Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis

Abstract

Sitosterolaemia is an extremely rare autosomal recessive disease, the key feature of which is the impairment of pathways that normally prevent absorption and retention of non-cholesterol sterols, for example plant sterols and shellfish sterols. The clinical manifestations are akin to familial hypercholesterolaemia (such as presence of tendon xanthomas and premature atherosclerosis), but with "normal to moderately elevated" cholesterol levels. The gene(s) causing sitosterolaemia was mapped to the STSL locus on human chromosome 2p21, and mutations in either of the two genes that comprise this locus, ABCG5 or ABCG8, cause this disease. Exact prevalence is unknown, but there are estimated to be 80-100 cases around the world. This rare disease has shed light into the molecular mechanisms that control sterol trafficking in the enterocyte and hepatocyte; ABCG5 and ABCG8 heterodimerise to form a sterol efflux transporter in the liver and intestine. In this review the pathophysiology, clinical manifestations and approach to clinical and laboratory diagnosis of this disease are described.

Missense Mutation inAbcg5in SHRSP Rats Does Not Accelerate Intestinal Absorption of Plant Sterols: Comparison with Wistar Rats

“…However, it has been found that plant sterols are deposited in the bodies of sitosterolemic patients. 1) Several mutations in ATP binding cassette transporter G5 (ABCG5) and in ATP binding cassette transporter G8 (ABCG8) were found in sitosterolemia. [1][2][3] ABCG5 and ABCG8 mainly express in the liver and the intestine.…”

“…1) Several mutations in ATP binding cassette transporter G5 (ABCG5) and in ATP binding cassette transporter G8 (ABCG8) were found in sitosterolemia. [1][2][3] ABCG5 and ABCG8 mainly express in the liver and the intestine. 4) In ABCG5/ABCG8-deficient mice, intestinal absorption of plant sterols was higher and biliary secretion of cholesterol was lower than in wild-type mice.…”

Clinical utility gene card for: Sitosterolaemia

“…4 On the basis of allele frequencies of loss-of-function variants (frameshift, nonsense and splicing only; not missense) in the ExAC database, sitosterolaemia has a global prevalence of at least 1 in 2.6 million for ABCG5 and 1 in 360 000 for ABCG8; the most common loss-of-function variant appears to be ABCG8 c.1083G4A (p.(Trp361Ter)) (Exome Aggregation Consortium; http://exac.broadinstitute.org/)…”

“…Patients with sitosterolaemia exhibit generalised hyperabsorption of dietary sterols including cholesterol, shellfish sterols and plant sterols (sitosterol, stigmasterol and campesterol), which, combined with impaired biliary excretion, leads to markedly elevated plasma levels of these plant sterols; 430-fold, with sitosterol being the most abundant species. 4,13 High levels of plant sterols in plasma are considered pathognomonic for sitosterolaemia, although elevations in plasma plant sterols may also be seen in primary biliary cirrhosis. 14 Cholesterol comprises only~80% of the total plasma sterols in patients with sitosterolaemia.…”

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

“…It has been estimated that sitosterolaemia occurs in 1 in 5 million people, although the true Introduction Sitosterolaemia (MIM #210250) is a very rare autosomal recessive disease characterized by excessive absorption and high plasma levels (＞30-fold) of plant sterols, particularly sitosterol and campesterol, the two major plant-derived sterols 1,2) . The clinical manifestations include tendon and tuberous xanthomas and premature atherosclerotic disease as a result of sterol deposition in the skin, tendons and coronary arteries [1][2][3] . Patients with sitosterolaemia, in whom there is Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8.…”