Tangier disease: Difference between revisions

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{{Infobox_Disease |
  Name          = Tangier disease |
  Image          = |
  Caption        = |
  DiseasesDB    = 12901 |
  ICD10          = {{ICD10|E|78|6|e|70}} |
  ICD9          = {{ICD9|272.5}}  |
  ICDO          = |
  OMIM          = 205400 |
  MedlinePlus    = |
  eMedicineSubj  = |
  eMedicineTopic = |
  MeshID        = D013631 |
}}
{{SI}}
{{SI}}
{{CMG}}; {{AE}} {{RT}}
'''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}} 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==
==Overview==
'''Tangier disease''' is a rare inherited disorder characterized by a severe reduction in the amount of high-density lipoprotein (HDL), often referred to as "good cholesterol," in the bloodstream. High-density lipoproteins are created when a type of protein in the bloodstream, apolipoprotein A1 (apoA1), picks up cholesterol from the cells. People with Tangier disease have a greatly reduced ability to transport cholesterol out of their cells, leading to a deficiency of high-density lipoproteins in the bloodstream and the accumulation of cholesterol in many body tissues. Reduced blood levels of high-density lipoproteins is sometimes described as hypolipoproteinemia.
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]].


People affected by this condition also have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). The tonsils are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature atherosclerosis, which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the clear covering of the eye (cornea), and early-onset cardiovascular 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 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==
Tangier disease (TD) is a genetic disorder of cholesterol transport named for the secluded island of Tangier, located off the coast of Virginia. TD was first identified in a five-year-old inhabitant of the island who had characteristic orange tonsils, very low levels of high density lipoprotein (HDL) or 'good cholesterol', and an enlarged liver and spleen.
*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>
{| class="wikitable"
!
![[Homozygous]]
![[Heterozygous]]
|-
|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==
==Pathophysiology==
[[High-density lipoproteins]] are created when a protein in the bloodstream, [[apolipoprotein A1]] ([[apoA1]]), combines with [[cholesterol]] and phospholipids. The cholesterol and phospholipids used to form HDL originate from inside cells but is transported out of the cell into the blood via the [[ABCA1]] transporter. People with Tangier disease have defective [[ABCA1]] transporters resulting in a greatly reduced ability to transport cholesterol out of their cells, which leads to an accumulation of cholesterol in many body tissues. Reduced blood levels of high-density lipoproteins is sometimes described as [[hypoalphalipoproteinemia]].
===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]]).<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>
*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>
**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==
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-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= 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 | | | | 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}}
 


===Genetics===
===Genetics===
[[Image:autorecessive.svg|thumb|left|120px|Tangier disease has an [[Recessive gene|autosomal recessive]] pattern of inheritance.]]
*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.


This condition is inherited in an [[autosomal recessive]] pattern, which means both copies 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.  
===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>.


[[Mutation]]s in the chromosome 9q31 lead to a defective ''[[ABCA1]]'' transporter. These mutations prevent the [[ABCA1]] protein from effectively transporting cholesterol and phospholipids out of cells for pickup by ApoA1 in the bloodstream.  
===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>


This inability to transport cholesterol out of cells leads to a deficiency of high-density lipoproteins in the circulation, which is a risk factor for [[coronary artery disease]] ([[CAD]]).  
== 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
|}


Additionally, the buildup of cholesterol in cells can be toxic, causing cell death or impaired function. These combined factors lead to the signs and symptoms of '''Tangier disease'''.
==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>


==Epidemiology and Demographics==
==Natural History, Complications and Prognosis==
* Tangier disease is a rare disorder with approximately 50 cases identified worldwide.  
* 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]].
* This disorder was originally discovered on Tangier Island off the coast of Virginia, but has now been identified in people from many different countries.
*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==
==Diagnosis==
People affected by this condition also have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function ([[neuropathy]]). The [[tonsil]]s are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature [[atherosclerosis]], which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen ([[splenomegaly]]), an enlarged liver ([[hepatomegaly]]), clouding of the [[cornea]], and early-onset cardiovascular disease.
===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.


==References==
==References==
{{reflist|2}}
{{reflist|2}}


==External links==
* {{NLM|tangierdisease}}
{{Lipidemias}}
[[Category:Disease]]
[[Category:Genetic disorders]]
[[Category:Genetic disorders]]
[[Category:Inborn errors of metabolism]]
[[Category:Inborn errors of metabolism]]
[[Category:Autosomal recessive disorders]]
[[Category:Autosomal recessive disorders]]
[[de:Tangier-Krankheit]]
[[it:Malattia di Tangier]]
[[nl:Ziekte van Tangier]]
[[pl:Choroba wyspy Tanger]]


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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

Classification

Homozygous Heterozygous
Presentation Symptomatic Asymptomatic
Lipid Profile
  • HDL < 5% of normal
  • Apo A1 < 1% of normal
  • LDL < 40% of normal
Pathophysiology Increased fractional catabolism of HDL and Apo A1 Enhanced clearance of HDL and Apo A1
2D Electrophoresis Only preβ-1 HDL present
CVD Risk Variable and related to non-HDL C and splenomegaly Not at higher risk when compared to non-carriers.[9]

Pathophysiology

Pathogenesis

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

Microscopic pathology

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

Associated Conditions

Conditions associated with Tangier disease include:

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 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 Asymptomatic
Lipid Profile
  • HDL < 5% of normal
  • Apo A1 < 1% of normal
  • LDL < 40% of normal
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

Diagnosis

History and Symptoms

Physical Examination

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

Laboratory Findings

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

2D Electrophoresis

Molecular Genotype sequencing

Treatment

Medical Therapy

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

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

  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  21. "Orphanet: Tangier disease".
  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.
  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.
  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.
  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.
  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)
  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.
  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.
  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.
  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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