Hypobetalipoproteinemia: Difference between revisions

Jump to navigation Jump to search
 
(62 intermediate revisions by 3 users not shown)
Line 1: Line 1:
__NOTOC__
__NOTOC__
{{Hypolipoproteinemia}}
{{SI}}
'''To view Lipoprotein Disorders Main Page [[ Lipoprotein disorders| Click here]]'''<br>
'''To view Hypolipoproteinemia Main Page [[ Hypolipoproteinemia | Click here]]''' <br>
{{CMG}} {{AE}} {{AKI}}
{{CMG}} {{AE}} {{AKI}}


Line 6: Line 8:


==Overview==
==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 less than 5th percentile. Clinical manifestations can vary from being totally asymptomatic to multiple features of vitamin deficiencies. Patients with severe disease present with diarrhea, vomiting and fat malabsorption. Clinical symptoms of vitamin E are seen early in the course of the disease as the amount of vitamin E is parallel to the total lipid level in the body. Failure to diagnose and to initiate timely vitamin supplementation in patients results in the development of neurological symptoms similar to spinocerebellar degeneration. The mutations causing low LDL levels are widely studied as newer lipid lowering therapies are based on similar mechanisms of these diseases.
These are a set of diseases caused my [[mutations]] in [[genes]] involved in [[Triglyceride|triglyceride(TG)]], [[cholesterol]] transport and [[metabolism]]. These diseases primarily cause low plasma [[LDL Cholesterol|LDL C]] and [[triglyceride]] levels less than in the 5th percentile of normal population. Clinical manifestations can vary from being completely asymptomatic to multiple features of [[vitamin]] deficiencies, and fat [[malabsorption]]. Clinical symptoms of [[vitamin E]] are seen early in the course of the disease as the amount of [[vitamin E]] is parallel to the total [[lipid]] level in the body. Failure to diagnose and to initiate timely [[vitamin]] supplementation results in the development of neurological symptoms. The mutations causing low [[LDL]] levels are widely studied as newer lipid lowering therapies are based on similar mechanisms of these diseases.


==Historical Perspective==
==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<ref name="pmid13745738">{{cite journal| author=SALT HB, WOLFF OH, LLOYD JK, FOSBROOKE AS, CAMERON AH, HUBBLE DV| title=On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea. | journal=Lancet | year= 1960 | volume= 2 | issue= 7146 | pages= 325-9 | pmid=13745738 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13745738  }} </ref>.
*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 familial [[homozygous]] hypobetalipoproteinemia from [[abetalipoproteinemia]].<ref name="pmid13745738">{{cite journal| author=SALT HB, WOLFF OH, LLOYD JK, FOSBROOKE AS, CAMERON AH, HUBBLE DV| title=On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea. | journal=Lancet | year= 1960 | volume= 2 | issue= 7146 | pages= 325-9 | pmid=13745738 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13745738  }} </ref>
*
*In 1961, Anderson suggested failure of formation of [[chylomicron]] and [[lipid]] [[malabsorption]] as a cause of severe [[steatorrhea]] in children. Patients did not have [[acanthocytes]] on the [[peripheral smear]] and neuro-ocular symptoms like familial hypobetalipoproteinemia. <ref name="pmid13861205">{{cite journal| author=ANDERSON CM, TOWNLEY RR, JOHANSEN P| title=Unusual causes of steatorrhoea in infancy and childhood. | journal=Med J Aust | year= 1961 | volume= 48(2) | issue=  | pages= 617-22 | pmid=13861205 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13861205  }} </ref>
*Roy in 1987 and Kane in 1989 described chylomicron retention disease. <ref name="pmid3792776">{{cite journal| author=Roy CC, Levy E, Green PH, Sniderman A, Letarte J, Buts JP et al.| title=Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B. Chylomicron retention disease. | journal=Gastroenterology | year= 1987 | volume= 92 | issue= 2 | pages= 390-9 | pmid=3792776 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3792776  }} </ref>
*In 2003, the mutation in SAR1B gene was identified by jones.<ref name="pmid12692552">{{cite journal| author=Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S et al.| title=Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. | journal=Nat Genet | year= 2003 | volume= 34 | issue= 1 | pages= 29-31 | pmid=12692552 | doi=10.1038/ng1145 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12692552  }} </ref>
*Conklin identified the [[ANGPTL3]] gene in 1999 and its function of inhibiting [[lipoprotein lipase]] was established in 2013 by Arca.<ref name="pmid23839332">{{cite journal| author=Arca M, Minicocci I, Maranghi M| title=The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism. | journal=Curr Opin Lipidol | year= 2013 | volume= 24 | issue= 4 | pages= 313-20 | pmid=23839332 | doi=10.1097/MOL.0b013e3283630cf0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23839332  }} </ref><ref name="pmid10644446">{{cite journal| author=Conklin D, Gilbertson D, Taft DW, Maurer MF, Whitmore TE, Smith DL et al.| title=Identification of a mammalian angiopoietin-related protein expressed specifically in liver. | journal=Genomics | year= 1999 | volume= 62 | issue= 3 | pages= 477-82 | pmid=10644446 | doi=10.1006/geno.1999.6041 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10644446  }} </ref>


==Pathophysiology==
==Pathophysiology==


===Pathogenesis===
===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.
Hypobetalipoproteinemias are caused by mutations in the genes involved in [[triglyceride]] [[transport]] and [[metabolism]].
*Apolipoprotein B is the major carrier for triglycerides and cholesterol from the intestine and liver to the periphery.
*[[Cholesterol]] and [[triglycerides]] are insoluble in the [[plasma]] and they require a [[transport protein]] in the form of [[apolipoprotein B]]. These [[lipoproteins]] transport [[cholesterol]] and [[trigylcerides]] in spherical particles with [[cholesterol esters]] and [[triglyceride]] forming the central core.
*Apo B exits in two forms, Apo B48 and Apo B100.
*[[Apolipoprotein B]] is the major carrier for [[triglycerides]] and [[cholesterol]] from the [[intestine]] and [[liver]] to the periphery.
*[[Apolipoprotein B]] exits in two forms: [[apolipoprotein B]]48 and [[apolipoprotein B]]100.




