that TD is a disorder of intacellular membrane traffic.[1]
- In 1998, the chromosomal locus (9q31) for TD was identified by Rust and Assmann. [2]
- In 1999, Genomic organization and the genetic defect was identified.[3]
- In 1999, the function of the ABCA1 transporter in the efflux of cellular cholesterol as phospholipid to HDL and ApoA-I was reported.[4].
- In later part of 1999, three different research groups reported different mutations in ABCA1 as causes of homozygous Tangier disease.[5][6]
- In 2000, three different research groups confirmed that mutation in ABCA gene could cause Tangier disease.[7]
Classification
- Homozygous and heterozygous Tangier disease.
| Homozygous | Heterozygous | |
|---|---|---|
| Presentation | Symptomatic | Asymptomatic |
| Lipid analysis | HDL < 5% of normal
Apo A1 < 1% of normal LDL < 40% of normal |
HDL C, Apo A1
and LDL 50% less than normal. |
| Pathophysiology | Increased fractional catabolism of
HDL proteins and Apo A1 [8] |
Enhanced clearance of HDL
and Apo A1 |
Pathophysiology
Pathogenesis
- Gene involved in the pathogenesis of TD include ATP-Binding Cassette tansporter gene (ABCA1), on chromosome 9q31. [9], which mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein (HDL). .[10]
- Mutation affects the the efflux of cholesterol from the cells, first step of reverse cholesterol transport, which leads to accumulation of cholesterol esters in the cells.
- The failure of lipidation of Apo-A1 results in rapid catabolism of Apo A1 in the kidney which is the primary cause for low Apo-A1 levels and not biosynthesis as Apo-A1 gene is sequenced in affected patients.[11]
Genetics
- Autosomal recessive inheritance.
- Multiple mutation sites are identified.
Microscopic pathology
- Affected tissues are infiltrated by cholesterol laden macrophages usually in the parafollicular areas of lymphoid tissues like tonsils, adenoids and lymph nodes.
- Bone marrow and gastrointestinal submucosa are also affected.[12]
- Hematologic features include:
- Hemolysis
- Thrombocytopenia
- Stomatocytosis
- Increased osmotic fragility result due to abnormal lipids in membrane.[13].
Associated Conditions
- Diabetes mellitus occurs in Tangier disease due to suggested involvement of ABCA1 in insulin secretion by beta cells of pancreas.[14]
- Anemia also occurs in Tangier disease due to abnormal lipids (decreased cholesterol-to-phosphatidylcholine ratio) in cell membrane leading to hemolysis.[15]
- Thrombocytopenia in Tangier occures as a result of splenomegaly.[16]
Reverse cholesterol transport
HDL C cycle of formation and recycling:[17]
| Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease causing to have only pre beta HDL on 2D electrophoresis. | |||||||||||||||||||
| Discoidal HDL particles are converted to medium spherical α-3 HDL and larger particles by the esterification of free cholesterol via the enzyme lecithin:cholesterol acyltransferase (LCAT) and the addition of apoA-II. | |||||||||||||||||||
| These particles are further converted to large and very large spherical α-2 and α-1 HDL by the actions of cholesteryl ester transfer protein (CETP). CETP transfers cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride | |||||||||||||||||||
| Very large α-1 HDL particles are preferential donors of cholesterol to the liver, and the constituents of these particles can recycle back to form very small discoidal particles and can re-enter the HDL cycle, or be catabolized directly by the kidney or liver | |||||||||||||||||||
Demographics, Natural History and Complications
- Tangier disease has been diagnosed in about 100 patients in many countries.[18]
- Cardiovascular disease risk is increased particularly in homozygotes and elderly patients with Tangier disease. Deposition of lipid filled macrophages in arterial wall results in accelerated atherosclerosis.[19]
Diagnosis
History and Symtoms
- The characteristic clinical presentation of TD include
- Tonsil enlargement in children.
- Loss of neurons and lipid accumulation in Schwann cells result in neuropathy. Two patterns of neuropathy have been noticed:
- Syringomyelia type loss of sensory and motor neurons in upper body.[20]
- Peripheral neuropathy with fluctuating loss of sensory and motor function.[21]
- Other less common features of presentation include:
- Abdominal discomfort due to hepatomegaly and splenomegaly.
- Visual disturbances due to corneal haziness.
- Premature myocardial infarction or stroke.
Physical Exam
- Large yellow-orange tonsils.
- Corneal opacity.
- Splenomegaly and hepatomegaly from accumulation of cholesterol esters in reticuloendothelial cells.
Laboratory Findings
Characteristic lab findings include:
- Plasma HDL cholesterol is very low or totally absent (usually below 5 mg/dL).
- Plasma total cholesterol is low (below 150 mg/dL).
- Triglyceride plasma levels are normal or elevated (up to 400 mg/dL).
- Serum concentrations of apoA-I and apoA-II lipo- proteins are below 5 mg/dL.
- Other laboratory findings include thrombocytopenia and stomatocytosis due to reduced cholesterol-to-phosphatidylcholine ratio in the cell membrane.
Genetic Testing
Gold standard for diagnosis: ABCA1 gene sequence analysis.
Others
Prebeta 1-HDL is identified on 2D electrophoresis after anti-apo A1 immunoblotting.[22]
Treatment
Medical Therapy
Surgical therapy
References
- ↑ Schmitz G, Assmann G, Robenek H, Brennhausen B (1985). "Tangier disease: a disorder of intracellular membrane traffic". Proc Natl Acad Sci U S A. 82 (18): 6305–9. PMC 391042. PMID 2994070.
