Tangier disease
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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]
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
Overview
Tangier disease is a rare autosomal recessive disorder characterised by severely decreased high-density lipoprotein (HDL), often referred to as "good cholesterol" in the bloodstream, caused by defective cholesterol efflux from macrophages. It manifests with enlarged and orange coloured 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, which were removed. Initially it was diagnosed as Niemann-Pick disease but a further investigation revealed an extremely high number of cholesterol filled macrophages (foam cells) in several other tissues, which included bone marrow 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.[1] 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.
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 codominant 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.
[2]
Biochemical phenotype is inherited in autosomal codominant pattern. Patients homozygous for this mutation have complete absence of HDL, heterozygotes on the other hand have one half of normal level of HDL.
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).
Associated conditions
- Diabetes Mellitus has been associated with Tangier disease due to suggested involvement of ABCA1 in insulin secretion by beta cells of pancreas.[3]
- Anemia has also been associated with Tangier disease due to abnormal lipids (decreased cholesterol-to-phosphatidylcholine ratio) in cell membrane leading to hemolysis.[4]
- Thrombocytopenia is associated with Tangier as a result of splenomegaly.[5]
Gross pathology
Prominent pathological features in Tangier disease are due to accumulation of foam cells in various tissues throughout the body like.
- 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 neurological symptoms is noticed : * Syringomyelia type loss of sensory and motor neurons in upper body.[6]
* Peripheral neuropathy with fluctuating loss of sensory and motor function.[7]
- Cardiovascular disease risk is increased particularly in homozygotes and elderly patients with Tangier. Deposition of lipid filled macrophages in arterial wall results in accelerated atherosclerosis.[8]
- Splenomegaly and hepatomegaly also present due to accumulation of cholesterol esters in reticuloendothelial cells.
- Corneal opacification occurs due to lipid deposition in corneal stroma.
Microscopic Pathology
Microscopically, affected tissues are infiltrated by foamy histiocytes. They are rounded, oval shaped cells with darkly stained nuclei. Lipid filled cytoplasm, numerous vacoules 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.[9]
Hematologic features like hemolysis, thrombocytopenia, stomatocytosis and increased osmotic fragility result due to abnormal lipids in membrane.[10]
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. [11]
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. Apolipoprotein A is superior for predicting Coronary Artery disease risk.
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, easy bruisability due to anemia and thrombocytopenia respectively can be present.[11]
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
- 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
No specific therapy is available til date for Tangier disease. Drugs increasing level of HDL are considered as possible therapeutic agents, however fibric acid derivatives and niacin have not been proven effective. 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.[12]
References
- ↑ "Transport of lipids from golgi to plasma membrane ... [Nat Genet. 2000] - PubMed - NCBI". Retrieved 11 September 2013.
- ↑ 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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 11.0 11.1 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.
- ↑ 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.
External links
- Tangier disease at NLM Genetics Home Reference