Journal of Inherited Metabolic Disease

, Volume 33, Issue 4, pp 437–443

Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children

  • Dau-Ming Niu
  • Kah-Wai Chong
  • Ju-Hui Hsu
  • Tina Jui-Ting Wu
  • Hsiao-Chi Yu
  • Cheng-Hung Huang
  • Ming-Yu Lo
  • Ching Fai Kwok
  • Lisa E. Kratz
  • Low-Tone Ho
Original Article


The clinical observation and treatment of young children with sitosterolemia has rarely been reported. We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. The R389H mutation was found in 50% of alleles. Three of these five patients received cholestyramine therapy with a very good response. However, all patients discontinued this therapy because of poor compliance. Finally, all patients were on ezetimibe therapy and had satisfactory total serum cholesterol levels, though their plant sterol levels were still higher than normal. Another noteworthy finding is that a female infant had a serum cholesterol level of 654 mg/dl at 7 months of age, despite being breast fed (with very tiny amounts of plant sterols) since birth and undergoing 4 months of ezetimibe administration. Although she failed to respond to ezetimibe during this period, she did show improvement when the therapy was started again at 2 years of age. It is possible that another 23-month-old female patient also responded more slowly to ezetimibe treatment than older patients.


  1. Belamarich PF, Deckelbaum RJ, Starc TJ, Dobrin BE, Tint GS, Salen G (1990) Response to diet and cholestyramine in a patient with sitosterolemia. Pediatrics 86:977–981PubMedGoogle Scholar
  2. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH (2000) Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775CrossRefPubMedGoogle Scholar
  3. Berginer VM, Gross B, Morad K, Kfir N, Morkos S, Aaref S, Falik-Zaccai TC (2009) Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat. Pediatrics 123:143–147CrossRefPubMedGoogle Scholar
  4. Bhattacharyya AK, Connor WE (1974) β-Sitosterolemia and xanthomatosis-a newly described lipid storage disease in two sisters. J Clin Invest 53:1033–1043CrossRefPubMedGoogle Scholar
  5. Bjorkhem I, Boberg KM, Leitersdorf E (2001) Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 2961–2988Google Scholar
  6. Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340CrossRefPubMedGoogle Scholar
  7. Graf GA, Yu L, Li WP, Gerard R (2003) ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem 278:48275–48282CrossRefPubMedGoogle Scholar
  8. Heimerl S, Langmann T, Moehle C (2002) Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia. Hum Mutat 20:151CrossRefPubMedGoogle Scholar
  9. Hidaka H, Nakamura T, Aoki T, Kojima H, Nakajima Y, Kosugi K, Hatanaka I, Harada M, Kobayashi M, Tamura A (1990) Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis. J Lipid Res 31:881–888PubMedGoogle Scholar
  10. Hubacek JA, Berge KE, Cohen JC, Hobbs HH (2001) Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat 18:359–360CrossRefPubMedGoogle Scholar
  11. Kruit JK, Drayer AL, Bloks VW (2008) Plant sterols cause macrothrombocytopenia in a mouse model of sitosterolemia. J Biol Chem 283:6281–6287CrossRefPubMedGoogle Scholar
  12. Kwiterovich PO Jr, Chen SC, Virgil DG, Schweitzer A, Arnold DR, Kratz LE (2003) Response of obligate heterozygotes for phytosterolemia to a low-fat diet and to a plant sterol ester dietary challenge. J Lipid Res 44:1143–1155CrossRefPubMedGoogle Scholar
  13. Lam CW, Cheng AW, Tong SF (2002) Novel donor splice site mutation of ABCG5 gene in sitosterolemia. Mol Genet Metab 75:178–180CrossRefPubMedGoogle Scholar
