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Latest revision as of 15:58, 4 April 2017

To view Lipoprotein Disorders Main Page Click here
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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: analphalipoproteinaemia, high density lipoprotein deficiency-type 1, high density lipoprotein deficiency-Tangier type, A-alphalipoprotein Neuropathy, alpha High Density Lipoprotein Deficiency Disease, Cholesterol thesaurismosis, Tangier Disease Neuropathy, Tangier Hereditary Neuropathy

Overview

Tangier Disease is a rare autosomal recessive disease caused by mutation in the ABCA1 gene on chromosome 9. It is characterized by low or absent High density lipoprotein (HDL) and apolipoprotein A1. The mutation affects the efflux of cholesterol from the cells via the ABCA transporter leading to the accumulation of cholesterol esters in the tonsils, peripheral nerves, liver, skin and corneas. Patients typically present with yellow-orange tonsillar enlargement, peripheral neuropathy and corneal opacity. Low HDL is an independent cardiovascular risk factor, therefore these patients are at an increased risk of developing premature coronary artery disease.

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 low density lipoprotein (LDL) cholesterol levels.
- The patients presented with mild corneal opacification, hepatosplenomegaly and orange-colored tonsils.
- Cholesterol-laden macrophages were found in their tonsils, bone marrow, nerves and smooth muscle cells.
In 1985, Francis and Oram, as well as Schmitz and Assmann, noted that Tangier's disease (TD) is a disorder of intracellular 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 were identified.^[3]
In 1999, the function of the ABCA transporter in the efflux of cellular cholesterol as phospholipid to HDL and apolipoprotein A1 was reported.^[4]
In the later part of 1999, three different research groups reported different mutations in ABCA1 can cause homozygous Tangier disease.^[5]^[6]
In 2000, three different research groups confirmed that mutations in the ABCA1 gene cause Tangier disease.^[7]

Classification

Tangier disease can be classified into homozygous or heterozygous based on the inheritance of the defective alleles. They differ in presentation, lipid analysis, pathophysiology and risk of cardiovascular disease (CVD).^[8]

	Homozygous	Heterozygous
Presentation	Symptomatic	Asymptomatic
Lipid Profile	HDL < 5% of normal Apo A1 < 1% of normal LDL < 40% of normal	HDLC, Apo A1 and LDL 50% less than normal
Pathophysiology	Increased fractional catabolism of HDL and Apo A1	Enhanced clearance of HDL and Apo A1
2D Electrophoresis	Only preβ-1 HDL present	Lack of large α-1 and α-2 HDL particles Normal preβ-1 HDL Only 50% of normal cellular cholesterol efflux
CVD Risk	Variable and related to non-HDL C and splenomegaly	Not at higher risk when compared to non-carriers.^[9]

Pathophysiology

Pathogenesis

The gene involved in the pathogenesis of Tangier disease is ATP-Binding Cassette tansporter gene (ABCA1), on chromosome 9q31, which mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein(HDL).^[10] ^[11]
The failure of lipidation of apolipoprotein A1 results in rapid catabolism of Apo A1 in the kidney, the primary cause for low Apo A1 levels.^[12]
- In Tangier disease normal Apo-A1 gene is sequenced ruling out the biosynthetic defect as the cause of low Apo A1.^[13]
The mutation affects the the efflux of cholesterol from the cells in the reverse cholesterol transport, leading to the accumulation of cholesterol esters in cells.

Reverse cholesterol transport

The following algorithm describes the HDL C formation and recycling:^[14]

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^[15]

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 Apo A 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

Genetics

Tangier disease cinical phenotype is transmitted as autosomal recessive and the biochemical phenotype is transmitted autosomal co-dominant.
Tangier disease patients with homozygous and compound heterozygous transmission have affected lipid levels and clinical symptoms.

Microscopic pathology

The characteristic microscopic features in Tangier disease on histopathological examination include:

Infiltration by cholesterol-laden macrophages are demonstrated in the parafollicular areas of lymphoid tissues like tonsils, adenoids and lymph nodes.
Bone marrow and gastrointestinal submucosa are also affected.^[16]
Rectal mucosa biopsy reveals foam cells in affected areas.
Hematologic features include:
- Hemolysis
- Thrombocytopenia
- Stomatocytosis
- Increased osmotic fragility results due to abnormal amounts of lipids in the membrane.^[17].

Associated Conditions

Conditions associated with Tangier disease include:

Diabetes mellitus due to involvement of ABCA1 in insulin secretion by beta cells of pancreas.^[18]
Anemia is to due to abnormal lipids (decreased cholesterol-to-phosphatidylcholine ratio) in cell membrane leading to hemolysis.^[19]
Thrombocytopenia can occur as a result of splenomegaly.^[20]

Differentiating Tangier disease from other diseases with low HDL C

Low HDL Diagnostic Features

	Familial LCAT Deficiency	Fish Eye Disease	Homozygous Tangier Disease	Heterozygous Tangier Disease	Apo A1 Deficiency
Gene Defect	LCAT	LCAT	ABCA1	ABCA1	Apo A1
Inheritance	Autosomal recessive	Autosomal recessive	Autosomal recessive	Autosomal recessive	Autosomal dominant
Pathogenesis	Loss of alpha and beta [[LCAT] function Failure of cholesterol ester formation.	Loss of alpha function only	Pre beta-1 HDL fails to picks up free cholesterol from cells due to mutation in ABCA1 transporter.	Similar to homozygous	Defective synthesis of Apo A1 resulting in failure of maturation of HDL causing defective reverse cholesterol transport.
Clinical Features	Annular corneal opacity Anemia Progressive renal disease with proteinuria	Corneal opacities only Normal renal function	Large yellow-orange tonsils Dense central corneal opacity Relapsing and remitting course of neuropathy	Asymptomatic	Corneal opacities Tuboeruptive, planar and palmar xanthomas Premature Heart Disease
Lipid Profile	Elevated free cholesterol HDL C < 10 mg/dL Low Apo A1 and Apo AII Elevated Apo E and triglycerides Low LDL C	Elevated free cholesterol HDL C < 27 mg/dL Apo A1＜30mg/dl and low Apo A2 Elevated Apo E and triglycerides Normal LDL and VLDL	HDL < 5% of normal Apo A1 < 1% of normal LDL < 40% of normal	HDL C, Apo A1 and LDL 50% less than normal.	Undetectable Apo A1 HDL C less than 10mg/dl Normal or low Apo AII LDL C normal Triglyceride normal or elevated
2D Gel Electrophoresis	Pre β-1 and α-4 HDL, LDL with β mobility due to Lipoprotien-X	Pre β-1and α-4 HDL with normal pre-β LDL	Only preβ-1 HDL present	Lack of large α-1 and α-2 HDL particles Normal preβ-1 HDL	Lack of Apo A1 containing HDL particles

Epidemiology and Demographics

The prevalence of Tangier disease is estimated to be less than 1/1,000,000.^[21]
Worldwide, Tangier disease has been diagnosed in about 100 patients.^[22]

Natural History, Complications and Prognosis

The symptoms of Tangier disease usually develop in the 1st decade of life with characteristic tonsillar enlargement and corneal opacities or in adulthood with symptoms of peripheral neuropathy.
Without treatment, the major debilitating feature is the relapsing and remitting course of neuropathy with loss of sensory and motor function which affects the quality of life.
Cardiovascular risk is variable in homozygous Tangier disease and is shown to be affected by the presence or absence of marked splenomegaly and the varying non-HDL-C levels.^[23] ^[24]
Patients who are heterozygous are not at higher risk of having a cardiovascular disease when compared to non-carriers.
Risk of developing premature CVD:^[23]
- Increased in patients without splenomegaly, anemia and who have normal LDL C levels.
- Patients with splenomegaly have anemia and low LDL C do not develop premature CVD.
Prognosis is usually good and depends mainly on the progression of peripheral neuropathy.

