Tangier disease

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.It is characterized by low or absent HDL, Apo A1 and accumalation of Cholesterol esters in multiple locations in the body including tonsil, peripheral nerves, liver, skin and cornea.

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 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.
• In 1985, Francis and Oram and also Schmitz and Assmann, noted that TD is a disorder of intacellular membrane traffic.
• In 1998, the chromosomal locus (9q31) for TD was identified by Rust and Assmann.
• In 1999, Genomic organization and the genetic defect was identified.
• In 1999, the function of the ABCA1 transporter in the efflux of cellular cholesterol as phospholipid to HDL and ApoA-I was reported..
• In later part of 1999, three different research groups reported various mutations in ABCA1 as causes of homozygous Tangier disease.
• In the following year (2000), three different research groups confirmed the finding that a genetic defect in the gene ABCA1 could cause Tangier disease.

Pathophysiology

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 mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein (HDL). .
• Mutation affects the the efflux of cholesterol from the cells, first step of reverse cholesterol transport, which leads to accumulation of cholesterol esters in the cells. This leads to the failure of lipidation onto ApoA1. These lipid poor Apo-A1 particles are rapily catabolized in the kidney leading to very low Apo-A1 levels in TD.
• HDL C complexity.

Reverse cholesterol transport

Very small discoidal Pre beta HDL picks up free cholesterol from cells via ABCA1 converting small discoidal pre beta HDL to small discoidal alpha4 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 helps remove the phospholipid from large HDL to convert it into small HDL.

Demographics, Natural History and Complications

• Tangier disease has been diagnosed in about 100 patients in many countries.

Diagnosis

History and Symtoms

• The characteristic clinical presentation of TD include
  • Tonsil enlargement in children.
  • Symptoms of peripheral neuropathy in adults.
  • Other less common features of presentation include clinical features of hepatomegaly, splenomegaly, premature myocardial infarction or stroke.

Physical Exam

• Large yellow-orange tonsils
• Corneal opacity
• 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.
  • Peripheral neuropathy with fluctuating loss of sensory and motor function.
• 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.
• Splenomegaly and hepatomegaly from accumulation of cholesterol esters in reticuloendothelial cells.

Laboratory Findings

Characteristic lab findings include:

• Plasma HDL cholesterol is virtually absent (usually below 5 mg/dL).
• Plasma total cholesterol is low (below 150 mg/dL).
• Triglyceride plasma levels are normal or elevated (up to 400 mg/dL).
• Serum concentrations of apoA-I and apoA-II lipo- proteins are below 5 mg/dL.

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. 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.
• Corneal opacification occurs due to lipid deposition in corneal stroma.

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. 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.

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

Associated Conditions

• Diabetes mellitus occurs in Tangier disease due to suggested involvement of ABCA1 in insulin secretion by beta cells of pancreas.
• Anemia also occurs in Tangier disease due to abnormal lipids (decreased cholesterol-to-phosphatidylcholine ratio) in cell membrane leading to hemolysis.
• Thrombocytopenia in Tangier occures as a result of splenomegaly.

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.

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.

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 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. 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.