Hypobetalipoproteinemia: Difference between revisions
Jump to navigation
Jump to search
| Line 58: | Line 58: | ||
|APOB | |APOB | ||
|SARA 2 | |SARA 2 | ||
|ANGPTL3 | |ANGPTL3<ref name="pmid1995762">{{cite journal| author=Fazio S, Sidoli A, Vivenzio A, Maietta A, Giampaoli S, Menotti A et al.| title=A form of familial hypobetalipoproteinaemia not due to a mutation in the apolipoprotein B gene. | journal=J Intern Med | year= 1991 | volume= 229 | issue= 1 | pages= 41-7 | pmid=1995762 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1995762 }} </ref> | ||
|- | |- | ||
|Pathophysiology | |Pathophysiology | ||
Revision as of 15:48, 18 November 2016
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]
Synonyms and keywords: Familial hypobetalipoproteinemia, FHBL, normotriglyceridemic hypobetalipoproteinemia
Overview
These are a set of diseases caused my mutations in genes involved in triglyceride(TG), cholesterol transport and metabolism. These diseases primarily cause low plasma LDL C and triglyceride levels.
Historical Perspective
- In 1960, Salt reported absence of betalipoprotein in the plasma of a patient associated with very low cholesterol levels in the parents. Low cholesterol levels in the parents differentiates it from abetalipoproteinemia[1].
Pathophysiology
Pathogenesis
- Cholesterol and triglycerides are insolublei in the plasma, so they require a transport protien in the form of apolipoprotein B. These lipoproteins transport cholesterol and trigylcerides in spherical particles in which the cholesterol esters and triglyceride form the central core.
- Apolipoprotein B is the major carrier for triglycerides and cholesterol from the intestine and liver to the periphery.
- Apo B exits in two forms, Apo B48 and Apo B100.
| APOB gene is responsible for the productoion of Apo B48 in intestine which is critical for the formation and secretion of chylomicrons[2] , and Apo B100 in the liver which is released into circulation as VLDL | Mutation in the APOB gene affects the translation of mRNA of Apo B. The severity depends whether the patient is homozygous or heterozygous for the mutation.[3]. | ||||||||||||||||||||
| MTP transfers triglycerides from cytsol onto nacent ApoB in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons.Mutation in MTP causes abetalipoproteinemia[4]. | In Apo B48 associated chylomicrons, transport of protiens from endoplasmic reticulum to golgi complex is dependent on coat protien complex 2(COP II), secretion-associated, Ras-related GTPase 1B (Sar1b) encoded by the gene SARA2 is a major part of the protein essential for this intra cellular transport[5]. Mutation in Sar1b causes chylomicron retention disease[6]. | ||||||||||||||||||||
| In the periphery by the action of lipoprotein lipase in the endothelium of the capillaries and glycosylphosphatidylinositol-anchored high-density lipoprotein- binding protein 1 (GPIHBP1)[7], a transporter for lipoprotien lipase triglycerides are hydrolysed to form free fatty acids and glycerol | |||||||||||||||||||||
| This results in the formation of VLDL remnant( Intermediate density lipoprotein) and chylomicron remnants The lipases are inhibited by Angiopoietin-like protein 3 (ANGPTL3) thereby decreasing the triglyceride and LDL C[8].[9] | Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia [10][11] . | ||||||||||||||||||||
| IDL on further removal of triglycerides forms a cholesterol ester rich LDL C, the chylomicron and VLDL remnants removal is Apo E dependent via the LDL receptors and LDL receptor related protiens[12] | |||||||||||||||||||||
| LDL C is removed from the circulation by binding to LDL receptors in the liver. The receptor degradation is enhanced by Proprotein convertase subtilisin kexin 9 (PCSK9)[13]. | Mutation causing loss of function of the enzyme causes low LDL C levels, and gain of function mutations are associated with familial hypercholesterolemia[14]. | ||||||||||||||||||||
Genetics
| Homozygous familial
hypobetalipoproteinemia |
Heterozygous familial
hypobetalipoprotienemia |
Chylomicron Retention
Disease |
Familial Combined
Hypolipidemia | |
|---|---|---|---|---|
| Inheritance | Autosomal Codominant | Autosomal codominant | Autosomal Recessive | Autosomal Codominant |
| Defective Gene | APOB gene on chromosome locus 2p23-24 | APOB | SARA 2 | ANGPTL3[15] |
| Pathophysiology | Absence of Apo B
results in absent plasma VLDL, TG and LDL C. |
Truncated Apo B protiens are formed
which affect the lipidation and secretion of the Apo B particles. These poorly lipidated particles are are rapidly catabolized. |
Intracellular transport of chylomicrons is affected ,resulting in the accumalation of lipids intracellularly in the intestine and liver[16]. | Loss of function mutation results in the failure of inhibition of Lipoprotien lipase, leading to low LDL, VLDL and HDL levels. |
Causes
The following are the list of causes for primary hypobetalipoproteinemia.