Diagnosis

History and Symptoms

The characteristic clinical presentation of Tangier disease includes:
- Throat pain due to enlarged tonsils
- Numbness, tingling, weakness of the extremities^[25]^[26]
- Other less common features of presentation include:

Physical Examination

The patients with Tangier disease usually present with the following findings:

Large yellow-orange tonsils due to the failure of uptake of lipid by HDL C. LDL C is relatively enriched with beta-carotene in these patients, which is taken up the reticuloendothelial cells giving the characteristic yellow orange color to the tissues.
Dense corneal opacity
Splenomegaly and hepatomegaly from accumulation of cholesterol esters in reticuloendothelial cells.
Evidence of relapsing and remitting course of neuropathy from the loss of neurons secondary to cholesterol accumulation in Schwann cells, presenting in two patterns:
- Syringomyelia type of loss of sensory and motor neurons in the upper body.^[27]
- Peripheral neuropathy with fluctuating loss of sensory and motor function.^[28]

Laboratory Findings

Tangier disease is diagnosed with characteristic laboratory finding of very low HDL C and Apo A1.

Plasma HDL C is usually below 5 mg/dL.
Serum concentrations of Apo A1 and Apo AII lipoproteins are below 5 mg/dL due to increased catabolism.
Plasma total cholesterol is usually below 150 mg/dL.
Triglyceride levels are normal or elevated (up to 400 mg/dL).
LDL C levels are decreased as the mutation results in up-regulation in the expression of LDL receptor,^[29] potentially reducing the risk of CVD even with very low HDL levels.
Other laboratory findings include thrombocytopenia and stomatocytosis due to reduced cholesterol-to-phosphatidylcholine ratio in the cell membrane.

2D Electrophoresis

Prebeta 1 HDL is identified on 2D electrophoresis after anti-apo A1 immunoblotting.^[30]

Molecular Genotype sequencing

The gold standard for of the diagnosis of Tangier disease is ABCA1 gene sequencing.

Treatment

Medical Therapy

There are no specific treatment measures are available for treatment of Tangier disease. The mainstay of therapy include:

Optimizing the LDL-C levels in Tangier patients with normal LDL-C levels using statin therapy is advised as they are at a higher risk of developing premature cardiovascular disease.^[23]
Trail of HDL infusion is ineffective as the apolipoprotien A1 which is required for the formation of HDL particle is very low.^[12]

Surgery

No surgical therapies are indicated.

Prevention

Primary Prevention

Patients with homozygous Tangier disease are at higher risk of developing cardiovascular disease at a young age, and according to 2013 ACC/AHA guidelines LDL C levels should be maintained below 70mg/dl.
Identifying and optimizing modifiable risk factors is advised.

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.
↑ Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P; et al. (2008). "Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease". JAMA. 299 (21): 2524–32. doi:10.1001/jama.299.21.2524. PMID 18523221.
↑ 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.
↑ ^12.0 ^12.1 Assmann G, Smootz E (1978). "High density lipoprotein infusion and partial plasma exchange in Tangier disease". Eur J Clin Invest. 8 (3): 131–5. PMID 211037.
↑ 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.
↑ 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.
↑ Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G; et al. (2009). "Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1". Biochemistry. 48 (46): 11067–74. doi:10.1021/bi901564g. PMID 19839639.
↑ 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.CS1 maint: PMC format (link)
↑ 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.
↑ "Orphanet: Tangier disease".
↑ 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.
↑ ^23.0 ^23.1 ^23.2 Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF (2016). "Diagnosis and treatment of high density lipoprotein deficiency". Prog Cardiovasc Dis. 59 (2): 97–106. doi:10.1016/j.pcad.2016.08.006. PMID 27565770.
↑ Iatan I, Alrasadi K, Ruel I, Alwaili K, Genest J (2008). "Effect of ABCA1 mutations on risk for myocardial infarction". Curr Atheroscler Rep. 10 (5): 413–26. PMID 18706283.
↑ 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)
↑ 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.
↑ Chung S, Timmins JM, Duong M, Degirolamo C, Rong S, Sawyer JK; et al. (2010). "Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism". J Biol Chem. 285 (16): 12197–209. doi:10.1074/jbc.M109.096933. PMC 2852959. PMID 20178985.
↑ 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.

Template:WH Template:WS

[pmid2994070-1] 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.

[pmid9731541-2] 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.

[pmid10535983-3] 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.

[pmid10092505-4] 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.

[pmid10431236-5] 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.

[pmid10431237-6] 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.

[pmid10706591-7] 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.

[pmid211412-8] 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.

[pmid18523221-9] Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P; et al. (2008). "Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease". JAMA. 299 (21): 2524–32. doi:10.1001/jama.299.21.2524. PMID 18523221.

[pmid10431238-10] 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.

[pmid25359426-11] Wang S, Smith JD (2014). "ABCA1 and nascent HDL biogenesis". Biofactors. 40 (6): 547–54. doi:10.1002/biof.1187. PMC 4294467. PMID 25359426.

[pmid211037-12] 12.0 ^12.1 Assmann G, Smootz E (1978). "High density lipoprotein infusion and partial plasma exchange in Tangier disease". Eur J Clin Invest. 8 (3): 131–5. PMID 211037.

[pmid8364014-13] 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.

[pmid21537175-14] 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.

[pmid19839639-15] Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G; et al. (2009). "Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1". Biochemistry. 48 (46): 11067–74. doi:10.1021/bi901564g. PMID 19839639.

[pmid162820-16] 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.CS1 maint: PMC format (link)

[pmid2757970-17] 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.

[pmid19556721-18] 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.

[pmid19470903-19] 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.

[pmid19723515-20] 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.

[urlOrphanet:_Tangier_disease-21] "Orphanet: Tangier disease".

[pmid22913675-22] 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.

[pmid27565770-23] 23.0 ^23.1 ^23.2 Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF (2016). "Diagnosis and treatment of high density lipoprotein deficiency". Prog Cardiovasc Dis. 59 (2): 97–106. doi:10.1016/j.pcad.2016.08.006. PMID 27565770.

[pmid18706283-24] Iatan I, Alrasadi K, Ruel I, Alwaili K, Genest J (2008). "Effect of ABCA1 mutations on risk for myocardial infarction". Curr Atheroscler Rep. 10 (5): 413–26. PMID 18706283.

[Gibbels-1985-25] 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-1985-26] 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)

[pmid2997405-27] 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.

[pmid4082916-28] 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.

[pmid20178985-29] Chung S, Timmins JM, Duong M, Degirolamo C, Rong S, Sawyer JK; et al. (2010). "Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism". J Biol Chem. 285 (16): 12197–209. doi:10.1074/jbc.M109.096933. PMC 2852959. PMID 20178985.

[pmid7583552-30] 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.

