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Tangier disease (TD) is a rare lipoprotein metabolism disorder characterized biochemically by an almost complete absence of plasma high-density lipoproteins (HDL), and clinically by liver, spleen, lymph node and tonsil enlargement along with peripheral neuropathy in children and adolescents, and, occasionally, cardiovascular disease in adults.
- ATP-binding cassette transporter A1 deficiency
- Defective adenosine triphosphate-binding cassette transporter A1
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Neonatal, Infancy, Childhood
- ICD-10: E78.6
- OMIM: 205400
- UMLS: C0039292
- MeSH: D013631
- GARD: 7731
- MedDRA: 10051875
Prevalence of TD is unknown. Approximately 100 cases have been described worldwide.
The clinical presentation and the severity of symptoms vary widely between patients. Although extremely low plasma HDL cholesterol may be detected fortuitously from birth, the most characteristic finding is large tonsils in children which take a particular orange-yellow color due to cholesterol deposition in lympho-monocytic cells. Patients may also show asymptomatic hepatosplenomegaly, lymph node enlargement, and abdominal pain. Cholesterol accumulation is also observed within the rectal mucosa. Anemia is sometimes observed. Signs of atherosclerosis and cardiovascular disease are not always observed and, when present, are associated with other major cardiovascular risk factors (e.g. high blood pressure, overweight, smoking). Isolated peripheral neuropathy is reported in over 50% of the cases under two major phenotypes: a motor and sensory relapsing-remitting mono/polyneuropathy with onset during childhood or adolescence, and a syringomyelia-like syndrome with facial diplegia in adults with a past history of tonsillectomy in childhood. In atypical cases, patients can also show signs of corneal opacity.
The disease is due to mutations in the ABCA1 gene (9q31) encoding the ATP-binding cassette transporter (ABC1), a cholesterol efflux regulatory protein that is able to orient cellular cholesterol towards the cell surface and to facilitate its transfer towards the core of HDL. Mutations in this gene result in severe deficiency of plasma HDL cholesterol and deposition of cholesteryl and retinyl esters and carotenoids in nonadipose tissues (peripheral nerves, dorsal roots, liver, spleen, tonsils, lymph nodes, cornea and intestinal mucosa).
The diagnosis is based on evidence of an abnormal lipoprotein profile characterized by isolated HDL deficiency (<5 mg/dL) and extremely low apolipoprotein A-I (ApoA1) levels (< 5 mg/dL), with only pre beta-1 HDL found by bidimensional electrophoresis in the plasma. Moderate hypertriglyceridemia, decreased LDL cholesterol levels, and occasionally, decreased total plasma cholesterol are noted. Liver function tests are usually normal. Anemia, thrombocytopenia and mild inflammation may be observed. Skin or rectal mucosa biopsy reveals foam cells in affected tissues. Diagnosis is confirmed by genetic testing.
The differential diagnosis includes Apolipoprotein A-I deficiency, LCAT deficiency (see these terms) and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, paradoxical response to fibrates) and malignancies.
Prenatal diagnosis is feasible but is usually not performed.
Transmission is autosomal recessive.
Management and treatment
The disease has no specific treatment. Tonsillectomy may be required in case of significant tonsillar enlargement. A low-fat diet helps in reducing liver enlargement and preventing atherosclerosis. LDL-lowering drugs are required in patients with overt signs of carotid atherosclerosis or cardiovascular disease. Therapies enhancing cellular cholesterol efflux by HDL (e.g. reconstituted HDL, CETP inhibitors) may reduce neuropathic and cardiovascular complications.
Prognosis is usually good and depends mainly on the progression of peripheral neuropathy. TD patients with extremely low HDL cholesterol (<20 mg/dL) present an increased risk of coronary artery disease in adulthood and should be offered regular cardiovascular and neurological monitoring.