Tangier disease

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Lipid Disorders Main Page

Overview

Causes

Classification

Abetalipoproteinemia
Hypobetalipoproteinemia
Familial hypoalphalipoproteinemia
LCAT Deficiency
Chylomicron retention disease
Tangier disease
Familial combined hypolipidemia

Differential Diagnosis

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 ApoA1. 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. These patients are at an increased risk of premature coronary artery disease as low HDL is an independent cardiovascular risk factor.

Historical Perspective

  • In 1960, Fredricson and colleagues described the disease in two young siblings from Tangier Island in the Chesapeake Bay.
  • In 1985, Francis and Oram, as well as Schmitz and Assmann, noted that Tangier's disease (TD) is a disorder of intracellular membrane traffic.[1]
  • In 1998, the chromosomal locus (9q31) for TD was identified by Rust and Assmann. [2]
  • In 1999, genomic organization and the genetic defect were identified.[3]
  • In 1999, the function of the ABCA1 transporter in the efflux of cellular cholesterol as phospholipid to HDL and ApoA-I was reported.[4]
  • In the later part of 1999, three different research groups reported different mutations in ABCA1 as causes of homozygous Tangier disease.[5][6]
  • In 2000, three different research groups confirmed that mutations in the ABCA gene can cause Tangier disease.[7]

Classification

Homozygous Heterozygous
Presentation Symptomatic Asymptomatic
Lipid analysis HDL < 5% of normal

Apo A1 < 1% of normal

LDL < 40% of normal

HDL C, Apo A1

and LDL 50% less than

normal.

Pathophysiology Increased fractional catabolism of

HDL proteins and Apo A1

Enhanced clearance of HDL

and Apo A1

2D Electrophoresis Only preβ-1 HDL present Lack of large α-1 and α-2 HDL particles

Normal preβ-1 HDL

Only 50% of normal cellular cholesterol efflux

CVD Risk Variable and related to non-HDL C

and splenomegaly

Not at higher risk when compared to

non-carriers.[9]

Pathophysiology

Pathogenesis

  • The gene involved in the pathogenesis of TD 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, which is the primary cause for low Apo-A1 levels.[12]
    • This implicates against biosynthesis as a cause, as the normal Apo-A1 gene is sequenced in affected patients.[13]
  • Mutation affects the the efflux of cholesterol from the cells as the first step in reverse cholesterol transport, which leads to accumulation of cholesterol esters in the cells.

Genetics

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

Microscopic pathology

Associated Conditions

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.

Reverse cholesterol transport

Below is the HDL C cycle of formation and recycling:[19]

 
 
 
Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter[20] 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
 
 
 

Epidemiology and Demographics

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

Natural History, Complications and Prognosis

  • The symptoms of Tangier disease usually develop in the 1st decade of life with characteristic tonsillar enlargement and corneal opacities or in adulthood with symptoms of peripheral neuropathy.
  • Without treatment, the major debilitating feature is the relapsing and remitting course of neuropathy with loss of sensory and motor function which affects the quality of life.
  • Cardiovascular risk is variable in homozygous Tangier patients 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 event when compared to non-carriers.
  • Risk of developing premature CVD:[23]
    • Increased: In patients without splenomegaly, anemia and have normal LDL C levels.
    • Patients with splenomegaly have anemia and low LDL C do not develop premature CVD.

Diagnosis

History and Symtoms

  • The characteristic clinical presentation of Tangier disease includes:
    • Throat pain from swollen tonsils.
    • Numbness or pain in the upper body, including difficulty moving[25][26]
    • Other less common features of presentation include:
      • Rapid heartbeat
      • Difficulty breathing
      • Abdominal pain
      • Vision loss
      • Nausea or vomiting
      • Chest pain
      • Confusion
      • Memory loss
      • Light-headedness

Physical Exam

  • Large yellow-orange tonsils due to the failure of uptake of lipid by HDL causes relative enrichment of the core of LDL by beta-carotene, resulting in enhanced uptake by the reticulo-endothelial cells which gives the characteristic colour to the tissues.
  • 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]
  • Abdominal examination may reveal discomfort due to hepatomegaly and splenomegaly
  • Occular examination may reveal visual disturbances due to corneal haziness.
  • Physical examination may reveal evidence of premature myocardial infarction or stroke.

Laboratory Findings

Characteristic lab findings include:

  • 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, 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]
    • This potentially reduces 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

Other Diagnostic Studies

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

Treatment

Medical Therapy

  • No specific treatment measures are available for treatment of TD.
  • 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.

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. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  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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