Skip to main content
SpringerLink
Log in

Update on Primary Hypobetalipoproteinemia

  • Rare Diseases and Lipid Metabolism (JAG López, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

“Primary hypobetalipoproteinemia” refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit Rev Clin Lab Sci. 2005;42:515–45.

    Article  CAS  PubMed  Google Scholar 

  2. Burnett JR, Bell DA, Hooper AJ, Hegele RA. Clinical utility gene card for: abetalipoproteinaemia. Eur J Hum Genet. 2012. doi:10.1038/ejhg.2012.30.

    Google Scholar 

  3. Burnett JR, Bell DA, Hooper AJ, Hegele RA. Clinical utility gene card for: familial hypobetalipoproteinaemia (APOB). Eur J Hum Genet. 2012. doi:10.1038/ejhg.2012.85.

    Google Scholar 

  4. Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

    Article  CAS  PubMed  Google Scholar 

  5. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5.

    Article  CAS  PubMed  Google Scholar 

  6. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis. 2007;193:445–8.

    Article  CAS  PubMed  Google Scholar 

  7. Peretti N, Sassolas A, Roy CC, et al. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J Rare Dis. 2010;5:24.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Hooper AJ, Burnett JR. Recent developments in the genetics of LDL deficiency. Curr Opin Lipidol. 2013;24:111–5.

    Article  CAS  PubMed  Google Scholar 

  9. Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363:2220–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Wetterau JR, Aggerbeck LP, Bouma ME, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992;258:999–1001.

    Article  CAS  PubMed  Google Scholar 

  11. Shoulders CC, Brett DJ, Bayliss JD, et al. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. Hum Mol Genet. 1993;2:2109–16.

    Article  CAS  PubMed  Google Scholar 

  12. Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr Metab (Lond). 2012;9:14.

    Article  CAS  Google Scholar 

  13. Ohashi K, Ishibashi S, Osuga J, et al. Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia. J Lipid Res. 2000;41:1199–204.

    CAS  PubMed  Google Scholar 

  14. Rehberg EF, Samson-Bouma ME, Kienzle B, et al. A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase. J Biol Chem. 1996;271:29945–52.

    Article  CAS  PubMed  Google Scholar 

  15. Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of the microsomal triglyceride transfer protein in abetalipoproteinemia. Annu Rev Nutr. 2000;20:663–97.

    Article  CAS  PubMed  Google Scholar 

  16. Kane JP, Havel RJ. Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Scriver CR, Beaudet AL, Sly WS, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001. p. 2717–52.

    Google Scholar 

  17. Delpre G, Kadish U, Glantz I, Avidor I. Endoscopic assessment in abetalipoproteinemia (Bassen-Kornzweig-syndrome). Endoscopy. 1978;10:59–62.

    Article  CAS  PubMed  Google Scholar 

  18. Tanyel MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am Fam Physician. 1997;55:197–201.

    CAS  PubMed  Google Scholar 

  19. Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008;3:19.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014. doi:10.1007/s10545-013-9665-4. This article discusses the diagnosis, assessment, treatment, and follow-up of ABL and homozygous FHBL.

  21. Chowers I, Banin E, Merin S, Cooper M, Granot E. Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients. Eye. 2001;15:525–30.

    Article  CAS  PubMed  Google Scholar 

  22. Muller DP. Vitamin E, and neurological function. Mol Nutr Food Res. 2010;54:710–8.

    Article  CAS  PubMed  Google Scholar 

  23. Kayden HJ, Hatam LJ, Traber MG. The measurement of nanograms of tocopherol from needle aspiration biopsies of adipose tissue: normal and abetalipoproteinemic subjects. J Lipid Res. 1983;24:652–6.

    CAS  PubMed  Google Scholar 

  24. Clarke MW, Hooper AJ, Headlam HA, Wu JH, Croft KD, Burnett JR. Assessment of tocopherol metabolism and oxidative stress in familial hypobetalipoproteinemia. Clin Chem. 2006;52:1339–45.

