Tangier Disease

Abstract

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.

The curious case of the orange coloured tonsils

“…Other factors contributing to inbreeding include ethnic isolation, royalty, religion and culture, socioeconomic class and small populations. Since its discovery Tangier disease has been diagnosed in approximately 100 patients from around the world [7].…”

Therapeutic ultrasound: Increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids

“…No abnormalities were observed in extensive laboratory tests and histology following infusion, attesting to the safety of the procedure. The present technology provides a potential method to increase HDL-C as a therapeutic option for the treatment of systemic atherosclerosis, and potentially for the treatment of monogenetic diseases including familial hypo-alphalipoproteinemia and Tangier Disease (17). …”

ATP-binding cassette transporter A1: From metabolism to neurodegeneration

“…TD is inherited as an autosomal recessive trait and almost all of the patients with clinical phenotype are compound heterozygotes. At present, more than 180 ABCA1 mutations have been listed in Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ABCA1) and more than 100 of missense, nonsense and frameshift mutations had been identified in patients with TD and in subjects with a phenotype of HDL deficiency (Puntoni et al, 2012). While there is a significantly increased risk of cardiovascular disease in TD patients, the phenotypic presentation is not always exactly the same.…”