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@@ Line 1: / Line 1: @@
 __NOTOC__
-{{Hypolipoproteinemia}}
+{{SI}}
+'''To view Lipoprotein Disorders Main Page [[ Lipoprotein disorders| Click here]]'''<br>
+'''To view Hypolipoproteinemia Main Page [[ Hypolipoproteinemia | Click here]]''' <br>
 {{CMG}}; {{AE}} {{RT}}, {{TS}} {{AKI}}
-{{SK}} 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
+{{SK}} analphalipoproteinaemia, high density lipoprotein deficiency-type 1, high density lipoprotein deficiency-Tangier type, A-alphalipoprotein Neuropathy, alpha High Density Lipoprotein Deficiency Disease, Cholesterol thesaurismosis, Tangier Disease Neuropathy, Tangier Hereditary Neuropathy
+==Overview==
+Tangier Disease is a rare [[autosomal recessive]] disease caused by [[mutation]] in the [[ABCA1]] [[gene]] on [[Chromosome 9 (human)|chromosome 9]]. It is characterized by low or absent [[HDL|High density lipoprotein (HDL)]] and [[apolipoprotein A1]]. The mutation affects the [[efflux]] of [[cholesterol]] from the cells via the ABCA transporter leading to the accumulation of [[cholesterol]] [[esters]] in the [[tonsils]], [[peripheral nerves]], [[liver]], [[skin]] and [[corneas]]. Patients typically present with yellow-orange tonsillar enlargement, peripheral [[neuropathy]] and [[corneal opacity]]. Low [[HDL]] is an independent cardiovascular risk factor, therefore these patients are at an increased risk of developing premature [[coronary artery disease]].
-==Overview==
+==Historical Perspective==
-Tangier is a disease causing low HDL C levels. Low HDL is an independent cardiovascular risk factor.It is characterized by low or absent HDL, Apo A1 and accumalation of Cholesterol esters in multiple locations in the body including tonsil, peripheral nerves, liver, skin and cornea.
+*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 Cholesterol|HDL C]], moderately elevated [[triglycerides]] and decreased [[LDL|low density lipoprotein (LDL)]] [[cholesterol]] levels.
+**The patients presented with mild [[Opacity (optics)|corneal opacification]], [[hepatosplenomegaly]] and orange-colored [[tonsils]].
+**[[Cholesterol]]-laden [[macrophages]] were found in their [[tonsils]], [[bone marrow]], [[nerves]] and [[smooth muscle cells]].
+* In 1985, Francis and Oram, as well as Schmitz and Assmann, noted that Tangier's disease (TD) is a disorder of  intracellular membrane traffic.<ref name="pmid2994070">{{cite journal| author=Schmitz G, Assmann G, Robenek H, Brennhausen B| title=Tangier disease: a disorder of intracellular membrane traffic. | journal=Proc Natl Acad Sci U S A | year= 1985 | volume= 82 | issue= 18 | pages= 6305-9 | pmid=2994070 | doi= | pmc=391042 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2994070  }} </ref>
+* In 1998, the [[chromosomal]] [[locus]] (9q31) for TD was identified by Rust and Assmann. <ref name="pmid9731541">{{cite journal| author=Rust S, Walter M, Funke H, von Eckardstein A, Cullen P, Kroes HY et al.| title=Assignment of Tangier disease to chromosome 9q31 by a graphical linkage exclusion strategy. | journal=Nat Genet | year= 1998 | volume= 20 | issue= 1 | pages= 96-8 | pmid=9731541 | doi=10.1038/1770 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9731541  }} </ref>
+*In 1999, genomic organization and the genetic defect were identified.<ref name="pmid10535983">{{cite journal| author=Remaley AT, Rust S, Rosier M, Knapper C, Naudin L, Broccardo C et al.| title=Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred. | journal=Proc Natl Acad Sci U S A | year= 1999 | volume= 96 | issue= 22 | pages= 12685-90 | pmid=10535983 | doi= | pmc=23050 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10535983  }} </ref>
+*In 1999, the function of the [[ABCA1|ABCA]] transporter in the [[efflux]] of cellular cholesterol as [[phospholipid]] to [[HDL]] and apolipoprotein A1 was reported.<ref name="pmid10092505">{{cite journal| author=Langmann T, Klucken J, Reil M, Liebisch G, Luciani MF, Chimini G et al.| title=Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages. | journal=Biochem Biophys Res Commun | year= 1999 | volume= 257 | issue= 1 | pages= 29-33 | pmid=10092505 | doi=10.1006/bbrc.1999.0406 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10092505  }} </ref>
+*In the later part of 1999, three different research groups reported different [[mutations]] in [[ABCA1]] can cause [[homozygous]] Tangier disease.<ref name="pmid10431236">{{cite journal| author=Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M et al.| title=Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. | journal=Nat Genet | year= 1999 | volume= 22 | issue= 4 | pages= 336-45 | pmid=10431236 | doi=10.1038/11905 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10431236  }} </ref><ref name="pmid10431237">{{cite journal| author=Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W et al.| title=The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. | journal=Nat Genet | year= 1999 | volume= 22 | issue= 4 | pages= 347-51 | pmid=10431237 | doi=10.1038/11914 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10431237  }} </ref>
+*In 2000, three different research groups confirmed that [[mutations]] in the ABCA1 gene cause Tangier disease.<ref name="pmid10706591">{{cite journal| author=Brousseau ME, Schaefer EJ, Dupuis J, Eustace B, Van Eerdewegh P, Goldkamp AL et al.| title=Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds. | journal=J Lipid Res | year= 2000 | volume= 41 | issue= 3 | pages= 433-41 | pmid=10706591 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10706591  }} </ref>
-==Historical perspective==
+==Classification==
-*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.
+*Tangier disease can be classified into [[homozygous]] or [[heterozygous]] based on the [[inheritance]] of the defective [[alleles]]. They differ in presentation, [[lipid]] analysis, pathophysiology and risk of [[Cardiovascular disease|cardiovascular disease (CVD)]].<ref name="pmid211412">{{cite journal| author=Schaefer EJ, Blum CB, Levy RI, Jenkins LL, Alaupovic P, Foster DM et al.| title=Metabolism of high-density lipoprotein apolipoproteins in Tangier disease. | journal=N Engl J Med | year= 1978 | volume= 299 | issue= 17 | pages= 905-10 | pmid=211412 | doi=10.1056/NEJM197810262991701 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=211412  }} </ref>
-* In 1985, Francis and Oram and also Schmitz and Assmann, noted that TD is a disorder of intacellular membrane traffic.<ref name="pmid2994070">{{cite journal| author=Schmitz G, Assmann G, Robenek H, Brennhausen B| title=Tangier disease: a disorder of intracellular membrane traffic. | journal=Proc Natl Acad Sci U S A | year= 1985 | volume= 82 | issue= 18 | pages= 6305-9 | pmid=2994070 | doi= | pmc=391042 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2994070  }} </ref>
+{| class="wikitable"
-* In 1998, the chromosomal locus (9q31) for TD was identified by Rust and Assmann. <ref name="pmid9731541">{{cite journal| author=Rust S, Walter M, Funke H, von Eckardstein A, Cullen P, Kroes HY et al.| title=Assignment of Tangier disease to chromosome 9q31 by a graphical linkage exclusion strategy. | journal=Nat Genet | year= 1998 | volume= 20 | issue= 1 | pages= 96-8 | pmid=9731541 | doi=10.1038/1770 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9731541  }} </ref>
+!
-*In 1999, Genomic organization and the genetic defect was identified.<ref name="pmid10535983">{{cite journal| author=Remaley AT, Rust S, Rosier M, Knapper C, Naudin L, Broccardo C et al.| title=Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred. | journal=Proc Natl Acad Sci U S A | year= 1999 | volume= 96 | issue= 22 | pages= 12685-90 | pmid=10535983 | doi= | pmc=23050 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10535983  }} </ref>
