Sitosterolemia

A number sign (#) is used with this entry because sitosterolemia is caused by homozygous or compound heterozygous mutation in the ABCG8 gene (605460) or in the ABCG5 gene (605459), both of which are located on chromosome 2p21.

Description

Sitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (summary by Berge et al., 2000).

Clinical Features

Bhattacharyya and Connor (1974) described 2 intellectually normal sisters of German and German-Swiss ancestry with tendinous and tuberous xanthoma and elevation of beta-sitosterol and 2 other plant sterols, campesterol and stigmasterol, in the blood. The authors proposed abnormally increased intestinal absorption. One of the 2 sisters complained of pains in the knees and ankles.

Shulman et al. (1976) pointed out that a diet high in vegetable oils (containing beta-sitosterol), prescribed to increase dietary polyunsaturated fat, could aggravate this condition. Khachadurian and Clancy (1978) observed phytosterolemia in 5 patients from 2 families.

Miettinen (1980) reported a patient with phytosterolaemia and hypersplenism who developed premature atherosclerotic arterial disease requiring a 3-vessel coronary bypass at the age of 29 years. The patient had initially been diagnosed with familial hypercholesterolaemia (143890), but did not have increased serum cholesterol levels. Biochemical studies showed that up to 30% of serum and bile sterols were plant sterols, including campesterol and beta-sitosterol, stigmasterol, and another major plant sterol, tentatively identified as avenasterol. Fecal analysis showed decreased biliary secretion of plant sterols. Treatment with cholestyramine brought about a modest increase in cholesterol elimination as bile acids, increased endogenous cholesterol synthesis, and reduced the plasma cholesterol by 21% and plant sterols by 16%.

Wang et al. (1981) reported an adult Chinese man with sitosterolemia who presented with tendinous and tuberous xanthomatosis and severe coronary artery disease. He also had chronic hemolytic anemia with stomatocytic erythrocytes.

Patients with phytosterolemia reported by Miettinen (1980), Wang et al. (1981), and Skrede et al. (1985) had episodic hemolysis or chronic hemolytic anemia. Increased content of sitosterol in red cells was believed to be responsible for their fragility.

Hatanaka et al. (1990) described spinal cord compression with paraplegia in a patient with xanthomas due to normocholesterolemic sitosterolemia.

Rios et al. (2010) reported an 11-month old Romanian girl in whom sitosterolemia became evident after she was weaned from an exclusive breast milk diet.

Mediterranean Stomatocytosis/Macrothrombocytopenia

Ducrou and Kimber (1969) reported individuals of Mediterranean descent living in Australia who had recurrent abdominal pain and splenomegaly associated with stomatocytosis and reduced red cell life. Also among individuals of Mediterranean descent in Australia, Von Behrens (1975) found decreased platelet counts and increased platelet volume. The authors concluded that the macrothrombocytopenia was a benign morphologic variant. The individuals were Italian and Greek immigrants to Australia. This condition was referred to as 'Mediterranean stomatocytosis/macrothrombocytopenia (Rees et al., 2005; Stewart et al., 2006).

In correspondence, Stewart et al. (2006) and Stewart and Makris (2008) noted that there were no reports of stomatocytosis/macrothrombocytopenia in any Mediterranean countries, such as Italy or Greece, that there were no further reports of this condition after 1975, and that there was no clear evidence of autosomal dominant inheritance. These authors thus suggested that the cases of Mediterranean stomatocytosis/macrothrombocytopenia reported in Australia were acquired, and possibly the result of ingestion of local olive oil in Adelaide that may have contained some kind of impurity that inhibited the ABCG5 or ABCG8 proteins, or that the olive oil used at that time contained some kind of active molecule related to phytosterols.

Despite the assertion by Stewart and Makris (2008) that no reports of this condition appeared after 1975, Paulus and Casals (1978) reported peculiarities in megakaryocytes in persons with Mediterranean macrothrombocytopenia. The mean platelet counts in Mediterranean and northern European subjects were 161,000 and 219,000 per ml, respectively, and the mean platelet volumes were 17.8 and 12.4 fl, respectively. Brahimi et al. (1984) concluded that the prevalence of Mediterranean macrothrombocytopenia was low in Algeria.

Savoia et al. (2001) identified a common heterozygous mutation in the GP1BA gene (A156V; 606672.0004) in affected individuals from 6 of 12 Italian families believed to have Mediterranean macrothrombocytopenia. Stomatocytosis was not reported. These findings were consistent with a rare occurrence of autosomal dominant Bernard-Soulier syndrome (153670). However, the remaining 6 Italian families reported by Savoia et al. (2001) did not have GP1BA mutations, suggesting genetic heterogeneity. Molecular studies of the ABCG5 or ABCG8 genes were not performed.

