Tangier disease: epidemiology, pathophysiology, and management.
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.
Institute of Clinical Physiology, National Council of Research, Pisa, Italy. mpuntoni@ifc.cnr.it
Mariarita
M
Puntoni
Francesco
F
Sbrana
Federico
F
Bigazzi
Tiziana
T
Sampietro
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000577:Amides; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood*; D002648:Child; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000378:metabolism; D015195:Drug Design; D004952:Esters; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D009154:Mutation; D023303:Oxazolidinones / Q000627:therapeutic use; D013438:Sulfhydryl Compounds / Q000627:therapeutic use; D013631:Tangier Disease / Q000453:epidemiology / Q000503:physiopathology / Q000628:therapy*; D014280:Triglycerides / Q000097:blood
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D004952:Esters; D008075:Lipoproteins, HDL; D023303:Oxazolidinones; D013438:Sulfhydryl Compounds; D014280:Triglycerides; C411602:dalcetrapib; D002784:Cholesterol; C530884:anacetrapib