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]

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 and peripheral neuropathy.

Historical Perspective

Tangier disease (TD) is named after Tangier Island, Virginia where it was diagnosed for the first time in two siblings in 1959. Significantly decreased level of HDL in parents of first two cases established the genetic nature of disorder. On further investigation several other residents of the same island were found to have markedly reduced HDL.

Pathophysiology

High-density lipoproteins are created when a protein in the bloodstream, apolipoprotein A1 (apoA1), combines with cholesterol and phospholipids. The cholesterol and phospholipids used to form HDL originate from inside cells but is transported out of the cell into the blood via the ABCA1 transporter. People with Tangier disease have defective ABCA1 transporters resulting in a greatly reduced ability to transport cholesterol out of their cells, which leads to an accumulation of cholesterol in many body tissues. Reduced blood levels of high-density lipoproteins is sometimes described as hypoalphalipoproteinemia.

Genetics

File:Autorecessive.svg

This condition is inherited in an autosomal recessive pattern, which means both copies 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.

Mutations in the chromosome 9q31 lead to a defective ABCA1 transporter. 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).

Additionally, the buildup of cholesterol in cells can be toxic, causing cell death or impaired function. These combined factors lead to the signs and symptoms of Tangier disease.

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