+![[Homozygous]]
-*In 1999, the function of the ABCA1 transporter in the efflux of cellular cholesterol as phospholipid to HDL and ApoA-I was reported.<ref name="pmid10092505">{{cite journal| author=Langmann T, Klucken J, Reil M, Liebisch G, Luciani MF, Chimini G et al.| title=Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages. | journal=Biochem Biophys Res Commun | year= 1999 | volume= 257 | issue= 1 | pages= 29-33 | pmid=10092505 | doi=10.1006/bbrc.1999.0406 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10092505  }} </ref>.
+![[Heterozygous]]
-*In later part of 1999, three different research groups reported various mutations in ABCA1 as causes of homozygous Tangier disease.<ref name="pmid10431236">{{cite journal| author=Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M et al.| title=Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. | journal=Nat Genet | year= 1999 | volume= 22 | issue= 4 | pages= 336-45 | pmid=10431236 | doi=10.1038/11905 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10431236  }} </ref><ref name="pmid10431237">{{cite journal| author=Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W et al.| title=The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. | journal=Nat Genet | year= 1999 | volume= 22 | issue= 4 | pages= 347-51 | pmid=10431237 | doi=10.1038/11914 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10431237  }} </ref>
+|-
-*In the following year (2000), three different research groups confirmed the finding that a genetic defect in the gene ABCA1 could cause Tangier disease.<ref name="pmid10706591">{{cite journal| author=Brousseau ME, Schaefer EJ, Dupuis J, Eustace B, Van Eerdewegh P, Goldkamp AL et al.| title=Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds. | journal=J Lipid Res | year= 2000 | volume= 41 | issue= 3 | pages= 433-41 | pmid=10706591 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10706591  }} </ref>
+|Presentation
+|Symptomatic
+|Asymptomatic
+|-
+|Lipid Profile
+|
+*[[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]] and [[Apo A1]]
+|Enhanced clearance of  [[HDL]] and [[Apo A1]]
+|-
+|[[2D Electrophoresis]]
+|Only preβ-1 [[HDL]] present
+|
+*Lack of large α-1 and α-2 [[HDL]] particles
+*Normal preβ-1 [[HDL]]
+*Only 50% of normal cellular [[cholesterol efflux]]
+|-
+|[[CVD Risk]]
+|Variable and related to non-[[HDL]] C and [[splenomegaly]]
+|Not at higher risk when compared to non-carriers.<ref name="pmid18523221">{{cite journal| author=Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P et al.| title=Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. | journal=JAMA | year= 2008 | volume= 299 | issue= 21 | pages= 2524-32 | pmid=18523221 | doi=10.1001/jama.299.21.2524 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18523221  }} </ref>
+|}
 ==Pathophysiology==
 ===Pathogenesis===
-* TD is caused by a homozygous or compound heterozygous mutation in the ATP-Binding Cassette transporter A1 (ABCA1) gene (600046) on chromosome 9q31 <ref name="pmid10431238">{{cite journal| author=Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC et al.| title=Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. | journal=Nat Genet | year= 1999 | volume= 22 | issue= 4 | pages= 352-5 | pmid=10431238 | doi=10.1038/11921 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10431238  }} </ref>, which mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein (HDL). .<ref name="pmid25359426">{{cite journal| author=Wang S, Smith JD| title=ABCA1 and nascent HDL biogenesis. | journal=Biofactors | year= 2014 | volume= 40 | issue= 6 | pages= 547-54 | pmid=25359426 | doi=10.1002/biof.1187 | pmc=4294467 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25359426  }} </ref>
+*The gene involved in the pathogenesis of Tangier disease is [[ATP-Binding Cassette tansporter]] [[gene]] ([[ABCA1]]), on [[chromosome]] 9q31, which mediates the secretion of cellular free [[cholesterol]] and [[phospholipids]] to an extracellular acceptor, [[apolipoprotein AI]], to form nascent [[high-density lipoprotein]]([[HDL]]).<ref name="pmid10431238">{{cite journal| author=Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC et al.| title=Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. | journal=Nat Genet | year= 1999 | volume= 22 | issue= 4 | pages= 352-5 | pmid=10431238 | doi=10.1038/11921 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10431238  }} </ref> <ref name="pmid25359426">{{cite journal| author=Wang S, Smith JD| title=ABCA1 and nascent HDL biogenesis. | journal=Biofactors | year= 2014 | volume= 40 | issue= 6 | pages= 547-54 | pmid=25359426 | doi=10.1002/biof.1187 | pmc=4294467 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25359426  }} </ref>
-*Mutation affects the the efflux of cholesterol the first step of reverse cholesterol transport, which leads to accumalation of cholesterol esters in the cells. It prevents the conversion of the lipid-poor apoA-I particles into pre-beta HDL and it causes a rapid catabolism of ApoA1 by the kidney.
+*The failure of lipidation of [[apolipoprotein A1]] results in rapid [[catabolism]] of [[Apo A1]] in the kidney, the primary cause for low [[Apo A1]] levels.<ref name="pmid211037">{{cite journal| author=Assmann G, Smootz E| title=High density lipoprotein infusion and partial plasma exchange in Tangier disease. | journal=Eur J Clin Invest | year= 1978 | volume= 8 | issue= 3 | pages= 131-5 | pmid=211037 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=211037  }} </ref>
-*HDL C complexity.<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>
+**In Tangier disease normal [[Apo-A1]] [[gene]] is sequenced ruling out the biosynthetic defect as the cause of low [[Apo A1]].<ref name="pmid8364014">{{cite journal| author=Emmerich J, Vergès B, Tauveron I, Rader D, Santamarina-Fojo S, Shaefer J et al.| title=Familial HDL deficiency due to marked hypercatabolism of normal apoA-I. | journal=Arterioscler Thromb | year= 1993 | volume= 13 | issue= 9 | pages= 1299-306 | pmid=8364014 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8364014  }} </ref>
+*The [[mutation]] affects the the [[efflux]] of [[cholesterol]] from the cells in the [[reverse cholesterol transport]], leading to the accumulation of [[cholesterol esters]] in cells.
-===Reverse cholesterol transport===
+==Reverse cholesterol transport==
+The following algorithm describes the [[HDL]] C 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 | | | | A01 | | | |A01= Very small discoidal Pre beta HDL picks up free cholesterol from cells via ABCA1 converting small discoidal pre beta HDL to small discoidal alpha4 HDL, this intitial step of reverse cholesterol transport is disrupted in Tangier disease}}
+{{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<ref name="pmid19839639">{{cite journal| author=Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G et al.| title=Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1. | journal=Biochemistry | year= 2009 | volume= 48 | issue= 46 | pages= 11067-74 | pmid=19839639 | doi=10.1021/bi901564g | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19839639  }} </ref>}}
 {{Family tree | | | | |!| | | | | }}
-{{Family tree | | | | B01 | | | |B01= Then LCAT converts small discoidal α-4 HDL to larger spherical alpha HDL converting free cholesterol into cholesterol esters (CE). Lipoprotien lipase is also required for this step}}