  14. Lee MH, Lu K, Hazard S, Yu H (2001a) Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 27:79–83CrossRefPubMedGoogle Scholar
  15. Lee MH, Lu K, Patel SB (2001b) Genetic basis of sitosterolemia. Curr Opin Lipidol 12:141–149CrossRefPubMedGoogle Scholar
  16. Low LC, Lin HJ, Lau KS, Kung AW, Yeung CY (1991) Phytosterolemia and pseudohomozygous type II hypercholesterolemia in two Chinese patients. J Pediatr 118:746–749CrossRefPubMedGoogle Scholar
  17. Lu K, Lee MH, Hazard S, Brooks-Wilson A (2001) Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet 69:278–290CrossRefPubMedGoogle Scholar
  18. Lütjohann D, von Bergmann K, Sirah W, Macdonell G, Johnson-Levonas AO, Shah A, Lin J, Sapre A, Musliner T (2008) Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, open-label extension study. Int J Clin Pract 62:1499–1510CrossRefPubMedGoogle Scholar
  19. Mannucci L, Guardamagna O, Bertucci P (2007) Beta-sitosterolaemia: a new nonsense mutation in the ABCG5 gene. Eur J Clin Invest 37:997–1000CrossRefPubMedGoogle Scholar
  20. Masana L, Joven J, Rubiés-Prat J, Lewis B (1990) Low density lipoprotein metabolism and receptor studies in a patient with pseudohomozygous familial hypercholesterolaemia. Acta Paediatr Scand 79(4):475–476CrossRefPubMedGoogle Scholar
  21. McArthur RG, Roncari DA, Little JA (1986) Phytosterolemia and hypercholesterolemia in childhood. J Pediatr 108:254–256CrossRefPubMedGoogle Scholar
  22. Moghadasian MH (2004) Cerebrotendinous xanthomatosis: clinical course, genotypes and metabolic backgrounds. Clin Invest Med 27:42–50PubMedGoogle Scholar
  23. Morganroth J, Levy RI, McMahon AE, Gotto AM Jr (1974) Pseudohomozygous type II hyperlipoproteinemia. J Pediatr 85:639–643CrossRefPubMedGoogle Scholar
  24. Musliner T, Cselovszky D, Sirah W, McCrary Sisk C, Sapre A, Salen G, Lütjohann D, von Bergmann K (2008) Efficacy and safety of ezetimibe 40 mg vs. ezetimibe 10 mg in the treatment of patients with homozygous sitosterolaemia. Int J Clin Pract 62:995–1000CrossRefPubMedGoogle Scholar
  25. Mymin D, Wang J, Frohlich J (2003) Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8. Circulation 107:791CrossRefPubMedGoogle Scholar
  26. Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK (2005) Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 25:2654–2660CrossRefPubMedGoogle Scholar
  27. Nguyen LB, Shefer S, Salen G, Ness GC, Tint GS, Zaki FG, Rani I (1990) A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis. J Clin Invest 86:923–931CrossRefPubMedGoogle Scholar
  28. Nguyen LB, Cobb M, Shefer S (1991) Regulation of cholesterol biosynthesis in sitosterolemia: effects of lovastatin, cholestyramine, and dietary sterol restriction. J Lipid Res 32:1941–1948lPubMedGoogle Scholar
  29. Patel SB, Salen G, Hidaka H (1998a) Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J Clin Invest 102:1041–1044CrossRefPubMedGoogle Scholar
  30. Patel SB, Honda A, Salen G (1998b) Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis. J Lipid Res 39:1055–1061PubMedGoogle Scholar
  31. Parsons HG, Jamal R, Baylis B (1995) A marked and sustained reduction in LDL sterols by diet and cholestyramine in sitosterolemia. Clin Invest Med 18:389–400PubMedGoogle Scholar
  32. Rajaratnam RA, Gylling H, Miettinen TA (2000) Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol 35:1185–1191CrossRefPubMedGoogle Scholar
  33. Rees DC, Iolascon A, Carella M (2005) Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/ macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol 130:297–309CrossRefPubMedGoogle Scholar