- ↑ Rust S, Walter M, Funke H, von Eckardstein A, Cullen P, Kroes HY; et al. (1998). "Assignment of Tangier disease to chromosome 9q31 by a graphical linkage exclusion strategy". Nat Genet. 20 (1): 96–8. doi:10.1038/1770. PMID 9731541.
- ↑ Remaley AT, Rust S, Rosier M, Knapper C, Naudin L, Broccardo C; et al. (1999). "Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred". Proc Natl Acad Sci U S A. 96 (22): 12685–90. PMC 23050. PMID 10535983.
- ↑ Langmann T, Klucken J, Reil M, Liebisch G, Luciani MF, Chimini G; et al. (1999). "Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages". Biochem Biophys Res Commun. 257 (1): 29–33. doi:10.1006/bbrc.1999.0406. PMID 10092505.
- ↑ Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M; et al. (1999). "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency". Nat Genet. 22 (4): 336–45. doi:10.1038/11905. PMID 10431236.
- ↑ Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W; et al. (1999). "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease". Nat Genet. 22 (4): 347–51. doi:10.1038/11914. PMID 10431237.
- ↑ Brousseau ME, Schaefer EJ, Dupuis J, Eustace B, Van Eerdewegh P, Goldkamp AL; et al. (2000). "Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds". J Lipid Res. 41 (3): 433–41. PMID 10706591.
- ↑ Schaefer EJ, Blum CB, Levy RI, Jenkins LL, Alaupovic P, Foster DM; et al. (1978). "Metabolism of high-density lipoprotein apolipoproteins in Tangier disease". N Engl J Med. 299 (17): 905–10. doi:10.1056/NEJM197810262991701. PMID 211412.
- ↑ Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC; et al. (1999). "Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1". Nat Genet. 22 (4): 352–5. doi:10.1038/11921. PMID 10431238.
- ↑ Wang S, Smith JD (2014). "ABCA1 and nascent HDL biogenesis". Biofactors. 40 (6): 547–54. doi:10.1002/biof.1187. PMC 4294467. PMID 25359426.
- ↑ Emmerich J, Vergès B, Tauveron I, Rader D, Santamarina-Fojo S, Shaefer J; et al. (1993). "Familial HDL deficiency due to marked hypercatabolism of normal apoA-I". Arterioscler Thromb. 13 (9): 1299–306. PMID 8364014.
- ↑ Ferrans VJ, Fredrickson DS (1975). "The pathology of Tangier disease. A light and electron microscopic study". Am J Pathol. 78 (1): 101–58. PMC 1915033. PMID 162820.
- ↑ Reinhart WH, Gössi U, Bütikofer P, Ott P, Sigrist H, Schatzmann HJ; et al. (1989). "Haemolytic anaemia in analpha-lipoproteinaemia (Tangier disease): morphological, biochemical, and biophysical properties of the red blood cell". Br J Haematol. 72 (2): 272–7. PMID 2757970.
- ↑ Koseki M, Matsuyama A, Nakatani K, Inagaki M, Nakaoka H, Kawase R; et al. (2009). "Impaired insulin secretion in four Tangier disease patients with ABCA1 mutations". J Atheroscler Thromb. 16 (3): 292–6. PMID 19556721.
- ↑ Sampietro T, Puntoni M, Bigazzi F, Pennato B, Sbrana F, Dal Pino B; et al. (2009). "Images in cardiovascular medicine. Tangier disease in severely progressive coronary and peripheral artery disease". Circulation. 119 (20): 2741–2. doi:10.1161/CIRCULATIONAHA.108.812164. PMID 19470903.
- ↑ Hooper AJ, Robertson K, Ng L, Kattampallil JS, Latchem D, Willsher PC; et al. (2009). "A novel ABCA1 nonsense mutation, R1270X, in Tangier disease associated with an unrecognised bleeding tendency". Clin Chim Acta. 409 (1–2): 136–9. doi:10.1016/j.cca.2009.08.017. PMID 19723515.
- ↑ Asztalos BF, Tani M, Schaefer EJ (2011). "Metabolic and functional relevance of HDL subspecies". Curr Opin Lipidol. 22 (3): 176–85. doi:10.1097/MOL.0b013e3283468061. PMID 21537175.
- ↑ Puntoni M, Sbrana F, Bigazzi F, Sampietro T (2012). "Tangier disease: epidemiology, pathophysiology, and management". Am J Cardiovasc Drugs. 12 (5): 303–11. doi:10.2165/11634140-000000000-00000. PMID 22913675.
- ↑ Serfaty-Lacrosniere C, Civeira F, Lanzberg A, Isaia P, Berg J, Janus ED; et al. (1994). "Homozygous Tangier disease and cardiovascular disease". Atherosclerosis. 107 (1): 85–98. PMID 7945562.
- ↑ Gibbels, E.; Schaefer, HE.; Runne, U.; Schröder, JM.; Haupt, WF.; Assmann, G. (1985). "Severe polyneuropathy in Tangier disease mimicking syringomyelia or leprosy. Clinical, biochemical, electrophysiological, and morphological evaluation, including electron microscopy of nerve, muscle, and skin biopsies". J Neurol. 232 (5): 283–94. PMID 2997405.
- ↑ Pietrini, V.; Rizzuto, N.; Vergani, C.; Zen, F.; Ferro Milone, F. (1985). "Neuropathy in Tangier disease: A clinicopathologic study and a review of the literature". Acta Neurol Scand. 72 (5): 495–505. PMID 4082916. Unknown parameter
|month=ignored (help) - ↑ Huang Y, von Eckardstein A, Wu S, Langer C, Assmann G (1995). "Generation of pre-beta 1-HDL and conversion into alpha-HDL. Evidence for disturbed HDL conversion in Tangier disease". Arterioscler Thromb Vasc Biol. 15 (10): 1746–54. PMID 7583552.