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.

Modulation of high-density lipoproteins in a population in istanbul, Turkey, with low levels of high-density lipoproteins.

The extent to which high-density lipoprotein (HDL) cholesterol levels can be increased in patients with low HDL cholesterol is important because low HDL cholesterol levels increase the risk of coronary heart disease (CHD). During the past 14 years, we have assessed risk factors in Turks, a population in which extremely low HDL cholesterol levels (mean 36 mg/dl in men, 42 mg/dl in women) are a prime CHD risk factor. Although genetically determined to a significant extent, these low HDL cholesterol levels can be modulated by lifestyle factors, as in other populations. We measured the HDL cholesterol levels in men and women residing in Istanbul at 3 time points: 1990 to 1993, 1996 to 2000, and 2003. The mean HDL cholesterol levels increased from 45.3 +/- 9.5 mg/dl in 1990 to 1993 to 49.7 +/- 12 mg/dl in 2003 (p <0.0001) in women, but were virtually unchanged in men (38 +/- 8 vs 39 +/- 10 mg/dl). In contrast to previous years, the HDL cholesterol levels in women in 2003 were markedly affected by education level and socioeconomic status, averaging 56 +/- 9 mg/dl in those with a university education and 48 +/- 12 mg/dl in those with a primary school education. Part of this difference could be explained by less smoking and more exercise and lower body mass index (average 25.6 +/- 4.9 vs 29.7 +/- 5.1 kg/m(2)) of the highly educated women. It is important to note the increase in the prevalence of obesity between the 1990 to 1993 interval and 2003 in men and women, including a remarkable change from 9.4% to 45.2% among women with a primary school education. None of these factors affected the HDL cholesterol levels of men by >2 mg/dl at any of the 3 points. In conclusion, because CHD risk changes by as much as 2% to 4% per 1 mg/dl difference in HDL cholesterol level, the 8 mg/dl difference may reflect as much as a 20% to 30% reduction in CHD risk associated with the benefit of higher education in women. Why education failed to affect the HDL cholesterol levels in Turkish men remains unclear.

Tangier disease--a diagnostic challenge in countries endemic for leprosy.

A case of Tangier disease (TD) is reported from India. The patient had presented with indolent mononeuritis multiplex and trophic ulcers of 16 years duration mimicking Hansen's disease. He received antileprosy treatment for one and a half years. Nerve conduction studies revealed features of demyelinating neuropathy. Biopsies of the sural nerve and skin showed striking vacuolation of Schwann cells and myelin sheaths, and foamy vacuolated fibroblasts, respectively, and no evidence of Hansen's disease. Low levels of apolipoprotein A1 (ApoA1) and cholesterol in the serum and undetectable levels of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol in the blood confirmed the diagnosis of TD. This is the first reported case of TD from a tropical country-India. An attempt to establish a correct diagnosis should be made by demonstrating the histopathological and lipoprotein abnormality to avoid long term medications that are chosen empirically and are unnecessary. The importance of recognising this disease in a country where Hansen's disease is highly endemic cannot be overemphasised.

Dyslipidemia in young Japanese children: its relation to familial hypercholesterolemia and familial combined hyperlipidemia.

BACKGROUND: Most cases of dyslipidemia found in adults are non-familial. However, in children, especially young children, dyslipidemias other than familial hypercholesterolemia (FH) have not yet been characterized. METHODS: From April 1990 to March 1999, 56 181 children were screened, and 1380 showed abnormal levels of apolipoprotein B (more than 2.5 standard deviations above the mean). Among these, 1198 were re-examined and further characterized by measuring lipids and apolipoproteins, and by their familial histories. RESULTS: Seventy-seven percent of the children (928 of 1198) recalled were diagnosed as being dyslipidemic. Ninety-one children were FH, 423 were type IIa, 128 were type IIb, 98 were type IV, and 188 were hypoalphalipoproteinemia. The presumed incidence of FH was 0.19%, IIa 0.87%, IIb 0.26%, IV 0.20%, and hypoalphalipoproteinemia 0.39%, taking into account the percentage of subjects who refused recall. At regular follow-ups, in many children with type IIb, the phenotypic expression changes from type IIb to IIa or IV. Thus, lipid and apolipoprotein levels were determined in 77 family members in 34 families of children with type IIb. Forty-five family members were dyslipidemic (type IIa 18, type IIb 11, type IV 16). As a result, 27 children (79%) with type IIb met the criteria for familial combined hyperlipidemia. CONCLUSIONS: Children with dyslipidemia had more family or genetic background than adults. Unexpectedly, children with type IIb were mostly familial combined hyperlipidemia. Thus, setting appropriate eating patterns during childhood might be important for normalizing risk factors for atherosclerotic coronary heart disease, especially in children with FH or type IIb.