{{Family tree/start}}
{{Family tree/start}}
{{Family tree | | | | A01 |-|A02| |A01= APOB gene is responsible for the productoion of Apo B48 in intestine which is critical for the formation and secretion of chylomicrons<ref name="pmid25974693">{{cite journal| author=Dash S, Xiao C, Morgantini C, Lewis GF| title=New Insights into the Regulation of Chylomicron Production. | journal=Annu Rev Nutr | year= 2015 | volume= 35 | issue=  | pages= 265-94 | pmid=25974693 | doi=10.1146/annurev-nutr-071714-034338 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25974693  }} </ref> , and Apo B100 in the liver which is released into circulation as VLDL | A02= 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.<ref name="pmid26073401">{{cite journal| author=Di Leo E, Eminoglu T, Magnolo L, Bolkent MG, Tümer L, Okur I et al.| title=The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 400-5 | pmid=26073401 | doi=10.1016/j.jacl.2015.01.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073401  }} </ref>.}}
{{Family tree | | | | A01 |-|A02| |A01= APOB gene is responsible for the production of Apo B48 in [[intestine]] which is critical for the formation and secretion of [[chylomicrons]]<ref name="pmid25974693">{{cite journal| author=Dash S, Xiao C, Morgantini C, Lewis GF| title=New Insights into the Regulation of Chylomicron Production. | journal=Annu Rev Nutr | year= 2015 | volume= 35 | issue=  | pages= 265-94 | pmid=25974693 | doi=10.1146/annurev-nutr-071714-034338 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25974693  }} </ref> , and Apo B100 in the [[liver]] which is released into circulation as [[VLDL]]. | A02= Mutation in the APOB gene affects the translation of [[mRNA]] of [[apolipoprotein B]] causing familial hypobetalipoproteinemia. The severity of clinical phenotype in familial hypobetalipoproteinemia depends on length of trucated Apo B and zygosity.<ref name="pmid26073401">{{cite journal| author=Di Leo E, Eminoglu T, Magnolo L, Bolkent MG, Tümer L, Okur I et al.| title=The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 400-5 | pmid=26073401 | doi=10.1016/j.jacl.2015.01.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073401  }} </ref>}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | B01 |-| B02| |B01= 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<ref name="pmid10940349">{{cite journal| author=Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR| title=The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. | journal=Annu Rev Nutr | year= 2000 | volume= 20 | issue=  | pages= 663-97 | pmid=10940349 | doi=10.1146/annurev.nutr.20.1.663 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10940349  }} </ref>.|B02= 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<ref name="pmid15017362">{{cite journal| author=Shoulders CC, Stephens DJ, Jones B| title=The intracellular transport of chylomicrons requires the small GTPase, Sar1b. | journal=Curr Opin Lipidol | year= 2004 | volume= 15 | issue= 2 | pages= 191-7 | pmid=15017362 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15017362  }} </ref>. Mutation in Sar1b causes chylomicron retention disease<ref name="pmid12692552">{{cite journal| author=Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S et al.| title=Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. | journal=Nat Genet | year= 2003 | volume= 34 | issue= 1 | pages= 29-31 | pmid=12692552 | doi=10.1038/ng1145 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12692552  }} </ref>.}}
{{Family tree | | | | B01 |-| B02| |B01= MTP transfers [[triglycerides]] from [[cytsol]] onto nacent [[apolipoprotein B]] in [[endoplasmic reticulum]] which is required for assembly and secretion of [[VLDL]] and [[chylomicrons]]. [[Mutation]] in MTP causes [[abetalipoproteinemia]].<ref name="pmid10940349">{{cite journal| author=Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR| title=The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. | journal=Annu Rev Nutr | year= 2000 | volume= 20 | issue=  | pages= 663-97 | pmid=10940349 | doi=10.1146/annurev.nutr.20.1.663 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10940349  }} </ref>|B02= In [[Apo B]]48 associated [[chylomicrons]], transport of [[proteins]] 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 SAR1B is a major part of the protein essential for this intra cellular transport.<ref name="pmid15017362">{{cite journal| author=Shoulders CC, Stephens DJ, Jones B| title=The intracellular transport of chylomicrons requires the small GTPase, Sar1b. | journal=Curr Opin Lipidol | year= 2004 | volume= 15 | issue= 2 | pages= 191-7 | pmid=15017362 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15017362  }} </ref> Mutation in Sar1b causes chylomicron retention disease.<ref name="pmid12692552">{{cite journal| author=Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S et al.| title=Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. | journal=Nat Genet | year= 2003 | volume= 34 | issue= 1 | pages= 29-31 | pmid=12692552 | doi=10.1038/ng1145 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12692552  }} </ref>}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | C01 | | | |C01= 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)<ref name="pmid21844202">{{cite journal| author=Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P et al.| title=GPIHBP1, an endothelial cell transporter for lipoprotein lipase. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 11 | pages= 1869-84 | pmid=21844202 | doi=10.1194/jlr.R018689 | pmc=3196223 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21844202  }} </ref>, a transporter for lipoprotien lipase triglycerides are hydrolysed to form free fatty acids and glycerol }}
{{Family tree | | | | C01 | | | |C01= 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)<ref name="pmid21844202">{{cite journal| author=Young SG, Davies BS, Voss CV, Gin P, Weinstein MM, Tontonoz P et al.| title=GPIHBP1, an endothelial cell transporter for lipoprotein lipase. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 11 | pages= 1869-84 | pmid=21844202 | doi=10.1194/jlr.R018689 | pmc=3196223 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21844202  }} </ref>, a transporter for [[lipoprotien lipase]], [[triglycerides]] are hydrolysed to form [[free fatty acids]] and [[glycerol]].}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | D01 |-|D02| |D01= This results in the formation of VLDL remnant( Intermediate density lipoprotein) and chylomicron remnants
{{Family tree | | | | D01 |-|D02| |D01= 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<ref name="pmid19028676">{{cite journal| author=Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML et al.| title=The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. | journal=J Biol Chem | year= 2009 | volume= 284 | issue= 3 | pages= 1419-24 | pmid=19028676 | doi=10.1074/jbc.M808477200 | pmc=3769808 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19028676  }} </ref>.<ref name="pmid12401877">{{cite journal| author=Yoshida K, Shimizugawa T, Ono M, Furukawa H| title=Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. | journal=J Lipid Res | year= 2002 | volume= 43 | issue= 11 | pages= 1770-2 | pmid=12401877 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12401877  }} </ref>| D02= Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia <ref name="pmid19075393">{{cite journal| author=Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH et al.| title=Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. | journal=J Clin Invest | year= 2009 | volume= 119 | issue= 1 | pages= 70-9 | pmid=19075393 | doi=10.1172/JCI37118 | pmc=2613476 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19075393  }} </ref><ref name="pmid23661675">{{cite journal| author=Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K et al.| title=Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. | journal=Arterioscler Thromb Vasc Biol | year= 2013 | volume= 33 | issue= 7 | pages= 1706-13 | pmid=23661675 | doi=10.1161/ATVBAHA.113.301397 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23661675  }} </ref> .
The lipases are inhibited by [[Angiopoietin-like protein 3]] (ANGPTL3) thereby decreasing the [[triglyceride]] and [[LDL]] C.<ref name="pmid19028676">{{cite journal| author=Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML et al.| title=The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. | journal=J Biol Chem | year= 2009 | volume= 284 | issue= 3 | pages= 1419-24 | pmid=19028676 | doi=10.1074/jbc.M808477200 | pmc=3769808 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19028676  }} </ref><ref name="pmid12401877">{{cite journal| author=Yoshida K, Shimizugawa T, Ono M, Furukawa H| title=Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. | journal=J Lipid Res | year= 2002 | volume= 43 | issue= 11 | pages= 1770-2 | pmid=12401877 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12401877  }} </ref>| D02= Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia.<ref name="pmid19075393">{{cite journal| author=Romeo S, Yin W, Kozlitina J, Pennacchio LA, Boerwinkle E, Hobbs HH et al.| title=Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. | journal=J Clin Invest | year= 2009 | volume= 119 | issue= 1 | pages= 70-9 | pmid=19075393 | doi=10.1172/JCI37118 | pmc=2613476 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19075393  }} </ref><ref name="pmid23661675">{{cite journal| author=Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K et al.| title=Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. | journal=Arterioscler Thromb Vasc Biol | year= 2013 | volume= 33 | issue= 7 | pages= 1706-13 | pmid=23661675 | doi=10.1161/ATVBAHA.113.301397 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23661675  }} </ref>  
}}
}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | E01 | | | |E01= 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<ref name="pmid18626063">{{cite journal| author=Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK| title=LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. | journal=Physiol Rev | year= 2008 | volume= 88 | issue= 3 | pages= 887-918 | pmid=18626063 | doi=10.1152/physrev.00033.2007 | pmc=2744109 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18626063  }} </ref>}}
{{Family tree | | | | E01 | | | |E01= IDL on further removal of [[triglycerides]] forms a [[cholesterol ester]] rich [[LDL]] C. The [[chylomicron]] and [[VLDL]] remnants removal is [[apolipoprotein E]] dependent via the [[LDL receptor]]s and [[LDL]] receptor related protiens.<ref name="pmid18626063">{{cite journal| author=Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK| title=LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. | journal=Physiol Rev | year= 2008 | volume= 88 | issue= 3 | pages= 887-918 | pmid=18626063 | doi=10.1152/physrev.00033.2007 | pmc=2744109 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18626063  }} </ref>}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | F01 |-| F02| |F01=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)<ref name="pmid27534510">{{cite journal| author=Garvie CW, Fraley CV, Elowe NH, Culyba EK, Lemke CT, Hubbard BK et al.| title=Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor. | journal=Protein Sci | year= 2016 | volume= 25 | issue= 11 | pages= 2018-2027 | pmid=27534510 | doi=10.1002/pro.3019 | pmc=5079255 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27534510  }} </ref>.|F02= Mutation causing loss of function of the enzyme causes low LDL C levels, and gain of function mutations are associated with familial hypercholesterolemia<ref name="pmid25046268">{{cite journal| author=Marais AD, Kim JB, Wasserman SM, Lambert G| title=PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels. | journal=Pharmacol Ther | year= 2015 | volume= 145 | issue=  | pages= 58-66 | pmid=25046268 | doi=10.1016/j.pharmthera.2014.07.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25046268  }} </ref>.}}
{{Family tree | | | | F01 |-| F02| |F01= [[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]]).<ref name="pmid27534510">{{cite journal| author=Garvie CW, Fraley CV, Elowe NH, Culyba EK, Lemke CT, Hubbard BK et al.| title=Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor. | journal=Protein Sci | year= 2016 | volume= 25 | issue= 11 | pages= 2018-2027 | pmid=27534510 | doi=10.1002/pro.3019 | pmc=5079255 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27534510  }} </ref>|F02= Mutation causing loss of function of the enzyme causes low [[LDL]] C levels, and gain of function mutations are associated with familial hypercholesterolemia.<ref name="pmid25046268">{{cite journal| author=Marais AD, Kim JB, Wasserman SM, Lambert G| title=PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels. | journal=Pharmacol Ther | year= 2015 | volume= 145 | issue=  | pages= 58-66 | pmid=25046268 | doi=10.1016/j.pharmthera.2014.07.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25046268  }} </ref>}}
{{Family tree/end}}
{{Family tree/end}}


