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 ... 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).
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 ... 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 sitosteolemia 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.
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 ... 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.
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 ... 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 (dbSNP 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.
Formal diagnostic criteria for sitosterolemia have not been established....
DiagnosisFormal diagnostic criteria for sitosterolemia have not been established.The clinical features of sitosterolemia include the following: Tendon xanthomas or tuberous xanthomas which can occur in childhood and in unusual locations (heels, knees, elbows and buttocks) [Niu et al 2010]Premature atherosclerosis which can lead to angina, myocardial infarction, and sudden death [Kidambi & Patel 2008]Hemolytic anemia, variably present and usually associated with abnormally shaped erythrocytes (stomatocytes). Thrombocytopenia can be present and is usually associated with large platelets (macrothrombocytopenia). These abnormalities can be the initial presentation [Rees et al 2005, Su et al 2006] or the only clinical feature of the disorder [Wang et al 2011]. Note: The complete clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis. Furthermore, the phenotype in infants is likely to be highly dependent on diet. To Confirm/Establish the Diagnosis in a ProbandMeasure plasma plant sterol concentrations. The diagnosis of sitosterolemia is established in individuals who have greatly increased plant sterol concentrations (especially sitosterol, campesterol, and stigmasterol) in plasma and tissues. Shellfish sterols can also be elevated.Typical plant sterol concentrations in healthy individuals are 100 times lower than cholesterol (0.21 ± 0.7 mg/dL); thus, their small contribution to the total sterol concentration is negligible. These plant sterols and shellfish sterols are not detected by standard laboratory methods of cholesterol measurement and require specialized analysis typically utilizing gas chromatography (GC), gas chromatography/ mass spectrometry (GC/MS), or high pressure liquid chromatography (HPLC).In untreated individuals with sitosterolemia the sitosterol concentration can be 30-100 fold increased, i.e., as high as 10 to 65 mg/dL [Kidambi & Patel 2008]. Plasma concentrations of sitosterol above 1 mg/dL are considered to be diagnostic of sitosterolemia (except in infants, in whom further testing may be necessary; see Note following). Note: (1) In individuals with sitosterolemia the plant sterol transporters sterolin-1 (encoded by ABCG5) and sterolin-2 (encoded by ABCG8) are abnormal at birth; however, the increase in the plasma concentration of sitosterol and other plant sterols does not occur until foods with plant sterols are consumed and the plant sterols accumulate in the body. Thus, even using GC, GC/MS, or HPLC to measure plasma sitosterol concentrations, the diagnosis of sitosterolemia cannot be excluded until the child is consuming foods that contain plant oils. Formula-fed infants with sitosterolemia may have high plasma concentrations of cholesterol and plant sterols. (2) Breast-fed infants with sitosterolemia likely will not have increased concentrations of plant sterols until after weaning [Rios et al 2010]. Of note, one breastfed three month old with sitosterolemia had increased plasma concentrations of sitosterol [Niu et al 2010]. False positive results have been observed: Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols, probably due to immature transporters [Mellies et al 1976, Steiner 2011].Patients with cholestasis or liver disease who are on parenteral nutrition (which contains plant sterols) may be unable to effectively clear the plant sterols [Bindl et al 2000, Llop et al 2008, Kurvinen et al 2011]. Carriers for sitosterolemia may occasionally have mildly elevated concentration of sitosterol [Lee et al 2001]. (Note, however, that plasma concentrations of sitosterol are usually normal in carriers [Kwiterovich et al 2003]). False negative results can be observed in: Individuals using ezetimibe or ezetimibe combinations, or bile acid binding resin; AND/OR Individuals on a diet low in plant-derived foods.Note: (1) In general plasma cholesterol concentration is non-diagnostic because it can be normal in individuals with sitosterolemia, and elevations of plasma cholesterol concentration can be seen in numerous common disorders. (2) In sitosterolemia, plasma concentrations of cholesterol in children can be high, even in the range seen in homozygous familial hypercholesterolemia [Togo et al 2009, Niu et al 2010, Rios et al 2010]. Perform clinical molecular genetic testing when biochemical findings are atypical. ABCG5 and ABCG8 are the only genes in which mutations are known to cause sitosterolemia. Sterolin-1 (encoded by ABCG5) and sterolin-2 (encoded by ABCG8) form a heterodimer transporter; thus, affected individuals have biallelic mutations of either ABCG5 or