Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.

Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder.

Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. We show here that FHC in Amish individuals is associated with mutations in tight junction protein 2 (encoded by TJP2, also known as ZO-2) and bile acid Coenzyme A: amino acid N-acyltransferase (encoded by BAAT). The mutation of TJP2, which occurs in the first PDZ domain, reduces domain stability and ligand binding in vitro. We noted a morphological change in hepatic tight junctions. The mutation of BAAT, a bile acid-conjugating enzyme, abrogates enzyme activity; serum of individuals homozygous with respect to this mutation contains only unconjugated bile acids. Mutations in both TJP2 and BAAT may disrupt bile acid transport and circulation. Inheritance seems to be oligogenic, with genotype at BAAT modifying penetrance in individuals homozygous with respect to the mutation in TJP2.

We studied the effect of chenodeoxycholic acid in 17 patients with cerebrotendinous xanthomatosis. Before treatment, all subjects were symptomatic, with Achilles tendon xanthomas (in 15 of 17), cataracts (in 12 of 17), dementia (in 13 of 17), pyramidal-tract signs (in all 17), cerebellar dysfunction (in 13 of 17), mild peripheral neuropathy (in 7 of 17), electroencephalographic abnormalities (in 10 of 13), and abnormal cerebral computerized axial tomographic scans (in 10 of 12). After at least one year of chenodeoxycholic acid treatment (750 mg per day), dementia cleared in 10 subjects, and pyramidal and cerebellar signs disappeared in 5 and improved in another 8. Peripheral neuropathy was no longer detected in six. The electroencephalogram became normal in five and showed fewer abnormalities in another three subjects. Cerebral computerized axial tomographic scans improved in seven patients; the changes included the disappearance of a cerebellar xanthoma in one case. Concomitantly, mean plasma cholestanol levels declined threefold, and abnormal bile acid synthesis was suppressed. We conclude that long-term therapy with chenodeoxycholic acid may correct the biochemical abnormalities and arrest and possibly reverse the progression of cerebrotendinous xanthomatosis.

Background-Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops. Methods and Results-In this multicenter, double-blind, randomized, placebo-controlled study, we examined whether treatment with ezetimibe, an inhibitor of cholesterol absorption, reduces plant sterol levels in patients with sitosterolemia. After a 3-week placebo run-in, 37 patients were randomized to receive placebo (nϭ7) or ezetimibe 10 mg/d (nϭ30) for 8 weeks. Sitosterol concentrations decreased by 21% (PϽ0.001) in patients treated with ezetimibe compared with a nonsignificant 4% rise in those on placebo (between-group PϽ0.001). The reduction in sitosterol from baseline was progressive, with further decline observed at each subsequent biweekly visit. Campesterol also progressively declined, with a mean decrease after 8 weeks of 24% with ezetimibe and a mean increase of 3% with placebo treatment (between-group PϽ0.001). Reductions in plant sterol concentrations were similar irrespective of whether patients were undergoing concomitant treatment with resin or statin. Reductions in total sterols and apolipoprotein B were also observed. Ezetimibe was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events being reported. Conclusions-Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia, consistent with the hypothesis that ezetimibe inhibits the intestinal absorption of plant sterols as well as cholesterol, leading to reductions in plasma concentrations.