    Article  CAS  PubMed  Google Scholar 

  25. Schonfeld G, Lin X, Yue P. Familial hypobetalipoproteinemia: genetics and metabolism. Cell Mol Life Sci. 2005;62:1372–8.

    Article  CAS  PubMed  Google Scholar 

  26. Tarugi P, Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum. Adv Clin Chem. 2011;54:81–107.

    CAS  PubMed  Google Scholar 

  27. Whitfield AJ, Barrett PHR, van Bockxmeer FM, Burnett JR. Lipid disorders and mutations in the APOB gene. Clin Chem. 2004;50:1725–32.

    Article  CAS  PubMed  Google Scholar 

  28. Burnett JR, Shan J, Miskie BA, et al. A novel nontruncating APOB gene mutation, R463W, causes familial hypobetalipoproteinemia. J Biol Chem. 2003;278:13442–52.

    Article  CAS  PubMed  Google Scholar 

  29. Burnett JR, Zhong S, Jiang ZG, et al. Missense mutations in APOB within the betaalpha1 domain of human APOB-100 result in impaired secretion of apoB and apoB-containing lipoproteins in familial hypobetalipoproteinemia. J Biol Chem. 2007;282:24270–83.

    Article  CAS  PubMed  Google Scholar 

  30. Zhong S, Magnolo AL, Sundaram M, et al. Nonsynonymous mutations within APOB in human familial hypobetalipoproteinemia - evidence for feedback inhibition of lipogenesis and post-endoplasmic reticulum degradation of apolipoprotein B. J Biol Chem. 2010;285:6453–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Elias N, Patterson BW, Schonfeld G. Decreased production rates of VLDL triglycerides and apoB-100 in subjects heterozygous for familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 1999;19:2714–21.

    Article  CAS  PubMed  Google Scholar 

  32. Yao ZM, Blackhart BD, Linton MF, Taylor SM, Young SG, McCarthy BJ. Expression of carboxyl-terminally truncated forms of human apolipoprotein B in rat hepatoma cells. Evidence that the length of apolipoprotein B has a major effect on the buoyant density of the secreted lipoproteins. J Biol Chem. 1991;266:3300–8.

    CAS  PubMed  Google Scholar 

  33. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53:2515–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006;79:514–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Cariou B, Ouguerram K, Zair Y, et al. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2009;29:2191–7.

    Article  CAS  PubMed  Google Scholar 

  36. Ogata H, Akagi K, Baba M, et al. Fatty liver in a case with heterozygous familial hypobetalipoproteinemia. Am J Gastroenterol. 1997;92:339–42.

    CAS  PubMed  Google Scholar 

  37. Schonfeld G, Patterson BW, Yablonskiy DA, et al. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J Lipid Res. 2003;44:470–8.

    Article  CAS  PubMed  Google Scholar 

  38. Sankatsing RR, Fouchier SW, de Haan S, et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2005;25:1979–84.

    Article  CAS  PubMed  Google Scholar 

  39. Tanoli T, Yue P, Yablonskiy D, Schonfeld G. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res. 2004;45:941–7.

    Article  CAS  PubMed  Google Scholar 

  40. Visser ME, Lammers NM, Nederveen AJ, et al. Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia. Diabetologia. 2011;54:2113–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res. 2011;52:593–617.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Lonardo A, Tarugi P, Ballarini G, Bagni A. Familial heterozygous hypobetalipoproteinemia, extrahepatic primary malignancy, and hepatocellular carcinoma. Dig Dis Sci. 1998;43:2489–92.

    Article  CAS  PubMed  Google Scholar 

  43. Tarugi P, Lonardo A, Ballarini G, et al. A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5). J Hepatol. 2000;33:361–70.

    Article  CAS  PubMed  Google Scholar 

  44. Jones B, Jones EL, Bonney SA, et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet. 2003;34:29–31.

    Article  CAS  PubMed  Google Scholar 

  45. Siddiqi SA, Gorelick FS, Mahan JT, Mansbach 2nd CM. COPII proteins are required for Golgi fusion but not for endoplasmic reticulum budding of the pre-chylomicron transport vesicle. J Cell Sci. 2003;116:415–27.