===Genetics===
===Genetics===
 
The genetic defect, transmission and the result of the mutation in various diseases is described below:
{| class="wikitable"
{| class="wikitable"
!
!
Line 50: Line 56:
|-
|-
|Inheritance
|Inheritance
|Autosomal Codominant
|[[Autosomal codominant]]
|Autosomal codominant
|[[Autosomal codominant]]
|Autosomal Recessive
|[[Autosomal recessive]]
|Autosomal Codominant
|[[Autosomal codominant]]
|-
|-
|Defective Gene
|Defective Gene
|APOB gene on chromosome locus 2p23-24
|[[APOB]] gene on [[chromosome]] locus 2p23-24
|APOB gene  
|[[APOB]] gene  
|SAR1B gene
|[[SAR1B]] gene on [[chromosome]] 5q31
|ANGPTL3 gene on chromosome 1<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>
|[[ANGPTL3]] gene on [[chromosome]] 1<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
|Absence of Apo B  
|Absence of [[apolipoprotein B]] results in  absent plasma [[VLDL]], [[triglyceride]] and [[LDL]] C
results in  absent plasma  
|
 
*Truncated [[apolipoprotein B]] protein is formed which affects the lipidation and secretion of the [[apolipoprotein B]] particles.
VLDL, TG and LDL C.
*These poorly lipidated particles are  are rapidly [[catabolized]].
|Truncated Apo B protiens are formed
|Intracellular transport of [[chylomicrons]] is affected ,resulting in the accumulation of [[lipids]] in the cells of the [[intestine]] and [[liver]].<ref name="pmid17945526">{{cite journal| author=Charcosset M, Sassolas A, Peretti N, Roy CC, Deslandres C, Sinnett D et al.| title=Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein. | journal=Mol Genet Metab | year= 2008 | volume= 93 | issue= 1 | pages= 74-84 | pmid=17945526 | doi=10.1016/j.ymgme.2007.08.120 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17945526  }} </ref>
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<ref name="pmid17945526">{{cite journal| author=Charcosset M, Sassolas A, Peretti N, Roy CC, Deslandres C, Sinnett D et al.| title=Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein. | journal=Mol Genet Metab | year= 2008 | volume= 93 | issue= 1 | pages= 74-84 | pmid=17945526 | doi=10.1016/j.ymgme.2007.08.120 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17945526  }} </ref>.
|Loss of function mutation results in the failure of inhibition of Lipoprotien lipase, leading to low LDL, VLDL and HDL levels.
|Loss of function mutation results in the failure of inhibition of Lipoprotien lipase, leading to low LDL, VLDL and HDL levels.
|}
|}
*Less common causes of FHBL are mutations in PCSK9 and ANGPTL3 S17X<ref name="pmid22659251">{{cite journal| author=Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G et al.| title=Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 7 | pages= E1266-75 | pmid=22659251 | doi=10.1210/jc.2012-1298 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22659251  }} </ref>.
*Less common causes of familial hypobetalipoproteinemia are mutations in [[PCSK9]] and [[ANGPTL3]] [[S17X]].<ref name="pmid22659251">{{cite journal| author=Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G et al.| title=Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 7 | pages= E1266-75 | pmid=22659251 | doi=10.1210/jc.2012-1298 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22659251  }} </ref>  
*Mutations in loss of fucntion of PCSK9 do not cause any clinical symptoms but are shown to be associated with decreasing cardiovascular disease risk<ref name="pmid16554528">{{cite journal| author=Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH| title=Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. | journal=N Engl J Med | year= 2006 | volume= 354 | issue= 12 | pages= 1264-72 | pmid=16554528 | doi=10.1056/NEJMoa054013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16554528  }} </ref>.
*Mutations in loss of function of [[PCSK9]] do not cause any clinical symptoms but are shown to be associated with decreasing [[cardiovascular disease risk]].<ref name="pmid16554528">{{cite journal| author=Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH| title=Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. | journal=N Engl J Med | year= 2006 | volume= 354 | issue= 12 | pages= 1264-72 | pmid=16554528 | doi=10.1056/NEJMoa054013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16554528  }} </ref>
*Mutation in ANGPTL3 S17X causes low LDL C and TG levels along with reduction in plasma glucose level by increasing insulin sensitivity which is secondary to the increased lipoprotien lipase activity<ref name="pmid23661675">{{cite journal| author=Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K et al.| title=Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. | journal=Arterioscler Thromb Vasc Biol | year= 2013 | volume= 33 | issue= 7 | pages= 1706-13 | pmid=23661675 | doi=10.1161/ATVBAHA.113.301397 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23661675  }} </ref>.
*Mutation in [[ANGPTL3]] [[S17X]] causes low [[LDL]] C and [[triglyceride]] levels along with reduction in plasma [[glucose]] level by increasing [[insulin sensitivity]] which is secondary to the increased [[lipoprotien lipase]] activity.<ref name="pmid23661675">{{cite journal| author=Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K et al.| title=Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. | journal=Arterioscler Thromb Vasc Biol | year= 2013 | volume= 33 | issue= 7 | pages= 1706-13 | pmid=23661675 | doi=10.1161/ATVBAHA.113.301397 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23661675  }} </ref>