ABCG8. Asians primarily have mutations in ABCG5 and whites primarily have mutations in ABCG8.The below percentages are based on 85 patients from 18 publications (see attached mutations list).Table 1. Summary of Molecular Genetic Testing Used in SitosterolemiaView in own windowGene Symbol 1Proportion of Sitosterolemia Attributed to Mutations in This Gene 2Test MethodMutations Detected 3Test AvailabilityABCG530/85 Sequence analysisSequence variants 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletions 6Research onlyABCG855/85Sequence analysisSequence variants 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletions 7Research only1. See Table A. Genes and Databases for chromosome locus and protein name.2. From 18 publications [Berge et al 2000, Hubacek et al 2001, Lu et al 2001, Heimerl et al 2002, Wang et al 2004, Wilund et al 2004, Sehayek et al 2004, Rees et al 2005, Solcà et al 2005, Su et al 2006, Kratz et al 2007, Mannucci et al 2007, Togo et al 2009, Niu et al 2010, Rios et al 2010, Tsubakio-Yamamoto et al 2010, Keller et al 2011, Chong et al 2012]3. See Molecular Genetics for information on allelic variants.4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Although no deletions or duplications involving ABCG5 as causative of sitosterolemia have been reported, the identification of only one ABCG5 mutation in affected individuals could theoretically be explained by deletion of the other allele [Lu et al 2001].7. A gross deletion of exon 3 reported for ABCG8 [Lu et al 2001] appears to be disputed by another publication [Lee et al 2001]. Although a role for gross deletions of ABCG8 as causative of sitosterolemia remains unclear, the identification of only one ABCG8 mutation in affected individuals could theoretically be explained by deletion of the other allele [Heimerl et al 2002].Genetically Related (Allelic) Disorders No phenotypes other than those described in this GeneReview are associated with biallelic mutations in ABCG5 or ABCG8.
The clinical presentation of sitosterolemia varies from xanthomas and atherosclerosis and its complications to a milder phenotype with few to no specific symptoms and signs [Kidambi & Patel 2008]. Information on the natural history of sitosterolemia is limited due to the small number of affected individuals reported to date (see Prevalence). ...
Natural History The clinical presentation of sitosterolemia varies from xanthomas and atherosclerosis and its complications to a milder phenotype with few to no specific symptoms and signs [Kidambi & Patel 2008]. Information on the natural history of sitosterolemia is limited due to the small number of affected individuals reported to date (see Prevalence). Although the tuberous xanthomas are more typically seen in adults, they may appear at any age, even in children. Children may have xanthomas in unusual locations such as the buttocks, heels, elbows, and knees. Xanthomas have been reported in children as young as ages one to two years [Shulman et al 1976, Hubacek et al 2001, Niu et al 2010], four years [Togo et al 2009], and six years [Salen et al 2006, Mannucci et al 2007]. A child age ten years was reported with tendon xanthomas [Solcà et al 2005]. Intrafamilial variability has been reported: In one report the phenotypes differed in one consanguineous family in which three affected sibs and one affected first cousin had the same genotype [Wang et al 2004]. One child had abdominal pain, anemia, xanthomas, and early cardiac death; the others had high plasma concentrations of cholesterol and plant sterols but no other symptoms. In another consanguineous family the mother and brother of the proband were homozygous for the same nucleotide change in ABCG5. All had increased concentrations of plasma sitosterol; however, only the proband (age 6 years) had xanthomas. The mother and brother, who had no evidence of xanthomas, had much lower cholesterol concentrations [Mannucci et al 2007].Ten individuals with sitosterolemia with early-onset (age 5-33 years) atherosclerosis with or without sudden death have been reported [Miettinen 1980, Kwiterovich et al 1981, Salen et al 1985, Kolovou et al 1996, Heimerl et al 2002, Katayama et al 2003, Mymin et al 2003, Salen et al 2006, Tsubakio-Yamamoto et al 2010, Watts & Mitchell 1992]. Because of the limited number of reports, the incidence of coronary artery disease is not known. On occasion arthritis and splenomegaly are also seen.Miettinen et al [2006] described an individual with chronic non-A non-B hepatitis and cirrhosis in whom the diagnosis of sitosterolemia was serendipitously made by plasma analysis of sitosterol, and further confirmed by the finding of the biallelic ABCG8 mutations c.1173G>A (p.Trp361*) and c.1359G>T (p.Glu423Asp). Following liver transplantation, the sitosterolemia unexpectedly resolved and plant sterol levels fell to the same levels seen in unaffected individuals. Although it is unknown if the liver problem was initially due to the sitosterolemia, the findings suggest that “idiopathic” liver disease could indeed be undiagnosed sitosterolemia. The authors concluded that an unaffected liver can overcome the intestinal transport defect in clearing the plant sterols from the circulation.
