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 is a disease causing low HDL C levels. Low HDL is an independent cardiovascular risk factor.


Historical perspective

Pathophysiology

Pathogenesis

  • Autosomal rescessive.
  • HDL C complexity.[1]
  • Mutation of the ATP-Binding Cassette transporter A1 (ABCA1) which transfers cholesterol and phospholipids on to Apo A1 to form HDL.
  • Mutation affects the first step of reverse cholesterol transport, which leads to accumalation of lipid in the cells.



 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
Larger alpha HDL can donate the CE and free cholesterol to the liver via scavenger receptor-B1 (SR-B1)
  • 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 help to 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.[2] 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:
  1. Syringomyelia type loss of sensory and motor neurons in upper body.[3]
  2. Peripheral neuropathy with fluctuating loss of sensory and motor function.[4]

Genetics

This condition is inherited in an autosomal recessive pattern clinically, which means both alleles of the gene in each cell have mutations. 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.[6] This inability to transport cholesterol out of cells leads to a deficiency of high-density lipoproteins in the circulation, which is a risk factor for coronary artery disease (CAD).

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.[7]

Hematologic features like hemolysis, thrombocytopenia, stomatocytosis and increased osmotic fragility result due to abnormal lipids in membrane.[8]

Associated Conditions

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. [12]

Screening

Screening for Tangier is helpful in diagnosing this disease in parents and siblings of a patient. Lipid profile including HDL levels and apolipoprotein A levels is used as a screening method as they are significantly reduced to absent in patients.

Diagnosis

History

  • Directed history should be obtained to ascertain the presence of similar symptoms in any of the family members.

Symptoms

Tangier is a rare multisystem disease with high variability in clinical manifestations.

  • Enlarged orange colored tonsils is the most common presentation in children and adolescents.
  • Neuropathy is the presenting complaint in 50% of adult population. These patients can present with tingling sensation, numbness, loss of balance or weakness.
  • Other presentations include abdominal discomfort due to organomegaly, premature myocardial infarction in about 30% of adult population.
  • Minor alteration in vision can be present due to corneal haziness, however there have been reports of significant visual impairment.
  • Fatigue and easy bruisability due to anemia and thrombocytopenia respectively can be present.[12]

Physical Examination

Eye

  • Hazy cornea
  • Pallor

Throat

  • Enlarged tonsils that appear orange or yellow.

Abdomen

  • Hepatomegaly
  • Splenomegaly
  • Proctoscopy can show foam cell aggregates in colonic mucosa as orange brown spots of 1-2 mm size.

Neurologic

  • Decreased sensory and motor functions as a result of neuropathy.

Laboratory Findings

Other Tests

  • ABCA1 gene sequencing is the most specific test, however it's expensive and due to large size of the gene and rare nature of Tangier disease, it's not cost effective.
  • Other test which can be done is cholesterol efflux assay on fibroblasts (not specific).

Treatment

No specific therapy is available till date for Tangier disease. Patients are advised to take very low fat diet to reduce fat accumulation inside the cells. Drugs increasing level of HDL are considered as possible therapeutic agents, however old drugs like niacin, fibric acid derivatives and microsomal enzyme inducers have not been proven effective.[13][14] 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.[15]

References

  1. 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.
  2. "Transport of lipids from golgi to plasma membrane ... [Nat Genet. 2000] - PubMed - NCBI". Retrieved 11 September 2013.
  3. 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.
  4. 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)
  5. Serfaty-Lacrosniere C, Civeira F, Lanzberg A, Isaia P, Berg J, Janus ED; et al. (1994). "Homozygous Tangier disease and cardiovascular disease". Atherosclerosis. 107 (1): 85–98. PMID 7945562.
  6. Rust, S.; Rosier, M.; Funke, H.; Real, J.; Amoura, Z.; Piette, JC.; Deleuze, JF.; Brewer, HB.; Duverger, N. (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. Unknown parameter |month= ignored (help)
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 12.0 12.1 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.
  13. Franceschini G, Werba JP, D'Acquarica AL, Gianfranceschi G, Michelagnoli S, Sirtori CR (1995). "Microsomal enzyme inducers raise plasma high-density lipoprotein cholesterol levels in healthy control subjects but not in patients with primary hypoalphalipoproteinemia". Clin Pharmacol Ther. 57 (4): 434–40. doi:10.1016/0009-9236(95)90213-9. PMID 7712672.
  14. Markel A (2011). "The resurgence of niacin: from nicotinic acid to niaspan/laropiprant". Isr Med Assoc J. 13 (6): 368–74. PMID 21809737.
  15. Bishop BM (2013). "Systematic Review of CETP Inhibitors for Increasing High-Density Lipoprotein Cholesterol: Where Do These Agents Stand in the Approval Process?". Am J Ther. doi:10.1097/MJT.0b013e31828b8463. PMID 23567794.

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