  34. Salen G, Kwiterovich PO Jr, Shefer S (1985) Increased plasma cholestanol and 5 alpha-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis. J Lipid Res 26:203–209PubMedGoogle Scholar
  35. Salen G, Shefer S, Nguyen L (1992) Sitosterolemia. J Lipid Res 33:945–955PubMedGoogle Scholar
  36. Salen G, von Bergmann K, Lütjohann D (2004) Multicenter sitosterolemia study group. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation 109:966–971CrossRefPubMedGoogle Scholar
  37. Salen G, Starc T, Sisk CM (2006) Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis. Gastroenterology 130:1853–1857CrossRefPubMedGoogle Scholar
  38. Sethuraman G, Sugandhan S, Sharma G et al (2007) Familial homozygous hypercholesterolemia: report of two patients and review of the literature. Pediatr Dermatol 24:230–234CrossRefPubMedGoogle Scholar
  39. Schaefer JR, Scharnagl H, Baumstark MW, Schweer H, Zech LA, Seyberth H, Winkler K, Steinmetz A, März W (1997) Homozygous familial defective apolipoprotein B 100. Enhaced removal of apolipoprotein E containing VLDLs and decreased production of LDLs. Arterioscler Thromb Vasc Biol 17:348–353PubMedGoogle Scholar
  40. Su Y, Wang Z, Yang H et al (2006) Clinical and molecular genetic analysis of a family with sitosterolemia and co-existing erythrocyte and platelet abnormalities. Haematologica 91:1392–1395PubMedGoogle Scholar
  41. Sudhop T, Gottwald BM, von Bergmann K (2002) Serum plant sterols as a potential risk factor for coronary heart disease. Metabolism 51:1519–1521CrossRefPubMedGoogle Scholar
  42. Strassburg CP, Strassburg A, Kneip S et al (2002) Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut 50:259–265CrossRefPubMedGoogle Scholar
  43. Thomas HP, Vogt A, Wilund KR et al (2004) Autosomal recessive hypercholesterolemia in three sisters with phenotypic homozygous familial hypercholesterolemia: diagnostic and therapeutic procedures. Ther Apher Dial 8:275–280CrossRefPubMedGoogle Scholar
  44. Togo M, Hashimoto Y, Iso-O N, Kurano M, Hara M, Kadowaki T, Koike K, Tsukamoto K (2008) Identification of a novel mutation for phytosterolemia. Genetic analyses of 2 cases. Clin Chim Acta 401:165–169CrossRefPubMedGoogle Scholar
  45. Van Heek M, Farley C, Compton DS et al (2000) Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 129:1748–1754CrossRefPubMedGoogle Scholar
  46. Wang J, Joy T, Mymin D, Frohlich J et al (2004) Phenotypic heterogeneity of sitosterolemia. J Lipid Res 45:2361–2367CrossRefPubMedGoogle Scholar
  47. Yoshida A, Naito M, Miyazaki K (2000) Japanese sisters associated with pseudohomozygous familial hypercholesterolemia and sitosterolemia. J Atheroscler Thromb 7:33–38PubMedGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Dau-Ming Niu
    • 1
    • 2
  • Kah-Wai Chong
    • 1
  • Ju-Hui Hsu
    • 2
  • Tina Jui-Ting Wu
    • 2
  • Hsiao-Chi Yu
    • 2
  • Cheng-Hung Huang
    • 2
  • Ming-Yu Lo
    • 2
  • Ching Fai Kwok
    • 3
  • Lisa E. Kratz
    • 4
  • Low-Tone Ho
    • 5
  1. 1.Institute of Clinical Medicine, School of MedicineNational Yang-Ming UniversityTaipeiRepublic of China
  2. 2.Department of PediatricsTaipei Veterans General HospitalTaipeiRepublic of China
  3. 3.Department of MedicineTaipei Veterans General HospitalTaipeiRepublic of China
  4. 4.Kennedy Krieger InstituteBaltimoreUSA
  5. 5.Department of Medical Research and EducationTaipei Veterans General HospitalTaipeiRepublic of China

Personalised recommendations