Because of the small number of individuals with sitosterolemia reported to date, little information on genotype-phenotype correlations is available. ...
Genotype-Phenotype Correlations Because of the small number of individuals with sitosterolemia reported to date, little information on genotype-phenotype correlations is available.
Other disorders that cause xanthomas in children are: ...
Differential DiagnosisOther disorders that cause xanthomas in children are: Heterozygous familial hypercholesterolemia (FH)Homozygous familial hypercholesterolemia (FH) which can be distinguished from sitosterolemia because both parents of an affected child have hypercholesterolemia. In addition, finding large platelets (macrothrombocytopenia) in individuals with hypercholesterolemia increases the likelihood of identifying those with sitosterolemia. Cerebrotendinous xanthomatosis (CTX), which can be distinguished from sitosterolemia by increased concentrations of plasma cholestanol, childhood-onset of protracted diarrhea, and cataracts in CTX. Furthermore, adults with CTX typically have neurologic involvement.Sitosterolemia should be considered in any person with unexplained hemolysis and/or macrothrombocytopenia. The combination of hemolysis and thrombocytopenia can occur in the following conditions (in which large platelets are not observed):Liver diseaseThrombotic thrombocytopenic purpuraSystemic lupus erythematosus (SLE)Other conditions that cause stomatocytosis:Rhnull conditionAnalphalipiproteinemia (Tangier disease)Lecithin-cholesterol aceyl transferase (LCAT) deficiencyNote to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with sitosterolemia, the following evaluations are recommended: ...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with sitosterolemia, the following evaluations are recommended: Measurement of plasma concentrations of plant sterols (primarily beta-sitosterol and campesterol) and cholesterol, if not measured at the time of diagnosisDetermination of the size, number, and distribution of xanthomas (tendon and tuberous)Depending on the age of the patient, cardiology consultation to evaluate for atherosclerosis and cardiac valve abnormalities with consideration of coronary arteriography as neededComplete blood count with smear to look for platelet abnormalities and/or thrombocytopenia Evaluation for possible hemolysis/ hemolytic anemia Monitoring liver function (e.g., albumin, ALT, AST, ALP, bilirubin) [Miettinen et al 2006]Evaluation for arthralgias and/or arthritis If splenomegaly is significant, consultation with a hematologist and gastroenterologistTreatment of ManifestationsTreatment aims to reduce plasma concentration of plant sterols to as close as possible to normal concentrations (i.e., <1 mg/dL), to control plasma concentration of cholesterol, and to prevent xanthoma formation and/or reduce the size and number of xanthomas. Historically, treatment strategies included dietary restriction of intake of both animal- and plant-based sterols, ileal bypass surgery, and/or hepatic transplantation [Salen et al 2004, Wang et al 2004, Miettinen et al 2006, Lütjohann et al 2008, Niu et al 2010, Tsubakio-Yamamoto et al 2010]. Some of these treatments have only been partially effective. Current treatment therapies focus on the following:A diet low in shellfish sterols and plant sterols (i.e., avoidance of vegetable oils, margarine, nuts, seeds, avocados, chocolate, and shellfish) in conjunction with ezetimibe or other medications The sterol absorption inhibitor: ezetimibe (10 mg/d) [Salen et al 2004, Salen et al 2006, Lütjohann et al 2008, Musliner et al 2008, Niu et al 2010, Tsubakio-Yamamoto et al 2010], which alone may be sufficientBile acid sequestrants such as cholestryramine (8-15 g/d) which may be considered in those with incomplete response to ezetimibeTreatments should begin at the time of diagnosis. When tolerated, the combined treatments can decrease the plasma concentrations of cholesterol and sitosterol by 10% to 50%. Often existing xanthomas regress. Partial ileal bypass surgery (i.e., shortening of the ileum) has been used to increase intestinal bile acid loss. Partial or complete ileal bypass surgery in persons with sitosterolemia has resulted in at least 50% reduction of plasma and cellular sterol and stanol levels [Nguyen et al 1988, Nguyen et al 1990]. Arthritis, arthralgias, anemia, thromobocytopenia, and/or splenomegaly require treatment, the first step being management of the sitosterolemia, followed by routine management of the finding (by the appropriate consultants) as needed. Sitosterolemia does not respond to standard statin treatment. SurveillanceMonitor plasma concentrations of plant sterols (primarily beta-sitosterol and campesterol) and cholesterol, and the size, number, and distribution of xanthomas [Kidambi & Patel 2008] at least every six to 12 months.Monitor platelet count for thrombocytopenia, CBC