    Article  CAS  PubMed  Google Scholar 

  46. Peretti N, Roy CC, Sassolas A, et al. Chylomicron retention disease: a long term study of two cohorts. Mol Genet Metab. 2009;97:136–42.

    Article  CAS  PubMed  Google Scholar 

  47. Nakajima K, Kobayashi J, Mabuchi H, et al. Association of angiopoietin-like protein 3 with hepatic triglyceride lipase and lipoprotein lipase activities in human plasma. Ann Clin Biochem. 2010;47:423–31.

    Article  CAS  PubMed  Google Scholar 

  48. Shan L, Yu XC, Liu Z, et al. The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. J Biol Chem. 2009;284:1419–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Fazio S, Sidoli A, Vivenzio A, et al. A form of familial hypobetalipoproteinaemia not due to a mutation in the apolipoprotein B gene. J Intern Med. 1991;229:41–7.

    Article  CAS  PubMed  Google Scholar 

  50. Minicocci I, Montali A, Robciuc MR, et al. Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. J Clin Endocrinol Metab. 2012;97:E1266–75.

    Article  CAS  PubMed  Google Scholar 

  51. Minicocci I, Santini S, Cantisani V, et al. Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis. J Lipid Res. 2013;54:3481–90.

    Article  CAS  PubMed  Google Scholar 

  52. Robciuc MR, Maranghi M, Lahikainen A, et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013;33:1706–13. This article shows that although partial deficiency of ANGPTL3 did not affect lipase activity, complete deficiency decreased the levels of free fatty acids and improved insulin sensitivity.

    Article  CAS  PubMed  Google Scholar 

  53. Minicocci I, Cantisani V, Poggiogalle E, et al. Functional and morphological vascular changes in subjects with familial combined hypolipidemia: an exploratory analysis. Int J Cardiol. 2013;168:4375–8. Despite an approximately 50% reduction in the concentration of LDL cholesterol, ANGPTL3 homozygotes had increased CIMT.

    Article  PubMed  Google Scholar 

  54. Noto D, Cefalu AB, Valenti V, et al. Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia. Arterioscler Thromb Vasc Biol. 2012;32:805–9.

    Article  CAS  PubMed  Google Scholar 

  55. Ouguerram K, Zair Y, Kasbi-Chadli F, et al. Low rate of production of apolipoproteins B100 and AI in 2 patients with Anderson disease (chylomicron retention disease). Arterioscler Thromb Vasc Biol. 2012;32:1520–5.

    Article  CAS  PubMed  Google Scholar 

  56. Johansen CT, Dube JB, Loyzer MN, et al. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias. J Lipid Res. 2014;55:765–72. This article describes the design and performance of a targeted resequencing panel which has potential to aid in molecular diagnosis of dyslipidemias, including primary HBL.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Health and Medical Research Council Project Grant 1010133 (to Amanda J. Hooper and John R. Burnett) and a Practitioner Fellowship from the Royal Perth Hospital Medical Research Foundation (to John R. Burnett).

Conflict of Interest

Amanda J. Hooper and John R. Burnett declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital, Wellington Street, GPO Box X2213, Perth, WA, 6847, Australia

    Amanda J. Hooper & John R. Burnett

  2. School of Medicine & Pharmacology, University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia

    Amanda J. Hooper & John R. Burnett

  3. School of Pathology & Laboratory Medicine, University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia

    Amanda J. Hooper

Authors
  1. Amanda J. Hooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John R. Burnett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John R. Burnett.

Additional information

This article is part of the Topical Collection on Rare Diseases and Lipid Metabolism

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hooper, A.J., Burnett, J.R. Update on Primary Hypobetalipoproteinemia. Curr Atheroscler Rep 16, 423 (2014). https://doi.org/10.1007/s11883-014-0423-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-014-0423-3

Keywords

Search

Navigation