==Causes==
==Causes==
The following are the list of causes for primary hypobetalipoproteinemia.
The following are the list of causes of primary hypobetalipoproteinemia:
*Abetalipoproteinemia
*Abetalipoproteinemia
*Familial hypobetalipoproteinemia
*Familial hypobetalipoproteinemia
*Chylomicron Retention Disease
*Chylomicron retention disease
*PCSK9 deficiency
*PCSK9 deficiency
*Familial Combined Hypolipidemia
*Familial combined hypolipidemia


==Natural History, complications and Prognosis==
==Epidemiology and Demographics==
The prevalence of these diseases is as follows:<ref name="pmid26561704">{{cite journal |vauthors=De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Shapiro MD |title= |journal= |volume= |issue= |pages= |year= |pmid=26561704 |doi= |url=}}</ref>
{| class="wikitable"
{| class="wikitable"
!
!
!Homozygous Familial
!Prevalence
 
|-
|Abetalipoproteinemia
|<1:1,000,000
|-
|Familial
Hypobetalipoproteinemia
Hypobetalipoproteinemia
!Heterozygous Familial
|1:1000 – 1:3000
 
|-
Hypobetalipoproteinemia
|Chylomicron Retention  
!Chylomicron Retention
 
Disease
Disease
!Familial Combined
|Very rare
|-
|Familial Combined  
Hypolipidemia
Hypolipidemia
|Very rare
|-
|PCSK9 Deficiency
|Very rare
|}
==Natural History, complications and Prognosis==
{| class="wikitable"
!
!Homozygous Familial Hypobetalipoproteinemia
!Heterozygous Familial Hypobetalipoproteinemia
!Chylomicron Retention Disease
!Familial Combined Hypolipidemia
|-
|-
|Disease Course
|Disease Course
|Steatorrhea early in infancy and progression
|[[Steatorrhea]] early in [[infancy]] and progression to neurological symptoms which begin in the 1st or 2nd decade.
 
|Usually [[benign]], few patients may present with [[steatorrhea]].
to neurological symptoms which begin in the 1st or 2nd decade.
|Early onset of symptoms with [[diarrhea]] and [[failure to thrive]].
|Usually benign, few patients may
 
present with steatorrhea.
|Early onset of symptoms with
 
diarrhea and failure to thrive.
|Benign
|Benign
|-
|-
|Complications
|Complications
|Neurologic degeneration, Anemia, Blindness
|[[Neurologic degeneration]], [[Anemia]], [[Blindness]]
|Liver Cirrhosis,Hepatocellular carcinoma<ref name="pmid23723369">{{cite journal| author=Cefalù AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N et al.| title=A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. | journal=Arterioscler Thromb Vasc Biol | year= 2013 | volume= 33 | issue= 8 | pages= 2021-5 | pmid=23723369 | doi=10.1161/ATVBAHA.112.301101 | pmc=3870266 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23723369  }} </ref>
|
|Neurological symptoms with areflexia in the 1st decade, more severe symptoms like ataxia, myopathy and sensory neuropathy are seen with advancing age.<ref name="pmid2596948">{{cite journal| author=Lacaille F, Bratos M, Bouma ME, Jos J, Schmitz J, Rey J| title=[Anderson's disease. Clinical and morphologic study of 7 cases]. | journal=Arch Fr Pediatr | year= 1989 | volume= 46 | issue= 7 | pages= 491-8 | pmid=2596948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2596948  }} </ref>  
*[[Liver cirrhosis]], [[Hepatocellular carcinoma]].<ref name="pmid23723369">{{cite journal| author=Cefalù AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N et al.| title=A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. | journal=Arterioscler Thromb Vasc Biol | year= 2013 | volume= 33 | issue= 8 | pages= 2021-5 | pmid=23723369 | doi=10.1161/ATVBAHA.112.301101 | pmc=3870266 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23723369  }} </ref>
Retinopathy, poor bone mineralization.
|
*Neurological symptoms with [[areflexia]] in the 1st decade, more severe symptoms like [[ataxia]], [[myopathy]] and [[sensory neuropathy]] are seen with advancing age.<ref name="pmid2596948">{{cite journal| author=Lacaille F, Bratos M, Bouma ME, Jos J, Schmitz J, Rey J| title=[Anderson's disease. Clinical and morphologic study of 7 cases]. | journal=Arch Fr Pediatr | year= 1989 | volume= 46 | issue= 7 | pages= 491-8 | pmid=2596948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2596948  }} </ref>  
*[[Retinopathy]] and poor bone mineralization due to [[vitamin A]] and [[vitamin D]] deficiency.
|None
|None
|-
|-
|Prognosis
|Prognosis
|Early treatment has proven to show good prognosis. Without treatment it compromises the quality of life and shortens the life span<ref name="pmid18611256">{{cite journal| author=Zamel R, Khan R, Pollex RL, Hegele RA| title=Abetalipoproteinemia: two case reports and literature review. | journal=Orphanet J Rare Dis | year= 2008 | volume= 3 | issue=  | pages= 19 | pmid=18611256 | doi=10.1186/1750-1172-3-19 | pmc=2467409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18611256  }} </ref>.
|
*Poor [[prognosis]] when the diease manifests in early childhood.<ref name="pmid18611256">{{cite journal| author=Zamel R, Khan R, Pollex RL, Hegele RA| title=Abetalipoproteinemia: two case reports and literature review. | journal=Orphanet J Rare Dis | year= 2008 | volume= 3 | issue=  | pages= 19 | pmid=18611256 | doi=10.1186/1750-1172-3-19 | pmc=2467409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18611256  }} </ref>
*Excellent [[prognosis]] in moderate form without [[cytolysis]] and [[hepatic steatosis]].
 
