Tangier disease: Difference between revisions

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{{Hypolipoproteinemia}}
{{SI}}
'''To view Lipoprotein Disorders Main Page [[ Lipoprotein disorders| Click here]]'''<br>
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{{CMG}}; {{AE}} {{RT}}, {{TS}} {{AKI}}
{{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==
==Overview==
Tangier is a disease causing low HDL C levels. Low HDL is an independent cardiovascular risk factor.
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]].
 


==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==
*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 1990, Francis and Oram and also Schmitz and Assmann, noted that the fibroblasts lacked the ability to efflux cholesterol and phospholipids onto HDL or Apo A1.
{| class="wikitable"
* In 1998, the chromosomal locus (9q31) for TD was identified by Rust and Assmann.
!
*In 1999, Schmitz and team reported that the ABCA1 was involved in the  efflux of cellular cholesterol and phospholipid onto HDL and apoA-I.
![[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==
===Pathogenesis===
===Pathogenesis===
* TD is caused by a homozygous or compound heterozygous mutation in the ATP-Binding Cassette transporter A1 (ABCA1) gene (600046) on chromosome 9q31, which transfers cholesterol and phospholipids onto HDL.
*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 first step of reverse cholesterol transport, which leading to accumalation of cholesterol esters in the cells.
*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/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 alpha 4 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 | | | | |!| | | | | }}
{{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 | | | | |!| | | | | }}
{{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 | |,|-|-|^|-|-|.| | }}
{{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}}
{{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===
==Demographics, Natural History and Complications==
==Diagnosis==


==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===
===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]]).
*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===
===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>
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>.


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===
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>


===Associated Conditions===
== Differentiating Tangier disease from other diseases with low HDL C ==
* [[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>
===Low [[HDL]] Diagnostic Features===
* [[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>
{| class="wikitable"
* [[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>
!
!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==
==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>
* 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>
 
==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]].


==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==
==Diagnosis==
===History===
===History and Symptoms===
* Directed history should be obtained to ascertain the presence of similar symptoms in any of the family members.
*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]]


===Symptoms===
===Physical Examination===
Tangier is a rare multisystem disease with high variability in clinical manifestations.
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>


*Enlarged orange colored tonsils is the most common presentation in children and adolescents.
===Laboratory Findings===
*[[Neuropathy]] is the presenting complaint in 50% of adult population. These patients can present with tingling sensation, numbness, loss of balance or weakness.
Tangier disease is diagnosed with characteristic laboratory finding of very low [[HDL]] C and [[Apo A1]].  
*Other presentations include abdominal discomfort due to organomegaly, premature myocardial infarction in about 30% of adult population.
*Plasma [[HDL]] C is usually below 5 mg/dL.
*Minor alteration in vision can be present due to corneal haziness, however there have been reports of significant visual impairment.
*[[Serum]] concentrations of [[Apo A1]] and [[Apo AII]] [[lipoproteins]] are below 5 mg/dL due to increased [[catabolism]].
*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>
*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]].


===Physical Examination===
=== 2D Electrophoresis ===
====Eye====
* 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>
* Hazy cornea
* Pallor


====Throat====
===Molecular Genotype sequencing===
* Enlarged [[tonsils]] that appear orange or yellow.
* The gold standard for of the diagnosis of Tangier disease is [[ABCA1]] [[gene sequencing]].
====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==
==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>
===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}}


{{Lipopedia}}
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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

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  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.
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  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.
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  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.
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  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.
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  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.
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  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.
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