Tangier disease: Difference between revisions

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==Classification==
==Classification==
*Tangier disease can be classified into homozygous or [[heterozygous]] based on the inheritance of the defective alleles. They differ in presentation, [[lipid]] analysis, pathophysiology and risk of [[Cardiovascular disease|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>
*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"
{| class="wikitable"
!
!
!Homozygous
![[Homozygous]]
!Heterozygous
![[Heterozygous]]
|-
|-
|Presentation
|Presentation
Line 34: Line 34:
|Asymptomatic
|Asymptomatic
|-
|-
|Lipid analysis
|Lipid Profile
|HDL < 5% of normal  
|
Apo A1 < 1% of normal  
*[[HDL]] < 5% of normal  
 
*[[Apo A1]] < 1% of normal  
LDL < 40% of normal
*[[LDL]] < 40% of normal
|HDL C, Apo A1  
|
and LDL 50% less than  
*[[HDL]]C, [[Apo A1]] and [[LDL]] 50% less than normal  
 
normal.
|-
|-
|Pathophysiology
|Pathophysiology
|Increased fractional [[catabolism]] of  
|Increased fractional [[catabolism]] of [[HDL]] and [[Apo A1]]
HDL proteins and Apo A1  
|Enhanced clearance of  [[HDL]] and [[Apo A1]]
|Enhanced clearance of  HDL  
and Apo A1
|-
|-
|2D Electrophoresis
|[[2D Electrophoresis]]
|Only preβ-1 HDL present
|Only preβ-1 [[HDL]] present
|Lack of large α-1 and α-2 HDL particles
|
Normal preβ-1 HDL
*Lack of large α-1 and α-2 [[HDL]] particles
 
*Normal preβ-1 [[HDL]]
Only 50% of normal cellular cholesterol efflux
*Only 50% of normal cellular [[cholesterol efflux]]
|-
|-
|CVD Risk
|[[CVD Risk]]
|Variable and related to non-HDL C
|Variable and related to non-[[HDL]] C and [[splenomegaly]]
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>
|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>
|}
|}



Revision as of 18:59, 29 March 2017

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To view Lipoprotein Disorders Main Page Click here
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2], Twinkle Singh, M.B.B.S. [3] Aravind Kuchkuntla, M.B.B.S[4]

Synonyms and keywords: Familial alphalipoprotein deficiency, HDL deficiency - familial, high density lipoprotein deficiency, analphalipoproteinaemia, high density lipoprotein deficiency - type 1, high density lipoprotein deficiency - Tangier type, A-alphalipoprotein Neuropathy, alpha High Density Lipoprotein Deficiency Disease, Cholesterol thesaurismosis, Familial Hypoalphalipoproteinemia, Tangier Disease Neuropathy, Tangier Hereditary Neuropathy

Overview

Tangier 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

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

Reverse cholesterol transport

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

 
 
 
Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter[15] to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease causing to have only pre beta HDL on 2D electrophoresis.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discoidal HDL particles are converted to medium spherical α-3 HDL and larger particles by the esterification of free cholesterol via the enzyme lecithin:cholesterol acyltransferase (LCAT) and the addition of apoA-II.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These particles are further converted to large and very large spherical α-2 and α-1 HDL by the actions of cholesteryl ester transfer protein (CETP). CETP transfers cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very large α-1 HDL particles are preferential donors of cholesterol to the liver, and the constituents of these particles can recycle back to form very small discoidal particles and can re-enter the HDL cycle, or be catabolized directly by the kidney or liver
 
 
 


Genetics

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

Microscopic pathology

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

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 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 and defective reverse cholesterol transport.
Clinical Features
  • Annular corneal opacity
  • Anaemia
  • 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 Panel
  • Elevated Free cholesterol
  • HDL-C < 10 mg/dL
  • Low Apo A1 and Apo AII
  • Elevated Apo E and Triglycerides
  • Low LDL C
  • Elevated free cholesterol
  • HDL C < 27 mg/dL
  • Apo A1<30mg/dl and low Apo A2
  • Elevated Apo E and Triglycerides
  • Normal LDL and VLDL
  • HDL < 5% of normal
  • Apo A1 < 1% of normal
  • LDL < 40% of normal
  • HDL C, Apo A1 and LDL 50% less than normal.
  • Undetectable Apo A1
  • HDL C less than 10mg/dl
  • Normal or low Apo AII
  • LDL C normal
  • Triglyceride normal or elevated
2D Gel Electrophoresis Pre β-1 and α-4 HDL, LDL with β mobility due to Lipoprotien-X Pre β-1and α-4 HDL with normal pre-β LDL. Only preβ-1 HDL present
  • Lack of large α-1 and α-2 HDL particles
  • Normal preβ-1 HDL
Lack of Apo A1 containing HDL particles.


Epidemiology and Demographics

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

Natural History, Complications and Prognosis

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

Diagnosis

History and Symptoms

  • The characteristic clinical presentation of Tangier disease includes:
    • Throat pain from swollen tonsils.
    • Numbness, tingling, weakness of the extremities[25][26]
    • 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 colour 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: loss of sensory and motor neurons in the upper body.[27]
    • Peripheral neuropathy with fluctuating loss of sensory and motor function.[28]

Laboratory Findings

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

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

2D Electrophoresis

Molecular Genotype sequencing

  • The gold standard for of Tangier disease diagnosis is ABCA1 gene sequence analysis.

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 adviced as they are at a higher risk of developing premature cardiovascular disease.[23]
  • Trail of HDL infusion is ineffective as the apolipoprotien A1 which is required for the formation of HDL particle is very low.[12]

Surgery

No surgical therapies are indicated.

Prevention

Primary Prevention

  • Patients with homozygous Tangier disease are at higher risk of developing cardiovascular disease at a young age, and according to ATP III 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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