Tangier disease (ORPHA:31150)
A rare, genetic neurometabolic disease 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 multifocal peripheral neuropathy, corneal, skin and nail and, occasionally, cardiovascular disease.
Epidemiology
Tangier disease (TD) prevalence is unknown. Approximately 200 cases have been described worldwide.
Clinical description
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 in children is large tonsils with a particular orange-yellow color due to carotene-enriched low-density lipoprotein (LDL) tissue-accumulation. Patients may also show asymptomatic hepatosplenomegaly, lymph node enlargement, corneal opacities and skin lesions with onset typically in childhood or adolescence. Multi-organ and tissue cholesterol deposition is also observed from biopsies (skin, bone marrow, nerves, muscles, and rectal mucosa). Anemia and thrombocytopenia may be present. Signs of atherosclerosis and cardiovascular disease are not observed before adulthood and when present, are associated with other major cardiovascular risk factors (e.g. high blood pressure or plasma triglycerides, diabetes mellitus, smoking, etc.). Isolated peripheral neuropathy is reported in over 50% of 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 some cases, patients may also show signs of corneal opacity and skin lesions such as skin ulcer, painless scalds or burn scars.
Etiology
The disease is due to mutations in the ABCA1 gene (9q31) encoding the ATP-binding cassette transporter (ABCA1), a cholesterol-efflux regulatory protein that is able to orient intra-cellular cholesterol and phospholipid trafficking towards the cell surface and to facilitate lipid transfer towards HDL and reverse cholesterol transport. Mutations thus result in very low levels of plasma HDL cholesterol and deposition of cholesteryl, retinyl esters, phospholipids and carotenoids in various non-adipose tissues.
Diagnostic methods
The diagnosis is based on evidence of an abnormal lipoprotein profile characterized by isolated hypoalphalipoproteinemia, extremely low HDL cholesterol (<5 mg/dL) and 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- and non-HDL plasma cholesterol are noted together with anemia, thrombocytopenia and mild inflammation. Skin, muscle or rectal mucosa biopsy reveals foam cells in affected tissues. Diagnosis is confirmed by genetic testing.
Differential diagnosis
The differential diagnosis includes familial Apolipoprotein A-I deficiency, LCAT deficiency and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, retinoids, paradoxical response to fibrates), liver failure or malignancies. When neuropathic manifestations are present, a plasma lipoprotein profile may rule-out TD diagnosis from other non-uniform demyelinating polyneuropathies, especially when prominent in the upper extremities.
Antenatal diagnosis
Prenatal diagnosis is feasible but is usually not performed.
Genetic counseling
Transmission is autosomal recessive, although relatives may exhibit lowered plasma HDLC while remaining asymptomatic.
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 cardiovascular risk factors or overt signs of cardiovascular disease, especially when hepato-splenomegaly is absent. Therapies enhancing cellular cholesterol efflux by HDL are developed to reduce cardiovascular risk; anti-inflammatory agents and Miglustat (an iminosugar inhibitory of glycosyl-ceramide synthase) may correct neuropathic and skin manifestations despite being ineffective on plasma lipoprotein profile.
Prognosis
Prognosis is usually good and depends mainly on the progression of peripheral neuropathy. TD patients with extremely low plasma HDL cholesterol (<20 mg/dL) have increased risk of coronary artery disease in adulthood and should be offered regular cardiovascular and neurological monitoring.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Dr Pascale BENLIAN