Hipocolesterolemia familiar en la infancia / Familiar hypocholesterolemia during childhood

Mientras los estados hiperlipémicos se manifestarán sintomáticamente en la edad adulta, los trastornos que cursan con hipocolesterolemia , pueden dar síntomas desde los primeros años de la vida.Los trastornos hipocolesterolémicos se dividen en: aquellos con valores reducidos de lipoproteínas de alta densidad (HDL), rara vez sintomáticos en la infancia; los hipocolesterolémicos secundarios a un déficit de lipoproteínas, como resultado de una enfermedad subyacente; y los hipocolesterolémicos que cursan con valores bajos de quilomicrones (QM), lipoproteínas de muy baja densidad (VLDL) y lipoproteínas de baja densidad (LDL). Estos últimos son el grupo de mayor interés en pediatría porque en él se engloban una serie de enfermedades hereditarias con manifestaciones ya desde la infancia. Todas ellas son consecuencia de un déficit de la apoproteína B (Apo-B) transportadora en el plasma de dichas lipoproteínas. Se presenta el caso de una familia con 4 hijos; en que el padre y 3 hermanos son portadores de hipobetalipoproteinemia forma heterocigota. La presentación de esta familia permite la revisión de todas las enfermedades hereditarias hipocolesterolémicas (AU)

Expression and functional analyses of novel mutations of ATP-binding cassette transporter-1 in Japanese patients with high-density lipoprotein deficiency.

ATP-binding cassette transporter-1 (ABCA1) gene is mutated in patients with familial high-density lipoprotein deficiency (FHD). In order to know the molecular basis for FHD, we characterized three different ABCA1 mutations associated with FHD (G1158A/A255T, C5946T/R1851X, and A5226G/N1611D) with respect to their expression in the passaged fibroblasts from the patients and in the cells transfected with the mutated cDNAs. Fibroblasts from the all patients showed markedly decreased cholesterol efflux to apolipoprotein (apo)-Al. In the fibroblasts homozygous for G1158A/A255T, the immunoreactive mass of ABCA1 could not be detected, even when stimulated by 9-cis-retinoic acid and 22-R-hydroxycholesterol. In the fibroblasts homozygous for C5946T/R1851X, ABCA1 mRNA was comparable. Because the mutant ABCA1 protein (R1851X) was predicted to lack the epitope for the antibody used, we transfected FLAG-tagged truncated mutant (R1851X/ABCA1-FLAG) cDNA into Cos-7 cells, showing that the mutant protein expression was markedly reduced. The expression of N1611D ABCA1 protein was comparable in both fibroblasts and overexpressing cells, although cholesterol efflux from the cells was markedly reduced. These data indicated that, in the three patients investigated, the abnormalities and dysfunction of ABCA1 occurred at the different levels, providing important information about the expression, regulation, and function of ABCA1.

Hereditary neuropathy with liability to pressure palsies is not a major cause of idiopathic carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome is a debilitating neuropathy affecting millions of individuals. Although there are published reports of familial associations of carpal tunnel syndrome, the molecular mechanisms are unknown. OBJECTIVE: To determine the prevalence and potential role of the chromosome 17 microdeletion associated with hereditary neuropathy with liability to pressure palsies in patients diagnosed as having carpal tunnel syndrome. DESIGN: Prospective study. PATIENTS AND METHODS: Since hereditary neuropathy with liability to pressure palsies may present as carpal tunnel syndrome, we evaluated 50 patients with idiopathic carpal tunnel syndrome for hereditary neuropathy with liability to pressure palsies. RESULTS: No hereditary neuropathy with liability to pressure palsies deletions were detected. CONCLUSION: Molecular genetic testing for hereditary neuropathy with liability to pressure palsies in patients with idiopathic carpal tunnel syndrome is of limited value.

Genetic polymorphisms and mutations of the lipoprotein lipase gene in Japanese schoolchildren with hypoalphalipoproteinemia.

Lipoprotein lipase (LPL) is an important enzyme for the hydrolysis of TG on lipoproteins, and its activity is positively correlated with the plasma levels of high density lipoprotein cholesterol (HDL-C). To investigate the association between the LPL gene and low HDL-C levels, we studied two polymorphisms (Hind III and Pvu II) and three mutations (Asn291Ser, Gly188Glu and LPL(Arita)) of the LPL gene in 114 children with low HDL-C levels (<40 mg/dl) and 194 control children using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques (PCR-RFLP). The frequency of the Pvu II +/+ genotype was significantly higher in the children with low-HDL/high-TG (TG>100 mg/dl, 90th percentile level among Japanese schoolchildren) than in the other children (vs the low-HDL/normal-TG children, chi2 = 7.49, p < 0.01; vs control children, chi2 = 7.23, p < 0.01). Pvu II+ allele of the LPL gene was associated with elevated TG levels in low HDL-C groups. In addition, we found one heterozygote of LPL(Arita) (deletion of G at base 916 in exon 5, the most common mutation of LPL deficiency in Japanese), among the low-HDL/high-TG subjects. The other two variants were not detected in either the low-HDL children or control children. LPL Asn291Ser and Gly188Glu have been presumed to be rare in the Japanese population. In conclusion, our results suggest that hypoalphalipoproteinemia with elevated TG level may be associated with genetic variations of the LPL gene.

[Tangier disease: study of the first case in Spain]. / Enfermedad de Tangier: estudio del primer caso español.

The clinical, biochemical and pathological studies of the first case of Tangier's disease that, to our knowledge, has been detected in Spain are reported. The patient had all the characteristic features of the disease: hypercholesterolemia with very pronounced reduction of plasmatic high density lipoproteins, splenomegaly, orange yellow tonsils and peripheral neuropathy. In addition, he had pneumonia and pancytopenia. Neurological examination and computed tomography suggested cerebral involvement, not previously reported in this condition. Biopsies demonstrated lipid accumulation in the reticuloendothelial cells of diverse localizations and in Schwann's cells.