+{{Family tree | | | | B01 | | | |B01= 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 [[Apo A II]]}}
 {{Family tree | | | | |!| | | | | }}
+{{Family tree | | | | C01 | | | |C01= 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]]}}
 {{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 | C01 | | | | C02 |C01= Larger alpha HDL can donate the CE to  TG-rich lipoproteins (TRL) in
-exchange for TG via the action of CE transfer protein (CETP) or | C02= Larger alpha HDL can donate the CE and free cholesterol to the liver via scavenger receptor-B1 (SR-B1)}}
 {{Family tree/end}}
-*Studies show that during the above process Apo A1  can be recycled back to the discoidal HDL or be catabolized in the kidney by the action of the enzyme cubulin.
-*Studies also show that hepatic and endothelial lipase helps remove the phospholipid from large HDL to convert it into small HDL.
 ===Genetics===
+*Tangier disease cinical phenotype is transmitted as [[autosomal recessive]]  and the biochemical phenotype is transmitted [[autosomal co-dominant]].
+*Tangier disease patients with [[homozygous]] and [[compound heterozygous]] transmission have affected [[lipid]] levels and clinical symptoms.
-==Demographics, Natural History and Complications==
+===Microscopic pathology===
+The characteristic microscopic features in Tangier disease on histopathological examination include:
+*Infiltration by [[cholesterol]]-laden [[macrophages]] are demonstrated in the [[parafollicular]] areas of [[lymphoid]] tissues like [[tonsil]]s, [[adenoids]] and [[lymph nodes]].
+*[[Bone marrow]] and gastrointestinal [[submucosa]] are also affected.<ref name="pmid162820">{{cite journal| author=Ferrans VJ, Fredrickson DS| title=The pathology of Tangier disease. A light and electron microscopic study. | journal=Am J Pathol | year= 1975 | volume= 78 | issue= 1 | pages= 101-58 | pmid=162820 | doi= | pmc=PMC1915033 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=162820  }} </ref>
+*[[Rectal mucosa]] [[biopsy]] reveals [[foam cell]]s in affected areas.
+*Hematologic features include:
+**[[Hemolysis]]
+**[[Thrombocytopenia]]
+**[[Stomatocytosis]]
+**Increased [[osmotic fragility]] results due to abnormal amounts of [[lipids]] in the membrane.<ref name="pmid2757970">{{cite journal| author=Reinhart WH, Gössi U, Bütikofer P, Ott P, Sigrist H, Schatzmann HJ et al.| title=Haemolytic anaemia in analpha-lipoproteinaemia (Tangier disease): morphological, biochemical, and biophysical properties of the red blood cell. | journal=Br J Haematol | year= 1989 | volume= 72 | issue= 2 | pages= 272-7 | pmid=2757970 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2757970}}</ref>.
+===Associated Conditions===
+Conditions associated with Tangier disease include:
+* [[Diabetes mellitus]] due to involvement of [[ABCA1]] in [[insulin]] secretion by [[beta cells]] of [[pancreas]].<ref name="pmid19556721">{{cite journal| author=Koseki M, Matsuyama A, Nakatani K, Inagaki M, Nakaoka H, Kawase R et al.| title=Impaired insulin secretion in four Tangier disease patients with ABCA1 mutations. | journal=J Atheroscler Thromb | year= 2009 | volume= 16 | issue= 3 | pages= 292-6 | pmid=19556721 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556721  }} </ref>
+* [[Anemia]] is to due to abnormal [[lipids]] (decreased cholesterol-to-[[phosphatidylcholine]] ratio) in [[cell membrane]] leading to [[hemolysis]].<ref name="pmid19470903">{{cite journal| author=Sampietro T, Puntoni M, Bigazzi F, Pennato B, Sbrana F, Dal Pino B et al.| title=Images in cardiovascular medicine. Tangier disease in severely progressive coronary and peripheral artery disease. | journal=Circulation | year= 2009 | volume= 119 | issue= 20 | pages= 2741-2 | pmid=19470903 | doi=10.1161/CIRCULATIONAHA.108.812164 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19470903  }} </ref>
+* [[Thrombocytopenia]] can occur as a result of [[splenomegaly]].<ref name="pmid19723515">{{cite journal| author=Hooper AJ, Robertson K, Ng L, Kattampallil JS, Latchem D, Willsher PC et al.| title=A novel ABCA1 nonsense mutation, R1270X, in Tangier disease associated with an unrecognised bleeding tendency. | journal=Clin Chim Acta | year= 2009 | volume= 409 | issue= 1-2 | pages= 136-9 | pmid=19723515 | doi=10.1016/j.cca.2009.08.017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19723515  }} </ref>
+== Differentiating Tangier disease from other diseases with low HDL C ==
+===Low [[HDL]] Diagnostic Features===
+{| class="wikitable"
+!
+!Familial [[LCAT]] Deficiency
+!Fish Eye Disease
+![[Homozygous]] [[Tangier Disease]]
+![[Heterozygous]] [[Tangier Disease]]
+![[Apo A1]] Deficiency
+|-
+|[[Gene]] Defect
+|[[LCAT]]
+|[[LCAT]]
+|[[ABCA1]]
+|[[ABCA1]]
+|[[Apo A1]]
+|-
+|[[Inheritance]]
+|[[Autosomal recessive]]
+|[[Autosomal recessive]]
+|[[Autosomal recessive]]
+|[[Autosomal recessive]]
+|[[Autosomal dominant]]
+|-
+|Pathogenesis
+|
+*Loss of alpha and beta [[LCAT] function
+*Failure of [[cholesterol ester]] formation.
+|Loss of alpha function only
+|
+Pre beta-1 [[HDL]] fails to picks up free [[cholesterol]] from cells due to mutation in [[ABCA1]] transporter.
+|Similar to homozygous
+|Defective synthesis of [[Apo A1]] resulting in failure of maturation of [[HDL]] causing defective reverse cholesterol transport.
+|-
+|Clinical Features
+|
+*Annular [[corneal opacity]]
+*[[Anemia]]
+*Progressive [[renal disease]] with [[proteinuria]]
+|
+*[[Corneal opacities]] only
+*Normal renal function
+|
+*Large yellow-orange [[tonsils]]
+*Dense central [[corneal opacity]]
+*Relapsing and remitting course of [[neuropathy]]
+|Asymptomatic
+|
+*[[Corneal opacities]]
+*[[Tuboeruptive]], planar and palmar [[xanthomas]]
+*[[Premature Heart Disease]]
+|-
+|Lipid Profile
+|
+*Elevated free [[cholesterol]]
+*[[HDL]] C < 10 mg/dL
+*Low [[Apo A1]] and [[Apo AII]]
+*Elevated [[Apo E]] and [[triglycerides]]
+*Low [[LDL]] C
+|
+*Elevated free [[cholesterol]]
+*[[HDL]] C < 27 mg/dL
+*[[Apo A1]]＜30mg/dl and low Apo A2
+*Elevated [[Apo E]] and [[triglycerides]]
+*Normal [[LDL]] and [[VLDL]]
+|
+*[[HDL]] < 5% of normal
+*[[Apo A1]] < 1% of normal
+*[[LDL]] < 40% of normal
+|
+*[[HDL]] C, [[Apo A1]] and  [[LDL]] 50% less than normal.
+|
+*Undetectable [[Apo A1]]
+*[[HDL]] C less than 10mg/dl
+*Normal or low [[Apo AII]]
+*[[LDL]] C normal
+*[[Triglyceride]] normal or elevated
+|-
+|[[2D Gel Electrophoresis]]
+|Pre β-1 and α-4 [[HDL]], [[LDL]] with  β mobility due to [[Lipoprotien-X]]
+|Pre β-1and α-4 [[HDL]] with normal pre-β [[LDL]]
+|Only preβ-1 [[HDL]] present
+|
+*Lack of large α-1 and α-2 [[HDL]] particles
+*Normal preβ-1 [[HDL]]
+|Lack of [[Apo A1]] containing [[HDL]] particles
+|}
+==Epidemiology and Demographics==
+* The prevalence of Tangier disease is estimated to be less than 1/1,000,000.<ref name="urlOrphanet: Tangier disease">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=9288&Disease_Disease_Search_diseaseGroup=Tangier-disease&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Tangier-disease&title=Tangier-disease&search=Disease_Search_Simple |title=Orphanet: Tangier disease |format= |work= |accessdate=}}</ref>
+* Worldwide, Tangier disease has been diagnosed in about 100 patients.<ref name="pmid22913675">{{cite journal| author=Puntoni M, Sbrana F, Bigazzi F, Sampietro T| title=Tangier disease: epidemiology, pathophysiology, and management. | journal=Am J Cardiovasc Drugs | year= 2012 | volume= 12 | issue= 5 | pages= 303-11 | pmid=22913675 | doi=10.2165/11634140-000000000-00000 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22913675  }} </ref>
