Garelli Giulia - Gariglio Valeria
Category of disease
Metabolic disease – congenital alteration of lipoprotein metabolism.
DEFINITION
Disorder of cholesterol metabolism, characterized by low levels of high density lipoprotein (HDL). This disease is characterised by a decrease in the transport rate of cholesterol out of cells, resulting in shortages/deficiencies of cholesterol in the blood (hypo-lipoproteinemia) and increase of cholesterol in tissues (such as liver, spleen, tonsils, intestinal mucosa) causing hepatomegaly and splenomegaly.
http://malattierare.regione.veneto.it
http://ghr.nlm.nih.gov/condition/tangier-disease
http://www.healthline.com/galecontent/tangier-disease
So, this disease affects this pathway:
Lipoprotein pathway
EPIDEMIOLOGY
This disorder has been first identified on the island of Tangier, on the coast of Virginia but people suffering from this disease are found all over the world. It is a rare autosomal recessive disease, fewer than 100 families are known, and it affects both genders equally.
HealthLine assay, 2005
SIGNS AND SYMPTOMS
The disease occurs to persons aged from 20 years of age, with absence of plasma lipoproteins and the accumulation of cholesterol esters in many tissues, especially liver, spleen, lymphonodes, intestinal mucosa and tonsils.
Tonsils appear hyperplastic (widened and lobular) and orange. The rectal mucosa has an abnormal and distinctive appearance.
Furthermore there is a peripheral neuropathy, with clinical symptoms such as weakness, increased sweating, ptosis, loss of sensitivity to pain and temperature, and altered motility mainly related to the upper limbs. The risk of atherosclerosis increases.
The unusual appearance of the tonsils is due to an accumulation of cholesterol. Even when the tonsils are removed, small yellow patches at the back of the throat may be evident. The accumulation of cholesterol in the mucous membranes of the intestines results in the appearance of orange-brown spots on the rectum, and it can occasionally result in intermittent diarrhea and abdominal pain.
Enlarged orange tonsils
This disorder leads to deposits of fats in various tissues of the body including the cornea and the conjunctiva. This can lead to some vision loss, especially in older individuals (the deposits are progressive).
Some patients with Tangier disease, in addition to the clouding of the cornea may have difficulty blinking and closing their eyes properly leading to drying out of the cornea and additional vision problems.
It is important for patients to be followed by an ophthalmologist for treatment of dry eyes as lack of moisture can lead to serious corneal disease and loss of vision.
With regard to cardiovascular problems, given that so few people are known to be affected with Tangier disease, it is difficult to precisely predict their risk of developing arteriosclerosis and heart diseases.
Depending on their age, people with Tangier disease appear to have approximately four to six times increased risk for arteriosclerosis and heart disease. People over the age of 30 appear to have a six-fold increased risk. It is possible that Tangier patients are protected from higher risks of arteriosclerosis by having also lower than average levels of LDL-C in their blood stream.
America Heart Association: Tangier Disease with continuous massive and longitudinal diffuse calcification in the coronary arteries, 2000
However, the predisposition to develop cardiovascular problems is debated.
Mutazioni del gene ABCA1 aumentano i livelli di colesterolo HDL ma non diminuiscono il rischio di mortalità cardiovascolare, 2008
NCBI: Still more questions than answers, 2005
But one good thing was born from the reasearch about this disease: drugs that induce ABCA1 would increase clearance of cholesterol from tissues and inhibit intestinal absorption of dietary cholesterol. Thus, ABCA1-stimulating drugs would have the potential to both mobilise cholesterol from atherosclerotic lesions and eliminate cholesterol from the body. By reducing plaque formation and rupture independently of the atherogenic factors involved, these drugs would be powerful agents for treating CVD.
Novel approaches to treating cardiovascular disease, 2001
Lipoproteine ad alta densità: azioni aterosclerotiche, 2007
LESS COMMON SYMPTOMS
Less commonly seen symptoms are an enlarged liver, lymph nodes and thymus, and hemolytic anemia.
PATHOGENESIS
The disease is caused by a mutation of the gene of the transporter 1 which binds the ATP: ABCA1 ("ATP-Binding Cassette") protein which a domain that binds ATP and two trans-membrane domains with six helices.
Chromosome9(ABC1),_member_1_(ABCA1)
The protein, product of this gene, is a transporter of cholesterol and phospholipids out of cells. Mutations of this gene invalidate the protein's ability to bring these molecules across membranes and, as a consequence, the cholesterol-poor HDL, unable to retrieve it, are rapidly removed from circulation and destroyed.
"Mutations in ABCA1 in Tangier Disease and Familial High-density Lipoprotein Deficiency. 1999": Nature Genetics 22, no. 4 : 336-345.
DIAGNOSTIC TESTS
Diagnosis is made by examination of the oropharynx (the tonsils are hyperplastic and orange) and of the rectal mucosa (especially in the case of tonsillectomy) in patients with enlarged spleen or liver.
In affected patients, levels of HLD are smaller than 5mg/dl, the total cholesterol is below 150 mg/dl and triglycerides are slightly increased.
Plasma concentrations of apo A-1 and apo A-II are generally below 5 mg/dl.
(Prenatal testing is only available if ABCA1 gene changes are identified in the parents.)
THERAPY AND COMPLICATIONS
There is no specific therapy. It is recommended to reduce the introduction of triglycerides in the diet and also to reduce risk factors for atherosclerotic vascular disease such as smoking, hypertension, obesity and diabetes.
Occasionally organs such as the spleen and tonsils are removed because of extensive accumulation of cholesterol.
Histological Tissue
IMAGES
Pathway