Rees et al. (2005) presented molecular evidence that the stomatocytosis and macrothrombocytopenia observed in so-called Mediterranean stomatocytosis/macrothrombocytopenia actually represents the hematologic presentation of phytosterolemia. They reported 5 kindreds with a recessive condition characterized by mild hemolysis, marked stomatocytosis, low levels of very large platelets, and increased mean platelet volume, consistent with the description of the Mediterranean condition. However, none of the patients were of Mediterranean extraction. All patients had evidence of hemolysis with reticulocytosis, mild hyperbilirubinemia, and splenomegaly. All also had short stature. Some patients presented with abdominal pain, and some had a bleeding tendency. None of the patients had evidence of premature cardiovascular disease, but all were of a young age (less than 30 years). Patient platelets showed a consistent abnormality in ristocetin-induced agglutination, with variable aggregation in response to other agonists. Other forms of hereditary stomatocytosis (see, e.g., 185000 and 194380) were ruled out. Spectroscopic analysis of erythrocyte membrane lipids showed abnormal and increased levels of plant-derived phytosterols, including beta-sitosterol, stigmasterol, isofucosterol, stigmastanol, and campesterol. Plasma levels of phytosterols were also increased. All affected individuals in the families reported by Rees et al. (2005) had mutations in either the ABCG5 (2 families; see, e.g., 605459.0006) or the ABCG8 (3 families; see, e.g., 605460.0001) gene. These studies showed that the hematologic syndrome of Mediterranean stomatocytosis can result from an excess of plasma phytosterols, perhaps due to abnormal lipid content in red cell and platelet membranes.

Rees et al. (2005) predicted that the phenotype is highly dependent on diet, and it is therefore difficult to make convincing phenotype/genotype correlations. The studies also revealed increasing clinical diversity, both in the laboratory and clinical features of sitosterolemia. The Mediterranean population of Australia is renowned for its profuse olive oil consumption, and it is possible that the hematology observed in that population was the result of an environmental or dietary effect, which may have disappeared with time. Whatever the explanation for the Australian experience, the results of Rees et al. (2005) indicated that plasma phytosterols should be measured in patients with stomatocytic hemolysis and abnormally large platelets. In addition, platelet size should be reviewed in all patients with hypercholesterolemia.

Biochemical Features

Nguyen et al. (1990) found that hepatic cholesterol biosynthesis in sitosterolemia was severely depressed. Microsomal HMG-CoA reductase (142910), the enzyme that catalyzes the rate-limiting reaction in the pathway, was markedly decreased, reflecting a low level of mRNA. Further studies showed that patients with sitosterolemia had enhanced total and receptor-mediated uptake of low density lipoprotein (LDL), which presumably represented a compensation to provide cellular sterols that cannot be synthesized. The findings indicated that individuals with sitosterolemia have inadequate cholesterol biosynthesis, which is then offset by augmented receptor-mediated LDL catabolism in order to supply cellular sterols. Overall, the disorder is characterized by enhanced intestinal absorption of and decreased removal of plant sterols.

Salen et al. (1996) reviewed the abnormalities of cholesterol biosynthesis in sitosterolemia.

Inheritance

Kwiterovich et al. (1981) observed sitosterolemia among the Lancaster County, Pennsylvania, Amish. Beaty et al. (1986) analyzed data derived from 254 relatives of a 13-year-old Amish proband who died unexpectedly of advanced coronary atherosclerosis. Segregation analysis of sitosterol levels showed that the phenotype was a rare autosomal recessive. The recessive model was supported by the finding that plasma sitosterol levels in the parents and in 6 children born to 3 of the 5 sitosterolemics were well within the normal range.

Clinical Management

Stalenhoef (2003) provided pictures of a 17-year-old girl who presented with multiple xanthomas of the hands and Achilles tendons, as well as a family history of vascular disease. Phytosterolemia with xanthomatosis was diagnosed. The patient was told to follow a diet low in plant fats (margarines), nuts, chocolate, and seeds. In addition, bile acid resins were prescribed. Although the patient's plasma levels of plant sterols remained markedly elevated, her tendon xanthomas diminished markedly, as shown by photographs taken after an interval of 5 years.

