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] Aravind Kuchkuntla, M.B.B.S[4]

Synonyms and keywords: analphalipoproteinaemia, high density lipoprotein deficiency-type 1, high density lipoprotein deficiency-Tangier type, A-alphalipoprotein Neuropathy, alpha High Density Lipoprotein Deficiency Disease, Cholesterol thesaurismosis, 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 apolipoprotein A1. 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. Low HDL is an independent cardiovascular risk factor, therefore these patients are at an increased risk of developing premature coronary artery disease.

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 ABCA transporter in the efflux of cellular cholesterol as phospholipid to HDL and apolipoprotein A1 was reported.
• In the later part of 1999, three different research groups reported different mutations in ABCA1 can cause homozygous Tangier disease.
• In 2000, three different research groups confirmed that mutations in the ABCA1 gene cause Tangier disease.

Classification

• Tangier disease can be classified into homozygous or heterozygous based on the inheritance of the defective alleles. They differ in presentation, lipid analysis, pathophysiology and risk of cardiovascular disease (CVD).

	Homozygous	Heterozygous
Presentation	Symptomatic	Asymptomatic
Lipid Profile	HDL < 5% of normal Apo A1 < 1% of normal LDL < 40% of normal	HDLC, Apo A1 and LDL 50% less than normal
Pathophysiology	Increased fractional catabolism of HDL 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 Tangier disease 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 apolipoprotein A1 results in rapid catabolism of Apo A1 in the kidney, the primary cause for low Apo A1 levels.
  • In Tangier disease normal Apo-A1 gene is sequenced ruling out the biosynthetic defect as the cause of low Apo A1.
• The mutation affects the the efflux of cholesterol from the cells in the reverse cholesterol transport, leading to the accumulation of cholesterol esters in cells.

Reverse cholesterol transport

The following algorithm describes the HDL C 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 Apo A 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

Genetics

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

Microscopic pathology

The characteristic microscopic features in Tangier disease on histopathological examination include:

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

Associated Conditions

Conditions associated with Tangier disease include:

• Diabetes mellitus due to involvement of ABCA1 in insulin secretion by beta cells of pancreas.
• Anemia is to due to abnormal lipids (decreased cholesterol-to-phosphatidylcholine ratio) in cell membrane leading to hemolysis.
• Thrombocytopenia can occur 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	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 causing defective reverse cholesterol transport.
Clinical Features	Annular corneal opacity Anemia 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 Profile	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

Epidemiology and Demographics

• The prevalence of Tangier disease is estimated to be less than 1/1,000,000.
• Worldwide, Tangier disease has been diagnosed in about 100 patients.

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 disease 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 disease when compared to non-carriers.
• Risk of developing premature CVD:
  • Increased in patients without splenomegaly, anemia and who have normal LDL C levels.
  • Patients with splenomegaly have anemia and low LDL C do not develop premature CVD.
• Prognosis is usually good and depends mainly on the progression of peripheral neuropathy.

Diagnosis

History and Symptoms

• The characteristic clinical presentation of Tangier disease includes:
  • Throat pain due to enlarged tonsils
  • Numbness, tingling, weakness of the extremities
  • Other less common features of presentation include:
    • Abdominal pain
    • Vision loss
    • Fatigue
    • Shortness of breath on exertion

Physical Examination

The patients with Tangier disease usually present with the following findings:

• Large yellow-orange tonsils due to the failure of uptake of lipid by HDL C. LDL C is relatively enriched with beta-carotene in these patients, which is taken up the reticuloendothelial cells giving the characteristic yellow orange color to the tissues.
• Dense 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 type of loss of sensory and motor neurons in the upper body.
  • Peripheral neuropathy with fluctuating loss of sensory and motor function.

Laboratory Findings

Tangier disease is diagnosed with characteristic laboratory finding of very low HDL C and Apo A1.

• Plasma HDL C is usually below 5 mg/dL.
• Serum concentrations of Apo A1 and Apo AII lipoproteins are below 5 mg/dL due to increased catabolism.
• Plasma total cholesterol is usually below 150 mg/dL.
• Triglyceride 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, potentially reducing 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.

Molecular Genotype sequencing

• The gold standard for of the diagnosis of Tangier disease is ABCA1 gene sequencing.

Treatment

Medical Therapy

There are no specific treatment measures are available for treatment of Tangier disease. The mainstay of therapy include:

• Optimizing the LDL-C levels in Tangier patients with normal LDL-C levels using statin therapy is advised 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.

Prevention

Primary Prevention

• Patients with homozygous Tangier disease are at higher risk of developing cardiovascular disease at a young age, and according to 2013 ACC/AHA guidelines LDL C levels should be maintained below 70mg/dl.
• Identifying and optimizing modifiable risk factors is advised.