- Abetalipoproteinemia
- Familial hypobetalipoproteinemia
- Chylomicron Retention Disease
- PCSK9 deficiency
- Familial Combined Hypolipidemia
Natural History, complications and Prognosis
- 1 in 1000–3000: Heterozygous familial hypobetalipoproteinaemia[17].
Diagnosis
History and Physical
| Homozygous Familial
Hypobetalipoproteinemia |
Heterozygous Familial
Hypobetalipoproteinemia |
Chylomicron Retention
Disease |
Familial Combined
Hypolipidemia | |
|---|---|---|---|---|
| Age of Presentation | Infancy | Asymptomatic | 2months to 1 year | Asymptomatic |
| Clinical Symptoms |
|
|
Laboratory Results
| Homozygous Familial
Hypobetalipoproteinemia |
Heterozygous Familial
Hypobetalipoproteinemia |
Chylomicron Retention
Disease |
Familial Combined
Hypolipidemia | |
|---|---|---|---|---|
| Lipid analysis |
|
|
||
| Other findings |
|
|
|
|
Treatment=
Medical Therapy
Surgical Therapy
Prevention
References
- ↑ SALT HB, WOLFF OH, LLOYD JK, FOSBROOKE AS, CAMERON AH, HUBBLE DV (1960). "On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea". Lancet. 2 (7146): 325–9. PMID 13745738.
- ↑ Dash S, Xiao C, Morgantini C, Lewis GF (2015). "New Insights into the Regulation of Chylomicron Production". Annu Rev Nutr. 35: 265–94. doi:10.1146/annurev-nutr-071714-034338. PMID 25974693.
- ↑ Di Leo E, Eminoglu T, Magnolo L, Bolkent MG, Tümer L, Okur I; et al. (2015). "The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations". J Clin Lipidol. 9 (3): 400–5. doi:10.1016/j.jacl.2015.01.005. PMID 26073401.
- ↑ Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR (2000). "The role of the microsomal triglygeride transfer protein in abetalipoproteinemia". Annu Rev Nutr. 20: 663–97. doi:10.1146/annurev.nutr.20.1.663. PMID 10940349.
- ↑ Shoulders CC, Stephens DJ, Jones B (2004). "The intracellular transport of chylomicrons requires the small GTPase, Sar1b". Curr Opin Lipidol. 15 (2): 191–7. PMID 15017362.
- ↑ Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S; et al. (2003). "Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders". Nat Genet. 34 (1): 29–31. doi:10.1038/ng1145. PMID 12692552.
- ↑ Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P; et al. (2011). "GPIHBP1, an endothelial cell transporter for lipoprotein lipase". J Lipid Res. 52 (11): 1869–84. doi:10.1194/jlr.R018689. PMC 3196223. PMID 21844202.
- ↑ Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML; et al. (2009). "The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms". J Biol Chem. 284 (3): 1419–24. doi:10.1074/jbc.M808477200. PMC 3769808. PMID 19028676.