-*Tangier disease has been diagnosed in about 100 patients in many countries.
+==Natural History, Complications and Prognosis==
-*
+* The symptoms of Tangier disease usually develop in the 1st decade of life with characteristic [[tonsillar]] enlargement and [[corneal opacities]] or in adulthood with symptoms of peripheral [[neuropathy]].
+*Without treatment, the major debilitating feature is the [[relapsing]] and [[remitting]] course of [[neuropathy]] with loss of sensory and motor function which affects the quality of life.
+*[[Cardiovascular risk]] is variable in [[homozygous]] Tangier disease and is shown to be affected by the presence or absence of marked [[splenomegaly]] and the varying non-[[HDL-C]] levels.<ref name="pmid27565770">{{cite journal| author=Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF| title=Diagnosis and treatment of high density lipoprotein deficiency. | journal=Prog Cardiovasc Dis | year= 2016 | volume= 59 | issue= 2 | pages= 97-106 | pmid=27565770 | doi=10.1016/j.pcad.2016.08.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27565770  }} </ref> <ref name="pmid18706283">{{cite journal| author=Iatan I, Alrasadi K, Ruel I, Alwaili K, Genest J| title=Effect of ABCA1 mutations on risk for myocardial infarction. | journal=Curr Atheroscler Rep | year= 2008 | volume= 10 | issue= 5 | pages= 413-26 | pmid=18706283 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18706283  }} </ref>
+*Patients who are [[heterozygous]] are not at higher risk of having a [[cardiovascular disease]] when compared to non-carriers.
+*Risk of developing [[premature]] [[CVD]]:<ref name="pmid27565770" />
+**Increased in patients without [[splenomegaly]], [[anemia]] and who have normal [[LDL]] C levels.
+**Patients with [[splenomegaly]] have [[anemia]] and low [[LDL]] C do not develop [[premature CVD]].
+*[[Prognosis]] is usually good and depends mainly on the progression of [[peripheral neuropathy]].
 ==Diagnosis==
+===History and Symptoms===
+*The characteristic clinical presentation of Tangier disease includes:
+**[[Throat pain]] due to enlarged [[tonsils]]
+**[[Numbness]], [[tingling]], [[weakness]] of the extremities<ref name="Gibbels-1985">{{Cite journal  | last1 = Gibbels | first1 = E. | last2 = Schaefer | first2 = HE. | last3 = Runne | first3 = U. | last4 = Schröder | first4 = JM. | last5 = Haupt | first5 = WF. | last6 = Assmann | first6 = G. | title = Severe polyneuropathy in Tangier disease mimicking syringomyelia or leprosy. Clinical, biochemical, electrophysiological, and morphological evaluation, including electron microscopy of nerve, muscle, and skin biopsies. | journal = J Neurol | volume = 232 | issue = 5 | pages = 283-94 | month =  | year = 1985 | doi =  | PMID = 2997405 }}</ref><ref name="Pietrini-1985">{{Cite journal  | last1 = Pietrini | first1 = V. | last2 = Rizzuto | first2 = N. | last3 = Vergani | first3 = C. | last4 = Zen | first4 = F. | last5 = Ferro Milone | first5 = F. | title = Neuropathy in Tangier disease: A clinicopathologic study and a review of the literature. | journal = Acta Neurol Scand | volume = 72 | issue = 5 | pages = 495-505 | month = Nov | year = 1985 | doi =  | PMID = 4082916 }}</ref>
+**Other less common features of presentation include:
+***[[Abdominal pain]]
+***[[Vision loss]]
+***[[Fatigue]]
+***[[Shortness of breath]] on [[exertion]]
+===Physical Examination===
+The patients with Tangier disease usually present with the following findings:
+*Large yellow-orange tonsils due to the failure of uptake of lipid by [[HDL]] C. [[LDL]] C is relatively enriched with beta-carotene in these patients, which is taken up the [[reticuloendothelial cells]] giving the characteristic yellow orange color to the [[tissues]].
+*Dense [[corneal opacity]]
+*[[Splenomegaly]] and [[hepatomegaly]] from accumulation of [[cholesterol esters]] in [[reticuloendothelial]] cells.
+*Evidence of [[relapsing]] and [[remitting]] course of [[neuropathy]] from the loss of [[neurons]] secondary to [[cholesterol]] accumulation in [[Schwann cells]], presenting in two patterns:
+**[[Syringomyelia]] type of loss of [[sensory]] and [[motor]] [[neurons]] in the [[upper body]].<ref name="pmid2997405">{{cite journal| author=Gibbels E, Schaefer HE, Runne U, Schröder JM, Haupt WF, Assmann G| title=Severe polyneuropathy in Tangier disease mimicking syringomyelia or leprosy. Clinical, biochemical, electrophysiological, and morphological evaluation, including electron microscopy of nerve, muscle, and skin biopsies. | journal=J Neurol | year= 1985 | volume= 232 | issue= 5 | pages= 283-94 | pmid=2997405 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2997405  }} </ref>
+**[[Peripheral neuropathy]] with fluctuating loss of [[sensory]] and [[motor]] function.<ref name="pmid4082916">{{cite journal| author=Pietrini V, Rizzuto N, Vergani C, Zen F, Ferro Milone F| title=Neuropathy in Tangier disease: A clinicopathologic study and a review of the literature. | journal=Acta Neurol Scand | year= 1985 | volume= 72 | issue= 5 | pages= 495-505 | pmid=4082916 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4082916  }} </ref>
+===Laboratory Findings===
+Tangier disease is diagnosed with characteristic laboratory finding of very low [[HDL]] C and [[Apo A1]].
+*Plasma [[HDL]] C is usually below 5 mg/dL.
+*[[Serum]] concentrations of [[Apo A1]] and [[Apo AII]] [[lipoproteins]] are below 5 mg/dL due to increased [[catabolism]].
+*Plasma total [[cholesterol]] is usually below 150 mg/dL.
+*[[Triglyceride]] levels are normal or elevated (up to 400 mg/dL).
+*[[LDL]] C levels are decreased as the mutation results in up-regulation in the expression of [[LDL]] receptor,<ref name="pmid20178985">{{cite journal| author=Chung S, Timmins JM, Duong M, Degirolamo C, Rong S, Sawyer JK et al.| title=Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism. | journal=J Biol Chem | year= 2010 | volume= 285 | issue= 16 | pages= 12197-209 | pmid=20178985 | doi=10.1074/jbc.M109.096933 | pmc=2852959 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20178985  }} </ref> potentially reducing the risk of CVD even with very low HDL levels.
+*Other laboratory findings include [[thrombocytopenia]] and [[stomatocytosis]] due to reduced [[cholesterol]]-to-[[phosphatidylcholine]] ratio in the [[cell membrane]].
+=== 2D Electrophoresis ===
+* Prebeta 1 [[HDL]] is identified on 2D electrophoresis after anti-apo A1 [[immunoblotting]].<ref name="pmid7583552">{{cite journal| author=Huang Y, von Eckardstein A, Wu S, Langer C, Assmann G| title=Generation of pre-beta 1-HDL and conversion into alpha-HDL. Evidence for disturbed HDL conversion in Tangier disease. | journal=Arterioscler Thromb Vasc Biol | year= 1995 | volume= 15 | issue= 10 | pages= 1746-54 | pmid=7583552 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7583552  }} </ref>
+===Molecular Genotype sequencing===
+* The gold standard for of the diagnosis of Tangier disease is [[ABCA1]] [[gene sequencing]].
+==Treatment==
+===Medical Therapy===
+There are no specific treatment measures are available for treatment of Tangier disease. The mainstay of therapy include:
+*Optimizing the [[LDL]]-C levels in Tangier patients with normal [[LDL]]-C levels using [[statin]] therapy is advised as they are at a higher risk of developing [[premature]] [[cardiovascular disease]].<ref name="pmid27565770">{{cite journal| author=Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF| title=Diagnosis and treatment of high density lipoprotein deficiency. | journal=Prog Cardiovasc Dis | year= 2016 | volume= 59 | issue= 2 | pages= 97-106 | pmid=27565770 | doi=10.1016/j.pcad.2016.08.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27565770  }} </ref>
