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Tangier disease
Tangier disease (also known as Familial alpha-lipoprotein deficiency) or Hypoalphalipoproteinemia is a rare inherited disorder (autosomal recessive) familial disorder characterized by a severe reduction in the amount of high density lipoprotein (HDL), reduction in total cholesterol and increased triglyceride levels in serum.

History
In 1959, a five-year-old patient named Teddy Laird from Tangier Island, Virginia, presented with strikingly large and yellow-orange tonsils which were noticed by a physician during a tonsillectomy, which was the most common surgical procedure performed on children at the time. Histopathology examinations revealed many foam cells along the surface of the tonsils, in the septa, and extending into the lymph follicles. After initial diagnosis with Niemann-Pick Disease, he was transferred to Dr. Louis Avioli at the National Cancer Institute. Donald Fredrickson, then head of the Molecular Disease Branch, became aware of the case and had a hunch that the original diagnosis was incorrect. In 1960 he traveled with Dr. Avioli to Tangier Island for further investigation. After finding the same symptom in Teddy's sister and more investigations revealed an extremely high number of foam cells in not only the tonsils but a wide range of tissues including the bone marrow and spleen, a second trip to the island was made. The discovery made was of very low HDL cholesterol in both the sister and parents of Teddy, evidence for a genetic basis of the disease. The HDL patterns observed in remaining relatives were consistent with the inheritance of Tangier disease in Mendelian terms as an autosomal recessive. Autosomal recessive are more common in specific ethnic group with unaffected parents and the trait tends to skip generations. Also, males and females are equal in proportion while each offspring of carrier parents has 25% chance of being affected, 50% of being a carrier.

Tangier disease is caused by mutations in the 'ATP-Binding Cassette transporter A1' (ABCA1) gene, which encodes the membrane transporter ABCA1. The ABCA1 gene resides on chromosome 9q22-q31, contains 50 exons, and codes for a 2261-amino acid long membrane protein. This gene provides instructions for making a protein that releases cholesterol and phospholipids from cells. These substances are used to make HDL, which transports them to the liver. Tangier disease is a rare disorder with approximately 100 cases identified worldwide. More cases are likely undiagnosed.

Frequency
Tangier​ ​disease​ ​was​ ​first​ ​diagnosed​ ​in​ ​two​ ​children​ ​in​ ​1960​ ​and​ ​as​ ​of​ ​2006​ ​only​ ​approximately 50​ ​cases​ ​of​ ​Tangier​ ​Disease​ ​had​ ​been​ ​diagnosed​ ​worldwide​. ​ ​Between​ ​2006​ ​and December​ ​of​ ​2013,​ ​new​ ​diagnoses​ ​grew​ ​that​ ​number​ ​to​ ​around​ ​100​ ​individuals.​ ​​ ​Misdiagnosis and​ ​lack​ ​of​ ​diagnosis​ ​leave​ ​it​ ​nearly impossible​ ​to​ ​estimate​ ​the​ ​true​ ​frequency​ ​of​ ​Tangier Disease,​ ​however​ ​it​ ​is​ ​currently​ ​estimated​ ​to​ ​be​ ​approximately​ ​<1:1,000,000​.

Diagnosis
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 are transported out of the cell into the blood via the ABCA1 transporter. People with Tangier disease have defective ABCA1 transporters. This results in a reduced ability to transport cholesterol out of their cells, which leads to an accumulation of cholesterol and phospholipids in many body tissues, which can cause them to increase in size. Reduced blood levels of high-density lipoproteins is sometimes described as hypoalphalipoproteinemia.

People affected by this condition also have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). The tonsils are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature atherosclerosis, which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the cornea, type II diabetes and early-onset cardiovascular disease. Anemia and some inflammation can also be observed. In adult patients, neuropathy is a commonly observed symptom.

Clinical symptoms may or may not be present, which is why many people remain undiagnosed. Diagnosis can be based off of low Apo1 levels in the blood as well as HDL screenings and can lead to more individuals affected with the disease being diagnosed. However, these methods still do not give an accurate diagnosis of Tangiers. A gene sequence analysis of ABCA1 would be the most effective way to diagnose the disease. But a gene sequence analysis would be costly and complicated. Because Tangiers is so variable in its phenotype presentation, a correlation between genotype and phenotype has not been found. Prenatal testing is not common.

Genetics
Mutations to chromosome 9q31 lead to a defective ABCA1 transporter. ABCA1 is an ATP-binding cassette gene that makes proteins which are responsible for transportation of other molecules across the cell membrane. The ABCA1 proteins move cholesterol and phospholipids across the membrane and outside the cell, allowing the substrates to be picked up by the apolipoprotein A-1 (ApoA1). From here the ApoA1, cholesterol, and phospholipids combine to make high-density lipoproteins. The ABCA1 protein is found in many tissues but is highly concentrated in the liver and in macrophages.

Over 30 mutations in ABCA1 gene are linked to Tangier disease. Most mutations are missense mutations. Mutations are found throughout the protein, though most linked to Tangier disease are near or within ATP binding domains and the N-terminus. 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. Additionally, the buildup of cholesterol in cells can be toxic, causing cell death or impaired function. Tissues will often enlarge as more substrate accumulates. It also results in the tonsils growing and turning a yellow-orange color, neuropathies, enlarged spleen and liver, and ocular abnormalities. These combined factors lead to the signs and symptoms of Tangier disease.

This condition is inherited in an autosomal recessive pattern meaning that for the phenotype to appear, two copies of the allele must be present. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not display any of the symptoms of the disorder. Heterozygotes tend to have half the normal amount of  plasma HDL implying that the defect is co-dominant in nature. On the other hand, even though they only have one functional ABCA1allele, heterozygotes tend to have normal LDL levels implying a gene threshold effect.