for evidence of hemolytic anemia, and liver enzymes for elevation beginning at the time of diagnosis with the frequency determined by the severity of the clinical and biochemical findings.In those with longstanding untreated sitosterolemia, surveillance for atherosclerosis and coronary artery disease is indicated, with the level of monitoring determined by the severity of the clinical and biochemical findings.Agents/Circumstances to AvoidMargarines and other products containing stanols (e.g., campestanol and sitostanol), which are recommended for use by persons with hypercholesterolemia, are contraindicated in those with sitosterolemia as they can exacerbate plant stanol accumulation [Connor et al 2005].Note: Foods with high plant sterol content including shellfish, vegetable oils, margarine, nuts, avocados, and chocolate should be taken in moderation due to increased intestinal absorption of plant sterols in those with sitosterolemia [Bhattacharyya & Connor 1974]. Evaluation of Relatives at RiskEarly diagnosis of at-risk relatives either through measurement of plasma concentrations of plant sterols or through molecular genetic testing (if the family-specific mutations are known) allows early institution of treatment and surveillance to optimize outcome.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Guidelines for the management of women with sitosterolemia during pregnancy have not been established. While ezetimibe is indicated as therapy for individuals with sitosterolemia, no studies have been published on the fetal effects of ezetimibe when used during human pregnancy. Therefore, ezetimibe should be used with caution during pregnancy. Therapies Under InvestigationAsymptomatic individuals identified by molecular genetic testing in research studies are treated to maintain near-normal plasma plant sterol concentrations. Early treatment before xanthomas or other manifestations are present may prevent clinical manifestations. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Sitosterolemia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDABCG82p21ATP-binding cassette sub-family G member 8ABCG8 homepage - Mendelian genesABCG8ABCG52p21ATP-binding cassette sub-family G member 5ABCG5 homepage - Mendelian genesABCG5Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Sitosterolemia (View All in OMIM) View in own window 210250SITOSTEROLEMIA 605459ATP-BINDING CASSETTE, SUBFAMILY G, MEMBER 5; ABCG5 605460ATP-BINDING CASSETTE, SUBFAMILY G, MEMBER 8; ABCG8Molecular Genetic Pathogenesis Sterolin-1 (encoded by ABCG5) and sterolin-2 (encoded by ABCG8) form a heterodimer transporter; thus, affected individuals have biallelic mutations of either ABCG5 or ABCG8. ABCG5Normal allelic variants. ABCG5 comprises 13 exons. This gene is arranged head to head with ABCG8 with no more than 150 bases separating the start-transcription sites, with only 372 bases separating the two respective “ATG.”Pathologic allelic variants. Biallelic mutations in this gene seem to cause sitosterolemia in persons of Chinese, Japanese, and Indian heritage. Most are nonsense and missense mutations [Hazard & Patel 2007].Normal gene product. Sterolin-1 and sterolin-2 are two ATP-binding cassette half-transporters which belong to the G family members. They likely function as heterodimers. The highest expression is in the intestines and liver, functioning to selectively remove plant sterols. This transporter is thought to resecrete sterols, especially plant sterols, back into the intestinal lumen and from the liver into the bile [von Bergmann et al 2005]. Abnormal gene product. The effect of the defective heterodimer transporter (requiring one sterolin-1 and one sterolin-2) is increased cholesterol and sitosterol absorption and decreased sitosterol and cholesterol excretion into the bile. ABCG8Normal allelic variants. ABCG58 comprises 13 exons. This gene is arranged head to head with ABCG5 with no more that 150 bases separating the start-transcription sites, with only 372 bases separating the two respective “ATG.”Pathologic allelic variants. Biallelic mutations in this gene seem to cause sitosterolemia in persons of northern European heritage. Most are nonsense and missense mutations [Hazard & Patel 2007]. Normal gene product. Sterolin-2 and sterolin-1 are two ATP-binding cassette half-transporters which belong to the G family members. They likely function as heterodimers. The highest expression is in the intestines and liver, functioning to selectively remove plant sterols. This transporter is thought to resecrete sterols, especially plant sterols, back into the intestinal lumen and from the liver into the bile [von Bergmann et al 2005]. Abnormal gene product. The effect of the defective hetero dimer transporter (requiring one sterolin-1 and one sterolin-2) is increased cholesterol and sitosterol absorption and decreased sitosterol and cholesterol excretion into the bile.