+*Trail of [[HDL infusion]] is ineffective as the [[apolipoprotien A1]] which is required for the formation of [[HDL]] particle is very low.<ref name="pmid211037">{{cite journal| author=Assmann G, Smootz E| title=High density lipoprotein infusion and partial plasma exchange in Tangier disease. | journal=Eur J Clin Invest | year= 1978 | volume= 8 | issue= 3 | pages= 131-5 | pmid=211037 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=211037  }} </ref>
+===Surgery===
+No surgical therapies are indicated.
+==Prevention==
+===Primary Prevention===
+*Patients with [[homozygous]] Tangier disease are at higher risk of developing [[cardiovascular disease]] at a young age, and according to 2013 ACC/AHA guidelines [[LDL]] C levels should be maintained below 70mg/dl.
+*Identifying and optimizing modifiable risk factors is advised.
-==Overview==
-Tangier disease is a rare [[autosomal recessive]] disorder characterized by severely decreased [[high-density lipoprotein]] ([[HDL]]), often referred to as "good cholesterol".  It is caused by defective cholesterol efflux from [[macrophages]].  Clinically it manifests with enlarged and orange colored tonsils, [[hepatomegaly]], [[splenomegaly]], [[peripheral neuropathy]] and vision changes.
-==Historical Perspective==
-Tangier disease (TD) is named after Tangier Island, Virginia.  In 1959, a five year old patient named Teddy Laird from that island presented with strikingly large and yellow-orange tonsils.  Initially it was diagnosed as [[Niemann-Pick]] disease, a further investigation revealed an extremely high number of cholesterol filled macrophages ([[foam cells]]) in several other tissues, which included bone marrow, lymph nodes and spleen.  Presence of similar symptoms in his sister and discovery of very low [[HDL cholesterol]] in both the sister and parents of Teddy led to establishment of [[genetic]] basis of the disease.  Later on, several other residents of the same island were found to have markedly reduced HDL.  Since then only 100 cases of Tangier disease have been diagnosed.
-==Pathophysiology==
-Tangier disease is a rare disorder of [[lipid metabolism]] where impaired cholesterol efflux from [[reticuloendothelial]] cells result in absent to severely decreased [[HDL]].<ref name="www.ncbi.nlm.nih.gov">{{Cite web  | last =  | first =  | title = Transport of lipids from golgi to plasma membrane ... [Nat Genet. 2000] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed/10655069?dopt=Abstract | publisher =  | date =  | accessdate = 11 September 2013 }}</ref>
-[[HDL|High-density lipoproteins]] are created when a protein in the bloodstream, [[apolipoprotein A1]] ([[apoA1]]), combines with [[cholesterol]] and phospholipids.  Cholesterol and phospholipids used to form HDL originate from inside the cells.  [[ABCA1]] transporter is responsible for transporting them out into blood.  Defective [[ABCA1]] transporter in Tangier disease results in cholesterol esters accumulation in macrophages forming [[foam cells]].  These foam cells deposit in several non adipose tissues like tonsils, spleen, bone marrow, lymph nodes and liver causing them to enlarge.
-Prominent pathological features in Tangier disease are due to accumulation of foam cells in various tissues throughout the body.
-*Tonsils are conspicuously affected.  Enlarged, lobulated and strikingly yellow-orange colored tonsils are a hallmark of this disease.
-*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.<ref name="Gibbels-1985">{{Cite journal  | last1 = Gibbels | first1 = E. | last2 = Schaefer | first2 = HE. | last3 = Runne | first3 = U. | last4 = Schröder | first4 = JM. | last5 = Haupt | first5 = WF. | last6 = Assmann | first6 = G. | title = Severe polyneuropathy in Tangier disease mimicking syringomyelia or leprosy. Clinical, biochemical, electrophysiological, and morphological evaluation, including electron microscopy of nerve, muscle, and skin biopsies. | journal = J Neurol | volume = 232 | issue = 5 | pages = 283-94 | month =  | year = 1985 | doi =  | PMID = 2997405 }}</ref>
-# Peripheral neuropathy with fluctuating loss of sensory and motor function.<ref name="Pietrini-1985">{{Cite journal  | last1 = Pietrini | first1 = V. | last2 = Rizzuto | first2 = N. | last3 = Vergani | first3 = C. | last4 = Zen | first4 = F. | last5 = Ferro Milone | first5 = F. | title = Neuropathy in Tangier disease: A clinicopathologic study and a review of the literature. | journal = Acta Neurol Scand | volume = 72 | issue = 5 | pages = 495-505 | month = Nov | year = 1985 | doi =  | PMID = 4082916 }}</ref>
-* [[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]].<ref name="pmid7945562">{{cite journal| author=Serfaty-Lacrosniere C, Civeira F, Lanzberg A, Isaia P, Berg J, Janus ED et al.| title=Homozygous Tangier disease and cardiovascular disease. | journal=Atherosclerosis | year= 1994 | volume= 107 | issue= 1 | pages= 85-98 | pmid=7945562 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7945562  }} </ref>
-*[[Splenomegaly]] and [[hepatomegaly]] from accumulation of cholesterol esters in [[reticuloendothelial]] cells.
-*[[Corneal opacification]] occurs due to [[lipid]] deposition in corneal stroma.
-===Genetics===
-This condition is inherited in an [[autosomal recessive]] pattern clinically, which means both [[alleles]] of the [[gene]] in each cell have [[mutation]]s.  The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.  Biochemical phenotype is inherited in autosomal co-dominant pattern.  Patients homozygous for this mutation have complete absence of [[HDL]], heterozygotes on the other hand have one half of normal level of HDL.  [[Mutation]] on chromosome 9q31, where we find gene encoding [[ABCA1]] has been found to be the cause of Tangier disease.  These mutations prevent the [[ABCA1]] protein from effectively transporting cholesterol and phospholipids out of cells for pickup by ApoA1 in the bloodstream.<ref name="Rust-1999">{{Cite journal  | last1 = Rust | first1 = S. | last2 = Rosier | first2 = M. | last3 = Funke | first3 = H. | last4 = Real | first4 = J. | last5 = Amoura | first5 = Z. | last6 = Piette | first6 = JC. | last7 = Deleuze | first7 = JF. | last8 = Brewer | first8 = HB. | last9 = Duverger | first9 = N. | title = Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. | journal = Nat Genet | volume = 22 | issue = 4 | pages = 352-5 | month = Aug | year = 1999 | doi = 10.1038/11921 | PMID = 10431238 }}</ref>  This inability to transport [[cholesterol]] out of cells leads to a deficiency of high-density [[lipoprotein]]s in the circulation, which is a risk factor for [[coronary artery disease]] ([[CAD]]).
-===Microscopic Pathology===
-Microscopically, affected tissues are infiltrated by foamy [[histiocytes]].  They are rounded, oval shaped cells with darkly stained nuclei.  Lipid filled [[cytoplasm]], numerous [[vacuoles]] and a crystalline material seen on [[light microscopy]] are other characteristics of [[foam cells]].  They are present in [[parafollicular]] areas of [[lymphoid]] tissues like tonsils, [[adenoids]] and [[lymph nodes]].  [[Bone marrow]] and gastrointestinal [[submucosa]] are also affected.<ref name="pmid162820">{{cite journal| author=Ferrans VJ, Fredrickson DS| title=The pathology of Tangier disease. A light and electron microscopic study. | journal=Am J Pathol | year= 1975 | volume= 78 | issue= 1 | pages= 101-58 | pmid=162820 | doi= | pmc=PMC1915033 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=162820  }} </ref>
