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 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.
  • They described the condition to have very low plasma levels of HDL C, moderately elevated triglycerides and decreased low density lipoprotein (LDL) cholesterol levels.
  • The patients presented with mild corneal opacification, hepatosplenomegaly and orange-colored tonsils.
  • Cholesterol-laden macrophages were found in their tonsils, bone marrow, nerves and smooth muscle cells.
• In 1985, Francis and Oram, as well as Schmitz and Assmann, noted that Tangier's disease (TD) is a disorder of intracellular membrane traffic.
• In 1998, the chromosomal locus (9q31) for TD was identified by Rust and Assmann.
• In 1999, genomic organization and the genetic defect were 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 the later part of 1999, three different research groups reported different mutations in ABCA1 as causes of homozygous Tangier disease.
• In 2000, three different research groups confirmed that mutations in the ABCA gene can cause Tangier disease.

Classification

• Tangier can be classified into homozygous or heterozygous Tangier disease based on presentation, lipid analysis, pathophysiology, 2D electrophoresis, and risk of Cardiovascular disease (CVD).

	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.

Pathophysiology

Pathogenesis

• The gene involved in the pathogenesis of TD is ATP-Binding Cassette tansporter gene (ABCA1), 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)..
• 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.
  • This implicates against biosynthesis as a cause, as the normal Apo-A1 gene is sequenced in affected patients.
• 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

• Affected tissues are infiltrated by cholesterol-laden macrophages usually in the parafollicular areas of lymphoid tissues like tonsils, adenoids and lymph nodes.
• Bone marrow and gastrointestinal submucosa are also affected.
• Hematologic features include:
  • Hemolysis
  • Thrombocytopenia
  • Stomatocytosis
  • Increased osmotic fragility results due to abnormal amounts of lipids in the membrane..

Associated Conditions

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

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
Gene Defect	LCAT	LCAT	ABCA1	ABCA1
Inheritance	Autosomal Recessive	Autosomal Recessive	Autosomal Recessive	Autosomal Recessive
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
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
Lipid Panel	Elevated Free cholesterol HDL-C < 10 mg/dL Low Apo A1 and Apo A2 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.
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

Reverse cholesterol transport

Below is the HDL C cycle of formation and recycling:

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

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

Natural History, Complications and Prognosis

• Patients are diagnosed in the 1st decade of life with characteristic tonsillar enlargement and corneal opacities, adults are seek medical attention due to the symptoms of neuropathy.
• 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 .
• Patients who are heterozygous are not at higher risk of having a cardiovascular event when compared to non-carriers
• Risk of developing premature CVD:
  • 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
  • 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.
  • Peripheral neuropathy with fluctuating loss of sensory and motor function.
• 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.
  • 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

• Prebeta 1-HDL is identified on 2D electrophoresis after anti-apo A1 immunoblotting.

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.
• Trail of HDL infusion is ineffective as the apolipoprotien A1 which is required for the formation of HDL particle is very low.

Surgery

No surgical therapies are indicated.