|A familial syndrome of longevity has been observed in the benign forms of HBL and many patients live over the age of 85.<ref name="urlOrphanet: Hypobetalipoproteinemia">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=9290&Disease_Disease_Search_diseaseGroup=Hypobetalipoproteinemia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Hypobetalipoproteinemia&title=Hypobetalipoproteinemia&search=Disease_Search_Simple |title=Orphanet: Hypobetalipoproteinemia |format= |work= |accessdate=}}</ref>


|Few patients present with vitamin deficiency features which respond well to treatment.
|Poorly documented evidence on prognosis.<ref name="urlOrphanet: Chylomicron retention disease">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=998&Disease_Disease_Search_diseaseGroup=Hypobetalipoproteinemia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Chylomicron-retention-disease&title=Chylomicron-retention-disease&search=Disease_Search_Simple |title=Orphanet: Chylomicron retention disease |format= |work= |accessdate=}}</ref>
|Patients outcome is good with regular follow up and treatment.
|Good
|Good
|}
|}
Line 129: Line 148:
==Diagnosis==
==Diagnosis==


===History and Physical===
===History, Symptoms and Physical Examination===
Hypobetalipoproteinemias present with varying severity of similar symptoms based on the type of mutation as follows:
 
{| class="wikitable"
{| class="wikitable"
!
!
Line 142: Line 163:
|-
|-
|Age of Presentation
|Age of Presentation
|Infancy
|[[Infancy]]
|Asymptomatic
|Asymptomatic
|2months to 1 year
|2 months to 1 year
|Asymptomatic
|Asymptomatic
|-
|-
|Clinical Presentation
|History and Symptoms
|
|
*Similar to abetalipoproteinemia.
*Similar to [[abetalipoproteinemia]]
*Steatorrhea, Failure to Thrive.
*[[Steatorrhea]], [[failure to thrive]]
*Symptoms progress without treatment with vitamin E to reduced visual acuity, ataxia, dysarthria, loss of vibration and proprioception and areflexia as the posterior columns are affected.
*Without [[vitamin E]] replacement symptoms progress and include reduced [[visual acuity]], [[ataxia]], [[dysarthria]], [[loss of vibration]] and [[proprioception]] and [[areflexia]] as the [[posterior columns]] are affected
*Retinal Degeneration
*Essential fatty acid deficiency
|
|
*Patients are asymptomatic, malabsorption can occur in patients with short trucated apo B forming mutations<ref name="pmid11590210">{{cite journal| author=Tarugi P, Lonardo A, Gabelli C, Sala F, Ballarini G, Cortella I et al.| title=Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene. | journal=J Lipid Res | year= 2001 | volume= 42 | issue= 10 | pages= 1552-61 | pmid=11590210 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11590210  }} </ref>.
*Patients are asymptomatic, [[malabsorption]] can occur in patients with short trucated [[apolipoprotein B]] forming mutations<ref name="pmid11590210">{{cite journal| author=Tarugi P, Lonardo A, Gabelli C, Sala F, Ballarini G, Cortella I et al.| title=Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene. | journal=J Lipid Res | year= 2001 | volume= 42 | issue= 10 | pages= 1552-61 | pmid=11590210 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11590210  }} </ref>  
*Common feature is hepatic steatosis<ref name="pmid14967820">{{cite journal| author=Tanoli T, Yue P, Yablonskiy D, Schonfeld G| title=Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. | journal=J Lipid Res | year= 2004 | volume= 45 | issue= 5 | pages= 941-7 | pmid=14967820 | doi=10.1194/jlr.M300508-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14967820  }} </ref>.
*Common feature is [[hepatic steatosis]]<ref name="pmid14967820">{{cite journal| author=Tanoli T, Yue P, Yablonskiy D, Schonfeld G| title=Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. | journal=J Lipid Res | year= 2004 | volume= 45 | issue= 5 | pages= 941-7 | pmid=14967820 | doi=10.1194/jlr.M300508-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14967820  }} </ref>
|
|
*Diarrhea, steatorrhea, abdominal distention, and failure to thrive, neurological symptoms manifest if vitamin E supplementation is not initiated<ref name="pmid19285442">{{cite journal| author=Peretti N, Roy CC, Sassolas A, Deslandres C, Drouin E, Rasquin A et al.| title=Chylomicron retention disease: a long term study of two cohorts. | journal=Mol Genet Metab | year= 2009 | volume= 97 | issue= 2 | pages= 136-42 | pmid=19285442 | doi=10.1016/j.ymgme.2009.02.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19285442  }} </ref><ref name="pmid20920215">{{cite journal| author=Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J et al.| title=Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. | journal=Orphanet J Rare Dis | year= 2010 | volume= 5 | issue=  | pages= 24 | pmid=20920215 | doi=10.1186/1750-1172-5-24 | pmc=2956717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20920215  }} </ref>.
*[[Diarrhea]], [[steatorrhea]], [[abdominal distention]], and [[failure to thrive]], neurological symptoms manifest if [[vitamin E]] supplementation is not initiated.<ref name="pmid19285442">{{cite journal| author=Peretti N, Roy CC, Sassolas A, Deslandres C, Drouin E, Rasquin A et al.| title=Chylomicron retention disease: a long term study of two cohorts. | journal=Mol Genet Metab | year= 2009 | volume= 97 | issue= 2 | pages= 136-42 | pmid=19285442 | doi=10.1016/j.ymgme.2009.02.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19285442  }} </ref><ref name="pmid20920215">{{cite journal| author=Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J et al.| title=Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. | journal=Orphanet J Rare Dis | year= 2010 | volume= 5 | issue=  | pages= 24 | pmid=20920215 | doi=10.1186/1750-1172-5-24 | pmc=2956717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20920215  }} </ref>
*Essential fatty acid deficiency.
*Essential fatty acid deficiency.
|
|
*Normal health<ref name="pmid22659251">{{cite journal| author=Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G et al.| title=Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 7 | pages= E1266-75 | pmid=22659251 | doi=10.1210/jc.2012-1298 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22659251  }} </ref>
*Normal health<ref name="pmid22659251">{{cite journal| author=Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G et al.| title=Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 7 | pages= E1266-75 | pmid=22659251 | doi=10.1210/jc.2012-1298 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22659251  }} </ref>
   
|-
|Physical Examination
|
*[[Growth Retardation]]
*[[Malnutrition]]
*[[Retinal degeneration]] changes
*[[Hepatomegaly]]
*[[Truncal Ataxia]]
*[[Muscle weakness]] and [[atrophy]]
*Diminished [[deep tendon reflexes]]
*Loss of [[vibration sense]] and [[proprioception]]
|[[Hepatomegaly]]
|
*[[Growth Retardation]]
*[[Malnutrition]]
*[[Retinal degeneration]] changes
*[[Hepatomegaly]]
*[[Truncal Ataxia]]
*[[Muscle weakness]] and [[atrophy]]
*Diminished [[deep tendon reflexes]]
*Loss of [[vibration sense]] and [[proprioception]]


