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. 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

File:Autorecessive.svg

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. 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).

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.

 # Peripheral neuropathy with fluctuating loss of sensory and motor function.

• Cardiovascular disease risk is increased particularly in homozygotes and elderly patients with Tangier. Deposition of lipid filled macrophages in arterial wall results in enhanced atherosclerosis.
• 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 characterized by presence of 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 tissue like tonsils, adenoids and lymph nodes. Bone marrow and gastrointestinal submucosa are also affected.

Hematologic features like hemolysis, stomatocytosis and decreased osmotic fragility result due to abnormal lipid membrane.

Epidemiology and Demographics

• Tangier disease is a rare disorder with approximately 50 cases identified worldwide.
• This disorder was originally discovered on Tangier Island off the coast of Virginia, but has now been identified in people from many different countries.

Natural History, Complications and Prognosis

• Premature atherosclerosis
• Coronary heart disease

Diagnosis

History

• History of similar complaints in any of the family members should be inquired.

Symptoms

• Vision disturbances - due to clouding of the cornea
• Abdominal pain
• Neuropathy - tingling sensation in the fingers, pins and needle sensation, weakness

Physical Examination

Eye

• Hazy cornea

Diffuse hazy opacity of the right cornea in the patient with Tangier disease.

Throat

• Enlarged tonsils that appear orange or yellow.

Abdomen

• Hepatomegaly
• Splenomegaly

Laboratory Findings

• Lipid panel shows
  • Slightly elevated amounts of fat in the blood (mild hypertriglyceridemia)
  • Reduced HDL
  • Low total cholesterol

External links

• Tangier disease at NLM Genetics Home Reference