Tangier disease is one of the most severe forms of familial
high-density lipoprotein (HDL) deficiency. Since its discovery it has been diagnosed in about 100 patients and is characterized by severe plasma deficiency or absence of HDL,
apolipoprotein A-I (
apoA-I, the major HDL
apolipoprotein) and by accumulation of
cholesteryl esters in many tissues throughout the body. The biochemical signs of this condition are plasma HDL concentrations less than 5 mg/dL, low total plasma
cholesterol (below 150 mg/dL), and normal or high plasma
triglycerides.
Tangier disease is caused by mutations in the '
ATP-Binding Cassette transporter A1' (ABCA1) gene, which encodes the
membrane transporter ABCA1. This transporter plays a key role in the first step of reverse
cholesterol transport, through which the efflux of free
cholesterol from peripheral cells is transferred to
lipid-poor
apoA-I. The
Tangier disease clinical phenotype is inherited as an autosomal recessive trait, the biochemical phenotype is inherited as an autosomal co-dominant trait. Nearly all the children affected by
Tangier disease were identified on the basis of large, yellow-orange tonsils, while half of the adult patients affected by
Tangier disease came to medical attention because of symptoms of neuropathy. Diagnosis in the remaining subjects was related to the clinical features of
hepatomegaly,
splenomegaly, premature
myocardial infarction (about 30% of
Tangier disease cases) or
stroke,
thrombocytopenia,
anemia,
gastrointestinal disorders,
corneal opacities, hypocholesterolemia, low
HDL cholesterol, or following a familial screening of Tangier patients. To date there is no specific treatment for
Tangier disease. Old and recently designed drugs, known to increase HDL levels, have been shown to be ineffective in Tangier patients. The possible and more realistic therapeutic strategy should be designed to obtain a selective increase of mature HDL concentration to restore
cholesterol efflux. Recently designed drugs like the
cholesteryl ester transfer protein (CETP) inhibitors
dalcetrapib and
anacetrapib and reconstituted forms of HDL could be considered until the development of gene therapy.