|Normal Physical Exam
|}
|}


===Laboratory Results===
===Laboratory Results===
Definitive gold standard for diagnosis is [[gene sequencing]] for [[APOB]], [[MTTP]], [[SAR1B]], [[ANGPTL3]] to see the exact mutation.
Laboratory findings consistent with the diagnosis of hypobetalipoproteinemias include as follows:
{| class="wikitable"
{| class="wikitable"
!
!
Line 178: Line 220:
Hypolipidemia
Hypolipidemia
|-
|-
|Lipid analysis
|[[Lipid analysis]]
|
|
*ApoB <5th percentile  
*[[ApoB]] <5th percentile  
*LDL-C between 20- 50 mg/dL<ref name="pmid24288038">{{cite journal| author=Lee J, Hegele RA| title=Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. | journal=J Inherit Metab Dis | year= 2014 | volume= 37 | issue= 3 | pages= 333-9 | pmid=24288038 | doi=10.1007/s10545-013-9665-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24288038  }} </ref>
*[[LDL]]-C between 20- 50 mg/dL<ref name="pmid24288038">{{cite journal| author=Lee J, Hegele RA| title=Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. | journal=J Inherit Metab Dis | year= 2014 | volume= 37 | issue= 3 | pages= 333-9 | pmid=24288038 | doi=10.1007/s10545-013-9665-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24288038  }} </ref>
|
|
*LDL C is one third of normal value and not 50% of expected for age and sex.
*[[LDL]] C is one third of normal value and not 50% of expected for age and sex.
*Due to decreased production and increased catabolism of VLDL apo B-100<ref name="pmid9157951">{{cite journal| author=Welty FK, Lichtenstein AH, Barrett PH, Dolnikowski GG, Ordovas JM, Schaefer EJ| title=Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes. | journal=Arterioscler Thromb Vasc Biol | year= 1997 | volume= 17 | issue= 5 | pages= 881-8 | pmid=9157951 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9157951  }} </ref>. This causes decreased  secretion of triglycerides and low LDL  C levels<ref name="pmid10559016">{{cite journal| author=Elias N, Patterson BW, Schonfeld G| title=Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia. | journal=Arterioscler Thromb Vasc Biol | year= 1999 | volume= 19 | issue= 11 | pages= 2714-21 | pmid=10559016 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10559016  }} </ref>.
*Due to decreased production and increased catabolism of VLDL apo B-100.<ref name="pmid9157951">{{cite journal| author=Welty FK, Lichtenstein AH, Barrett PH, Dolnikowski GG, Ordovas JM, Schaefer EJ| title=Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes. | journal=Arterioscler Thromb Vasc Biol | year= 1997 | volume= 17 | issue= 5 | pages= 881-8 | pmid=9157951 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9157951  }} </ref> This causes decreased  secretion of triglycerides and low LDL  C levels.<ref name="pmid10559016">{{cite journal| author=Elias N, Patterson BW, Schonfeld G| title=Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia. | journal=Arterioscler Thromb Vasc Biol | year= 1999 | volume= 19 | issue= 11 | pages= 2714-21 | pmid=10559016 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10559016  }} </ref>
|
|
*LDL and HDL 50% of normal<ref name="pmid21235735">{{cite journal| author=Georges A, Bonneau J, Bonnefont-Rousselot D, Champigneulle J, Rabès JP, Abifadel M et al.| title=Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease). | journal=Orphanet J Rare Dis | year= 2011 | volume= 6 | issue=  | pages= 1 | pmid=21235735 | doi=10.1186/1750-1172-6-1 | pmc=3029219 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21235735  }} </ref>
*[[LDL]] and [[HDL]] 50% of normal<ref name="pmid21235735">{{cite journal| author=Georges A, Bonneau J, Bonnefont-Rousselot D, Champigneulle J, Rabès JP, Abifadel M et al.| title=Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease). | journal=Orphanet J Rare Dis | year= 2011 | volume= 6 | issue=  | pages= 1 | pmid=21235735 | doi=10.1186/1750-1172-6-1 | pmc=3029219 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21235735  }} </ref>
*Normal TG levels is the characteristic laboratory finding.
*Normal [[triglyceride]] levels is the characteristic laboratory finding.
|
|
*Homozygotes and compound heterozygotes show panhypolipidemia with LDL low TG and reduced HDL C<ref name="pmid20942659">{{cite journal| author=Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C et al.| title=Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 23 | pages= 2220-7 | pmid=20942659 | doi=10.1056/NEJMoa1002926 | pmc=3008575 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20942659  }} </ref>.
*[[Homozygotes]] and [[compound heterozygotes]] show panhypolipidemia with [[LDL]] low [[triglyceride]] and reduced [[HDL]] C.<ref name="pmid20942659">{{cite journal| author=Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C et al.| title=Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 23 | pages= 2220-7 | pmid=20942659 | doi=10.1056/NEJMoa1002926 | pmc=3008575 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20942659  }} </ref>
*Heterozygotes : Normal HDL, with LDL <25th percentile<ref name="pmid22659251">{{cite journal| author=Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G et al.| title=Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 7 | pages= E1266-75 | pmid=22659251 | doi=10.1210/jc.2012-1298 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22659251  }} </ref>.
*[[Heterozygotes]]: Normal [[HDL]], with [[LDL]] <25th percentile.<ref name="pmid22659251">{{cite journal| author=Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G et al.| title=Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 7 | pages= E1266-75 | pmid=22659251 | doi=10.1210/jc.2012-1298 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22659251  }} </ref>
|-
|-
|Other findings
|Other findings
|
|
*Low liposoluble vitamin level.
*Low fat soluble [[vitamin]] level.
 
*Mild elevation of [[LFT]]s
*Mild elevation of LFTs
*[[Acanthocytosis]]
*Acanthocytosis
|
|
*Mild elevation of LFTs
*Mild elevation of [[LFT]]s
|
|
*Failure of chylomicron secretion after a lipid rich meal.
*Failure of [[chylomicron]] secretion after a lipid rich meal.
*Low liposoluble vitamin level.
*Low fat soluble [[vitamin]] level.
*Endoscopy shows a typical white stippling.  
*[[Endoscopy]] shows a typical white stippling.  
*The enterocytes on biopsy show accumulations of large lipid droplets free in the cytoplasm as well as membrane-bound lipoprotein-sized structures.<ref name="pmid10521380">{{cite journal| author=Dannoura AH, Berriot-Varoqueaux N, Amati P, Abadie V, Verthier N, Schmitz J et al.| title=Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes. | journal=Arterioscler Thromb Vasc Biol | year= 1999 | volume= 19 | issue= 10 | pages= 2494-508 | pmid=10521380 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10521380  }} </ref>
*The [[enterocytes]] on [[biopsy]] show accumulations of large [[lipid]] droplets free in the [[cytoplasm]] as well as membrane-bound lipoprotein-sized structures.<ref name="pmid10521380">{{cite journal| author=Dannoura AH, Berriot-Varoqueaux N, Amati P, Abadie V, Verthier N, Schmitz J et al.| title=Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes. | journal=Arterioscler Thromb Vasc Biol | year= 1999 | volume= 19 | issue= 10 | pages= 2494-508 | pmid=10521380 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10521380  }} </ref>
*Mild elevation of liver transaminases.<ref name="pmid12960170">{{cite journal| author=Gusarova V, Brodsky JL, Fisher EA| title=Apolipoprotein B100 exit from the endoplasmic reticulum (ER) is COPII-dependent, and its lipidation to very low density lipoprotein occurs post-ER. | journal=J Biol Chem | year= 2003 | volume= 278 | issue= 48 | pages= 48051-8 | pmid=12960170 | doi=10.1074/jbc.M306898200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12960170  }} </ref>
*Mild elevation of [[liver transaminases]].<ref name="pmid12960170">{{cite journal| author=Gusarova V, Brodsky JL, Fisher EA| title=Apolipoprotein B100 exit from the endoplasmic reticulum (ER) is COPII-dependent, and its lipidation to very low density lipoprotein occurs post-ER. | journal=J Biol Chem | year= 2003 | volume= 278 | issue= 48 | pages= 48051-8 | pmid=12960170 | doi=10.1074/jbc.M306898200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12960170  }} </ref>
*Elevated Creatine Kinase
*Elevated [[creatine kinase]]
|
|
*None
*None
|}
|}
*Definitive gold standard for diagnosis is gene sequencing for APOB, MTTP, SAR1B, ANGPTL3 to see the exact mutation.
{| class="wikitable"
!
!Abetalipoprotienemia
!Familial Homozygous
Hypobetalipoproteinemia
!Familial Heterozygous
Hypobetalipoproteinemia
!PCSK9 deficiency
!Chylomicron Retention
Disease
!Familial Combined
Hypolipidemia
|-
|LDL C
|↓↓↓ (0)
|↓↓↓
|↓
|↓
|↓↓
|↓↓
|-
|Apo B
|↓↓↓( 0)
|↓↓↓
|↓
|N
|↓↓
|N
|-
|TG
|↓↓↓
|↓↓↓
|↓
|↓
|N
|↓
|-
|TC
|↓↓↓
|↓↓↓
|↓
|↓
|↓↓
|↓
|-
|HDL
|↓↓
|↓↓
|N
|N
|↓↓
|↓↓
|-
|VLDL
|↓↓
|↓↓
|↓
|N
|↓↓
|↓
|-
|Apo A1
|↓↓
|↓↓
|↓
|N
|↓↓
|N
|}
 
