Update on Primary Hypobetalipoproteinemia

Rare Diseases and Lipid Metabolism (JAG López, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Rare Diseases and Lipid Metabolism

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.

Keywords

Abetalipoproteinemia Apolipoprotein B Chylomicron retention disease Combined hypolipidemia Familial hypobetalipoproteinemia Hypobetalipoproteinemia Low-density lipoprotein 

Notes

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.

References

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

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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. 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. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Hooper AJ, Burnett JR. Recent developments in the genetics of LDL deficiency. Curr Opin Lipidol. 2013;24:111–5.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Wetterau JR, Aggerbeck LP, Bouma ME, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992;258:999–1001.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 12.
    Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr Metab (Lond). 2012;9:14.CrossRefGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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. 17.
    Delpre G, Kadish U, Glantz I, Avidor I. Endoscopic assessment in abetalipoproteinemia (Bassen-Kornzweig-syndrome). Endoscopy. 1978;10:59–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Tanyel MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am Fam Physician. 1997;55:197–201.PubMedGoogle Scholar
  19. 19.
    Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008;3:19.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 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. 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Muller DP. Vitamin E, and neurological function. Mol Nutr Food Res. 2010;54:710–8.PubMedCrossRefGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 25.
    Schonfeld G, Lin X, Yue P. Familial hypobetalipoproteinemia: genetics and metabolism. Cell Mol Life Sci. 2005;62:1372–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Tarugi P, Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum. Adv Clin Chem. 2011;54:81–107.PubMedGoogle Scholar
  27. 27.
    Whitfield AJ, Barrett PHR, van Bockxmeer FM, Burnett JR. Lipid disorders and mutations in the APOB gene. Clin Chem. 2004;50:1725–32.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 33.
    Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53:2515–24.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res. 2011;52:593–617.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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. PubMedCrossRefGoogle Scholar
  53. 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. PubMedCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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. PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Clinical Biochemistry, PathWest Laboratory Medicine WARoyal Perth HospitalPerthAustralia
  2. 2.School of Medicine & PharmacologyUniversity of Western AustraliaPerthAustralia
  3. 3.School of Pathology & Laboratory MedicineUniversity of Western AustraliaPerthAustralia

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