-Hematologic features like [[hemolysis]], [[thrombocytopenia]], [[stomatocytosis]] and increased [[Hereditary spherocytosis|osmotic fragility]] result due to abnormal lipids in membrane.<ref name="pmid2757970">{{cite journal| author=Reinhart WH, Gössi U, Bütikofer P, Ott P, Sigrist H, Schatzmann HJ et al.| title=Haemolytic anaemia in analpha-lipoproteinaemia (Tangier disease): morphological, biochemical, and biophysical properties of the red blood cell. | journal=Br J Haematol | year= 1989 | volume= 72 | issue= 2 | pages= 272-7 | pmid=2757970 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2757970}}</ref>
-===Associated Conditions===
-* [[Diabetes mellitus]] occurs in Tangier disease due to suggested involvement of [[ABCA1]] in insulin secretion by beta cells of pancreas.<ref name="pmid19556721">{{cite journal| author=Koseki M, Matsuyama A, Nakatani K, Inagaki M, Nakaoka H, Kawase R et al.| title=Impaired insulin secretion in four Tangier disease patients with ABCA1 mutations. | journal=J Atheroscler Thromb | year= 2009 | volume= 16 | issue= 3 | pages= 292-6 | pmid=19556721 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556721  }} </ref>
-* [[Anemia]] also occurs in Tangier disease due to abnormal lipids (decreased cholesterol-to-[[phosphatidylcholine]] ratio) in cell membrane leading to hemolysis.<ref name="pmid19470903">{{cite journal| author=Sampietro T, Puntoni M, Bigazzi F, Pennato B, Sbrana F, Dal Pino B et al.| title=Images in cardiovascular medicine. Tangier disease in severely progressive coronary and peripheral artery disease. | journal=Circulation | year= 2009 | volume= 119 | issue= 20 | pages= 2741-2 | pmid=19470903 | doi=10.1161/CIRCULATIONAHA.108.812164 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19470903  }} </ref>
-* [[Thrombocytopenia]] in Tangier occures as a result of [[splenomegaly]].<ref name="pmid19723515">{{cite journal| author=Hooper AJ, Robertson K, Ng L, Kattampallil JS, Latchem D, Willsher PC et al.| title=A novel ABCA1 nonsense mutation, R1270X, in Tangier disease associated with an unrecognised bleeding tendency. | journal=Clin Chim Acta | year= 2009 | volume= 409 | issue= 1-2 | pages= 136-9 | pmid=19723515 | doi=10.1016/j.cca.2009.08.017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19723515  }} </ref>
-==Epidemiology and Demographics==
-Autosomal recessive disorders tend to occur with increased frequency in geographically isolated communities.  Though originally discovered on secluded Tangier island off the coast of Virginia, Tangier disease has been now been identified in many other countries.  Till date, approximately 100 cases have been diagnosed. <ref name="pmid22913675">{{cite journal| author=Puntoni M, Sbrana F, Bigazzi F, Sampietro T| title=Tangier disease: epidemiology, pathophysiology, and management. | journal=Am J Cardiovasc Drugs | year= 2012 | volume= 12 | issue= 5 | pages= 303-11 | pmid=22913675 | doi=10.2165/11634140-000000000-00000 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22913675  }} </ref>
-==Screening==
-Screening for Tangier is helpful in diagnosing this disease in parents and siblings of a patient.  Lipid profile including [[HDL]] levels and apolipoprotein A levels is used as a screening method as they are significantly reduced to absent in patients.
-==Diagnosis==
-===History===
-* Directed history should be obtained to ascertain the presence of similar symptoms in any of the family members.
-===Symptoms===
-Tangier is a rare multisystem disease with high variability in clinical manifestations.
-*Enlarged orange colored tonsils is the most common presentation in children and adolescents.
-*[[Neuropathy]] is the presenting complaint in 50% of adult population. These patients can present with tingling sensation, numbness, loss of balance or weakness.
-*Other presentations include abdominal discomfort due to organomegaly, premature myocardial infarction in about 30% of adult population.
-*Minor alteration in vision can be present due to corneal haziness, however there have been reports of significant visual impairment.
-*Fatigue and easy bruisability due to anemia and [[thrombocytopenia]] respectively can be present.<ref name="pmid22913675">{{cite journal| author=Puntoni M, Sbrana F, Bigazzi F, Sampietro T| title=Tangier disease: epidemiology, pathophysiology, and management. | journal=Am J Cardiovasc Drugs | year= 2012 | volume= 12 | issue= 5 | pages= 303-11 | pmid=22913675 | doi=10.2165/11634140-000000000-00000 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22913675  }} </ref>
-===Physical Examination===
-====Eye====
-* Hazy cornea
-* Pallor
-====Throat====
-* Enlarged [[tonsils]] that appear orange or yellow.
-====Abdomen====
-* [[Hepatomegaly]]
-* [[Splenomegaly]]
-* Proctoscopy can show foam cell aggregates in colonic mucosa as orange brown spots of 1-2 mm size.
-====Neurologic====
-* Decreased sensory and motor functions as a result of neuropathy.
-===Laboratory Findings===
-* Lipid panel shows
-** Normal to slightly elevated amounts of triglycerides in blood (mild [[hypertriglyceridemia]])
-** Markedly reduced to absent [[HDL]]
-** [[Low total cholesterol]]
-** Absent to reduced apolipoprotein A
-===Other Tests===
-* ABCA1 gene sequencing is the most specific test, however it's expensive and due to large size of the gene and rare nature of Tangier disease, it's not cost effective.
-* Other test which can be done is cholesterol efflux assay on fibroblasts (not specific).
-==Treatment==
-No specific therapy is available till date for Tangier disease.  Patients are advised to take very low fat diet to reduce fat accumulation inside the cells.    Drugs increasing level of HDL are considered as possible therapeutic agents, however old drugs like niacin, fibric acid derivatives and microsomal enzyme inducers have not been proven effective.<ref name="pmid7712672">{{cite journal| author=Franceschini G, Werba JP, D'Acquarica AL, Gianfranceschi G, Michelagnoli S, Sirtori CR| title=Microsomal enzyme inducers raise plasma high-density lipoprotein cholesterol levels in healthy control subjects but not in patients with primary hypoalphalipoproteinemia. | journal=Clin Pharmacol Ther | year= 1995 | volume= 57 | issue= 4 | pages= 434-40 | pmid=7712672 | doi=10.1016/0009-9236(95)90213-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7712672  }} </ref><ref name="pmid21809737">{{cite journal| author=Markel A| title=The resurgence of niacin: from nicotinic acid to niaspan/laropiprant. | journal=Isr Med Assoc J | year= 2011 | volume= 13 | issue= 6 | pages= 368-74 | pmid=21809737 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21809737  }} </ref>  Newer drugs in this area include [[CETP]] inhibitors:  [[torcetrapib]] was one of the very first CETP inhibitors, but its trial was stopped due to increased cardiovascular diseases.  [[Anacetrapib]] and [[evacetrapib]], according to the recent literature are safer and more potent than [[torcetrapib]] and [[dalcetrapib]], however their role in Tangier disease has not been established and require further research.<ref name="pmid23567794">{{cite journal| author=Bishop BM| title=Systematic Review of CETP Inhibitors for Increasing High-Density Lipoprotein Cholesterol: Where Do These Agents Stand in the Approval Process? | journal=Am J Ther | year= 2013 | volume=  | issue=  | pages=  | pmid=23567794 | doi=10.1097/MJT.0b013e31828b8463 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23567794  }}</ref>
 ==References==
 {{reflist|2}}
-{{Lipopedia}}
-[[Category:Lipopedia]]
-[[Category:Disease]]
 [[Category:Genetic disorders]]
 [[Category:Inborn errors of metabolism]]