===Approach to patient with Low LDL C===
{{Family tree/start}}
{{Family tree | | | | | | A01 | | | |A01= Low [[LDL]] C <5th percentile}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | C01 | | | |C01= Rule out secondary causes of low [[LDL]]<br> [[Anemia]] <br> [[Criticial illness]]<br> [[Chronic inflammation]] <br> [[Chronic liver disease]] <br> [[Hyperthyroidism]] <br>[[Infection]] <br> [[Malabsorption]] <br>[[Malignancy]]}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | E01 | | | |E01= Once secondary causes are ruled out consider primary diseases based on analysis of [[Lipid profile]]}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | |,|-|-|-|^|-|-|.|}}
{{Family tree | |F01| | | | |F02| |F01= Normal [[Triglycerides]]| F02=Low [[Triglycerides]]}}
{{Family tree | | |!| | | | | | |!| | | | | | }}
{{Family tree | |G01| | | | |G02| | | |G01=Chlyomicron retention disease<br><SMALL>(Confirm with [[gene sequencing]])</SMALL>|G02=Screen the [[lipid profile]] of the patient's parents}}
{{Family tree | | | | | | | | | |!| | | | }}
{{Family tree | | | | | | | |,|-|^|-|-|.| }}
{{Family tree | | | | | | | H01| | |H02|H01=Normal Parental [[Lipid Profile]]|H02=If Parental [[Lipid Profile]] <50% of Normal on:<br>*[[LDL]]<br>*Total [[Cholesterol]]<br>*[[Triglycerides]]}}
{{Family tree | | | | | | | |!| | | | |!| }}
{{Family tree | | | | | | |I01| | |I02|I01=Abetalipoproteinemia<br><SMALL>(Confirm with [[gene sequencing]])</SMALL>|I02=Familial Homozygous hypobetalipoproteinemia<br><SMALL>(Confirm with [[gene sequencing]])</SMALL>}}
{{Family tree/end}}


==Treatment==
==Treatment==


===Medical Therapy===
===Medical Therapy===
*The main goals of management of FHBL include early diagnosis and early initiation of low fat diet and fat soluble vitamin supplementation in all symptomatic patients, with yearly follow up to assess the growth and nutritional status, diet compliance, neurological function, lipid panel.
*The mainstay of management of familial hypobetalipoproteinemia include early diagnosis and early initiation of [[low fat diet]] and [[fat soluble vitamin]] supplementation in all symptomatic patients, with yearly follow up to assess the growth and nutritional status, diet [[compliance]], neurological function, lipid panel.
*FHBL heterozygous patients with elevates liver transaminases regular imaging is recommended to monitor for progression of fatty liver to cirrhosis or hepatocellular carcinoma<ref name="pmid24751931">{{cite journal| author=Welty FK| title=Hypobetalipoproteinemia and abetalipoproteinemia. | journal=Curr Opin Lipidol | year= 2014 | volume= 25 | issue= 3 | pages= 161-8 | pmid=24751931 | doi=10.1097/MOL.0000000000000072 | pmc=4465983 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24751931  }} </ref>.
*FHBL heterozygous patients with elevated [[liver enzyme]], regular [[ultrasound]] imaging is recommended to monitor for progression of [[fatty liver]] to cirrhosis or hepatocellular carcinoma.<ref name="pmid24751931">{{cite journal| author=Welty FK| title=Hypobetalipoproteinemia and abetalipoproteinemia. | journal=Curr Opin Lipidol | year= 2014 | volume= 25 | issue= 3 | pages= 161-8 | pmid=24751931 | doi=10.1097/MOL.0000000000000072 | pmc=4465983 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24751931  }} </ref>
====Chylomicron Retention Disease Management====
====Chylomicron Retention Disease Management====
*If the patient is diagnosed early in the course of the disease diet modification and oral supplementation of vitamins improved outcomes<ref name="pmid20920215">{{cite journal| author=Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J et al.| title=Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. | journal=Orphanet J Rare Dis | year= 2010 | volume= 5 | issue=  | pages= 24 | pmid=20920215 | doi=10.1186/1750-1172-5-24 | pmc=2956717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20920215  }} </ref>.
*If the patient is diagnosed early in the course of the disease [[diet modification]] and oral supplementation of [[vitamins]] improved outcomes.<ref name="pmid20920215">{{cite journal| author=Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J et al.| title=Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. | journal=Orphanet J Rare Dis | year= 2010 | volume= 5 | issue=  | pages= 24 | pmid=20920215 | doi=10.1186/1750-1172-5-24 | pmc=2956717 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20920215  }} </ref>
**Low-fat diet
**[[Low-fat diet]]
**Vegetable oil enriched in essential fatty acids ± Enriched in medium-chain triglycerides.
**Vegetable oil enriched in essential fatty acids ± Enriched in medium-chain [[triglycerides]]
**Vitamin E (hydrosoluble form): 50 IU/kg/d
**[[Vitamin E]] (hydrosoluble form): 50 IU/kg/d
**Vitamin A: 15,000 IU/d (adjust according to plasma levels)
**[[Vitamin A]]: 15,000 IU/d (adjust according to plasma levels)
**Vitamin D: 800-1200 IU/kg/d or 100,000 IU/2 month if < 5 y old, and 600,000 IU/2 month if > 5 y old  
**[[Vitamin D]]: 800-1200 IU/kg/d or 100,000 IU/2 month if < 5 y old, and 600,000 IU/2 month if > 5 y old
**Vitamin K: 15 mg/week (adjust according to INR and plasma levels)
**[[Vitamin K]]: 15 mg/week (adjust according to [[INR]] and plasma levels)
*If patient is diagnosed late and with neurological disease combined oral and parental supplementation of fatty acids-intralipid 20%2g/kg/month, vitamin E 4 to 6 mg/kg/month,  vitamin A 500 IU/kg/month once a month is recommended.
*If patient is diagnosed late and with neurological disease, combined oral and parental supplementation is recommended:
**[[Fatty acids]]-intralipid 20% 2g/kg/month
**[[Vitamin E]] 4 to 6 mg/kg/month
**[[Vitamin A]] 500 IU/kg/month once a month is recommended
=====Follow up=====
=====Follow up=====
*Annual follow up to 10years to assess the growth and nutritional status, diet compliance, neurological function, lipid panel.
*Annual follow up to 10 years to assess the [[growth]] and nutritional status, diet compliance, neurological function, [[lipid profile]].
*Every 3year follow up to check bone mineral density, liver function with ultrasound, ophthalmologic exam for fundus, color vision, visual evoked potentials and electroretinography after the age of 10years.
*Every 3 year follow up to check [[bone mineral density]], [[liver function]] with [[ultrasound]], [[ophthalmologic exam]] for [[fundus]], color vision, visual evoked potentials and [[electroretinography]] after the age of 10years.
*Echocardiography in adulthood.
*[[Echocardiography]] in adulthood.