The patient of Rios et al. (2010), who presented with xanthomas of the Achilles tendon and very high plasma cholesterol levels after weaning from breastfeeding, was treated with ezetimibe, a lipid-lowering agent that reduces the absorption of plant sterols as well as cholesterol. The plasma cholesterol level fell progressively into the normal range, but the plant sterol levels remained elevated despite the patient consuming a low cholesterol, low plant sterol diet.

Mapping

By studying 10 well-characterized families with sitosterolemia, Patel et al. (1998) localized the genetic defect to 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lod score = 4.49 at theta = 0.0).

Lu et al. (2001) constructed a high-resolution YAC and BAC contig map encompassing a physical distance of approximately 2 Mb between microsatellite markers D2S2294 and D2S2291. Eight previously identified genes and 60 ESTs were mapped to these contigs, representing a high-resolution physical and transcript map with complete coverage of the minimal region containing the sitosterolemia locus.

Lee et al. (2001) studied 30 families which were assembled from around the world and had no evidence of genetic heterogeneity. A maximum multipoint lod score of 11.49 was obtained for marker D2S2998. Using both homozygosity mapping and informative recombination events, the critical interval containing the sitosterolemia gene was narrowed to a region defined by markers D2S2294 and Afm210xe9, a distance of approximately 2 cM. Homozygosity and haplotype sharing was identified in probands from nonconsanguineous marriages from a number of families, strongly supporting the existence of a founder effect among Amish/Mennonite, Finnish/Norwegian, and Japanese populations.

Molecular Genetics

Berge et al. (2000) identified homozygosity or compound heterozygosity for several mutations in 2 adjacent, oppositely oriented genes that encode members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family, ABCG8 (see 605460.0001-605460.0008) and ABCG5 (see 605459.0001), in 9 patients with sitosterolemia. The 2 genes are expressed at highest levels in liver and intestine. In mice, cholesterol feeding upregulates expression of both genes. Based on their data, Berge et al. (2000) concluded that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis. Treatment with a low cholesterol diet resulted in a reduction of plasma cholesterol from a high of 800 in some patients to a low of 106.

Lee et al. (2001) identified homozygosity for mutations in the ABCG5 gene (605459.0001-605459.0004) in 9 unrelated sitosterolemia patients.

Rios et al. (2010) reported an 11-month old Romanian girl with xanthomas and marked hypercholesterolemia. While she was initially thought to have primary hypercholesterolemia (see 143890), mutations in the candidate genes LDLRAP1 (605747), LDLR (606945), PCSK9 (607786), APOE (107741), and APOB (107730) were excluded. Whole-genome sequencing revealed 2 nonsense mutations in ABCG5, gln16 to ter (Q16X; 605459.0007) and arg446 to ter (R446X; 605459.0008). Sitosterolemia became evident after she was weaned from an exclusive breast milk diet.

Population Genetics

In a Swiss woman with sitosterolemia who had typical xanthomas and also mitral and aortic valvular disease, Solca et al. (2005) identified homozygosity for the G574R mutation in the ABCG8 gene (605460.0002). Extended haplotype analysis of this patient and 2 Amish-Mennonite patients with the same mutation revealed that the Swiss patient and 1 of the Amish-Mennonite patients shared identical SNPs, with a minor difference between the 2 Amish-Mennonite patients. Solca et al. (2005) concluded that the G574R mutation in the Amish-Mennonite population originated in Europe more than 250 years ago.

In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified the ABCG8 sitosterolemia mutation ser107 to ter (rs137854891, 605460.0010) in heterozygous state in 127 individuals among 1,515 screened and in homozygous state in 4, for a carrier frequency of 0.084 (1 in 12). This mutation is private to the Hutterite population.

Animal Model

In Abcg5/Abcg8-deficient mice, Yang et al. (2004) demonstrated that accumulation of plant sterols perturbed cholesterol homeostasis in the adrenal gland, with a 91% reduction in its cholesterol content. Despite very low cholesterol levels, there was no compensatory increase in cholesterol synthesis or in lipoprotein receptor expression. Adrenal cholesterol levels returned to near-normal levels in mice treated with ezetimibe, which blocks phytosterol absorption. In cultured adrenal cells, stigmasterol but not sitosterol inhibited SREBP2 (600481) processing and reduced cholesterol synthesis; stigmasterol also activated the liver X receptor (see LXRA, 602423) in a cell-based reporter assay. Yang et al. (2004) concluded that selected dietary plant sterols disrupt cholesterol homeostasis by affecting 2 critical regulatory pathways of lipid metabolism.