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Niemann-Pick type C disease/cholesterol-processing abnormality
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The adenosine triphosphatase (ATP)-binding cassette transporter A1 (ABACA1) is also upregulated in response to increased cellular cholesterol, leading to high-density lipoprotein (HDL) particle formation. Mutations in this ABACA1 lead to increased intracellular cholesterol and very low levels of HDL in Tangier disease [90]. Mutations in NPC1 appear to impair also the regulation and activity of ABACA1 [91]. Fibroblasts from patients with NPC disease were shown to have decreased efflux of labeled LDL-cholesterol mediated by apolipoprotein A-I. These fibroblasts also displayed diminished ABCA1 mRNA and protein in both basal and cholesterol stimulated states. Furthermore, 17 of 21 patients studied had low levels of HDL-cholesterol. This observation can provide another diagnostic aid in evaluating children for NPC disease.
Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In Tangier disease, the spleen enlargement is connected with the accumulation of cholesteryl esters within reticuloendothelial cells.193 The disease is characterized by extremely low plasma HDL cholesterol and HDL apoproteins. In this disease, the primary defect is the abnormality in apoA-I structure, leading to a binding failure with HDL lipids and increased clearance.12,193,194,560 The susceptibility to atherosclerosis is increased in Tangier disease, but not to the extent shown by the epidemiological relationship between ischemic heart disease and HDL cholesterol in the general population.561 There are other genetic conditions where low HDL concentrations are connected with enhanced atherogenesis. Genetically determined familial hyperalphalipoproteinemia with high plasma HDL levels is rarely accompanied with clinical complications of atherosclerosis.226 Abnormalities have been reported recently in HDL in homozygous familial hypercholesterolemia.227 Also, high HDL cholesterol levels have been associated with increased mortality from carcinoma,333,701 but this possibility was not supported by a comprehensive study.96,280,284,286
Atherosclerosis and Coronary Heart Disease
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
Other mutations have also been described resulting in defective HDL metabolism, a complete absence of HDL, or altered processing of HDL particles. Among the latter is Tangier disease with rapid clearance of HDL from circulation, however, the exact underlying genetic alteration has not been established so far. Frame-shift and nonsense mutations leading to apo A-I deficiency and premature atherosclerotic changes have been described in the apo A-I gene.
A novel pathogenic variant in LCAT causing FLD. A case report
Published in Acta Clinica Belgica, 2022
Nuria Goñi Ros, Ricardo González-Tarancón, Paula Sienes Bailo, Elvira Salvador-Ruperez, Martín Puzo Bayod, José Puzo Foncillas
In conclusion, FLD and FED are two syndromes caused by loss-of-function mutations in the LCAT gene, and they share common biochemical features. The important differences in circulating lipoproteins and clinical manifestations between both syndromes should also be taken into account, since patients with FLD may develop kidney failure but not premature cardiovascular disease (CVD); while, in contrast, patients with FED may get premature CVD but not kidney failure [19,20]. Furthermore, there are other hereditary disorders with severe HDL deficiency, such as Tangier disease (OMIM#205400), which is biochemically characterized by an almost complete absence of HDL in plasma, and clinically characterized by an abnormal growth of the liver, spleen, lymph nodes and tonsils, as well as peripheral neuropathy or cardiovascular disease. Therefore, the different clinical profile between patients with FED and FLD, and the existence of other diseases with similar clinical features underline the need for a timely differential diagnosis aiming to address patients to preventive programs and future available therapies [2].
Gene of the issue: ANO6 and Scott Syndrome
Published in Platelets, 2020
Sarah L. Millington-Burgess, Matthew T. Harper
A missense mutation in the ABCA1 gene was identified in a third Scott patient (VW) (c.6064G>A (ABCA1 R1925Q))[27] which reduced its expression in lymphocytes. This mutation, however, has not been found in any other Scott Syndrome patients and ABCA1 is now known to play a role in cholesterol efflux [28]. ABCA1 mutations cause Tangier disease, patients of which expose normal platelet PS [29,30].