- ↑ Yoshida K, Shimizugawa T, Ono M, Furukawa H (2002). "Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase". J Lipid Res. 43 (11): 1770–2. PMID 12401877.
- ↑ Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH; et al. (2009). "Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans". J Clin Invest. 119 (1): 70–9. doi:10.1172/JCI37118. PMC 2613476. PMID 19075393.
- ↑ Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K; et al. (2013). "Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids". Arterioscler Thromb Vasc Biol. 33 (7): 1706–13. doi:10.1161/ATVBAHA.113.301397. PMID 23661675.
- ↑ Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK (2008). "LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies". Physiol Rev. 88 (3): 887–918. doi:10.1152/physrev.00033.2007. PMC 2744109. PMID 18626063.
- ↑ Garvie CW, Fraley CV, Elowe NH, Culyba EK, Lemke CT, Hubbard BK; et al. (2016). "Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor". Protein Sci. 25 (11): 2018–2027. doi:10.1002/pro.3019. PMC 5079255. PMID 27534510.
- ↑ Marais AD, Kim JB, Wasserman SM, Lambert G (2015). "PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels". Pharmacol Ther. 145: 58–66. doi:10.1016/j.pharmthera.2014.07.004. PMID 25046268.
- ↑ Fazio S, Sidoli A, Vivenzio A, Maietta A, Giampaoli S, Menotti A; et al. (1991). "A form of familial hypobetalipoproteinaemia not due to a mutation in the apolipoprotein B gene". J Intern Med. 229 (1): 41–7. PMID 1995762.
- ↑ Charcosset M, Sassolas A, Peretti N, Roy CC, Deslandres C, Sinnett D; et al. (2008). "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein". Mol Genet Metab. 93 (1): 74–84. doi:10.1016/j.ymgme.2007.08.120. PMID 17945526.
- ↑ Burnett JR, Bell DA, Hooper AJ, Hegele RA (2015). "Clinical utility gene card for: Familial hypobetalipoproteinaemia (APOB)--Update 2014". Eur J Hum Genet. 23 (6). doi:10.1038/ejhg.2014.225. PMC 4795065. PMID 25335495.
- ↑ Tarugi P, Lonardo A, Gabelli C, Sala F, Ballarini G, Cortella I; et al. (2001). "Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene". J Lipid Res. 42 (10): 1552–61. PMID 11590210.
- ↑ Tanoli T, Yue P, Yablonskiy D, Schonfeld G (2004). "Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity". J Lipid Res. 45 (5): 941–7. doi:10.1194/jlr.M300508-JLR200. PMID 14967820.
- ↑ Peretti N, Roy CC, Sassolas A, Deslandres C, Drouin E, Rasquin A; et al. (2009). "Chylomicron retention disease: a long term study of two cohorts". Mol Genet Metab. 97 (2): 136–42. doi:10.1016/j.ymgme.2009.02.003. PMID 19285442.
- ↑ Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J; et al. (2010). "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. 5: 24. doi:10.1186/1750-1172-5-24. PMC 2956717. PMID 20920215.
- ↑ Welty FK, Lichtenstein AH, Barrett PH, Dolnikowski GG, Ordovas JM, Schaefer EJ (1997). "Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes". Arterioscler Thromb Vasc Biol. 17 (5): 881–8. PMID 9157951.
- ↑ Elias N, Patterson BW, Schonfeld G (1999). "Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia". Arterioscler Thromb Vasc Biol. 19 (11): 2714–21. PMID 10559016.
- ↑ Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C; et al. (2010). "Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia". N Engl J Med. 363 (23): 2220–7. doi:10.1056/NEJMoa1002926. PMC 3008575. PMID 20942659.
- ↑ Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G; et al. (2012). "Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization". J Clin Endocrinol Metab. 97 (7): E1266–75. doi:10.1210/jc.2012-1298. PMID 22659251.