===Surgical Therapy===
===Surgical Therapy===

Latest revision as of 15:26, 4 April 2017

WikiDoc Resources for Hypobetalipoproteinemia

Articles

Most recent articles on Hypobetalipoproteinemia

Most cited articles on Hypobetalipoproteinemia

Review articles on Hypobetalipoproteinemia

Articles on Hypobetalipoproteinemia in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Hypobetalipoproteinemia

Images of Hypobetalipoproteinemia

Photos of Hypobetalipoproteinemia

Podcasts & MP3s on Hypobetalipoproteinemia

Videos on Hypobetalipoproteinemia

Evidence Based Medicine

Cochrane Collaboration on Hypobetalipoproteinemia

Bandolier on Hypobetalipoproteinemia

TRIP on Hypobetalipoproteinemia

Clinical Trials

Ongoing Trials on Hypobetalipoproteinemia at Clinical Trials.gov

Trial results on Hypobetalipoproteinemia

Clinical Trials on Hypobetalipoproteinemia at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Hypobetalipoproteinemia

NICE Guidance on Hypobetalipoproteinemia

NHS PRODIGY Guidance

FDA on Hypobetalipoproteinemia

CDC on Hypobetalipoproteinemia

Books

Books on Hypobetalipoproteinemia

News

Hypobetalipoproteinemia in the news

Be alerted to news on Hypobetalipoproteinemia

News trends on Hypobetalipoproteinemia

Commentary

Blogs on Hypobetalipoproteinemia

Definitions

Definitions of Hypobetalipoproteinemia

Patient Resources / Community

Patient resources on Hypobetalipoproteinemia

Discussion groups on Hypobetalipoproteinemia

Patient Handouts on Hypobetalipoproteinemia

Directions to Hospitals Treating Hypobetalipoproteinemia

Risk calculators and risk factors for Hypobetalipoproteinemia

Healthcare Provider Resources

Symptoms of Hypobetalipoproteinemia

Causes & Risk Factors for Hypobetalipoproteinemia

Diagnostic studies for Hypobetalipoproteinemia

Treatment of Hypobetalipoproteinemia

Continuing Medical Education (CME)

CME Programs on Hypobetalipoproteinemia

International

Hypobetalipoproteinemia en Espanol

Hypobetalipoproteinemia en Francais

Business

Hypobetalipoproteinemia in the Marketplace

Patents on Hypobetalipoproteinemia

Experimental / Informatics

List of terms related to Hypobetalipoproteinemia

To view Lipoprotein Disorders Main Page Click here
To view Hypolipoproteinemia Main Page Click here
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 less than in the 5th percentile of normal population. Clinical manifestations can vary from being completely asymptomatic to multiple features of vitamin deficiencies, and fat malabsorption. Clinical symptoms of vitamin E are seen early in the course of the disease as the amount of vitamin E is parallel to the total lipid level in the body. Failure to diagnose and to initiate timely vitamin supplementation results in the development of neurological symptoms. The mutations causing low LDL levels are widely studied as newer lipid lowering therapies are based on similar mechanisms of these diseases.

Historical Perspective

Pathophysiology

Pathogenesis

Hypobetalipoproteinemias are caused by mutations in the genes involved in triglyceride transport and metabolism.


 
 
 
APOB gene is responsible for the production of Apo B48 in intestine which is critical for the formation and secretion of chylomicrons[7] , and Apo B100 in the liver which is released into circulation as VLDL.
 
Mutation in the APOB gene affects the translation of mRNA of apolipoprotein B causing familial hypobetalipoproteinemia. The severity of clinical phenotype in familial hypobetalipoproteinemia depends on length of trucated Apo B and zygosity.[8]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MTP transfers triglycerides from cytsol onto nacent apolipoprotein B in endoplasmic reticulum which is required for assembly and secretion of VLDL and chylomicrons. Mutation in MTP causes abetalipoproteinemia.[9]
 
In Apo B48 associated chylomicrons, transport of proteins 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 SAR1B is a major part of the protein essential for this intra cellular transport.[10] Mutation in Sar1b causes chylomicron retention disease.[4]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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)[11], 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.[12][13]
 
Loss of function mutations or complete absence of ANGPTL3 gene cause familial combined hypolipidemia.[14][15]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDL on further removal of triglycerides forms a cholesterol ester rich LDL C. The chylomicron and VLDL remnants removal is apolipoprotein E dependent via the LDL receptors and LDL receptor related protiens.[16]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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).[17]
 
Mutation causing loss of function of the enzyme causes low LDL C levels, and gain of function mutations are associated with familial hypercholesterolemia.[18]
 
 

Genetics

The genetic defect, transmission and the result of the mutation in various diseases is described below:

Homozygous familial

hypobetalipoproteinemia(FHBL)

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 gene SAR1B gene on chromosome 5q31 ANGPTL3 gene on chromosome 1[19]
Pathophysiology Absence of apolipoprotein B results in absent plasma VLDL, triglyceride and LDL C Intracellular transport of chylomicrons is affected ,resulting in the accumulation of lipids in the cells of the intestine and liver.[20] 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 of primary hypobetalipoproteinemia:

  • Abetalipoproteinemia
  • Familial hypobetalipoproteinemia
  • Chylomicron retention disease
  • PCSK9 deficiency
  • Familial combined hypolipidemia

Epidemiology and Demographics

The prevalence of these diseases is as follows:[23]

Prevalence
Abetalipoproteinemia <1:1,000,000
Familial

Hypobetalipoproteinemia

1:1000 – 1:3000
Chylomicron Retention

Disease

Very rare
Familial Combined

Hypolipidemia

Very rare
PCSK9 Deficiency Very rare

Natural History, complications and Prognosis

Homozygous Familial Hypobetalipoproteinemia Heterozygous Familial Hypobetalipoproteinemia Chylomicron Retention Disease Familial Combined Hypolipidemia
Disease Course Steatorrhea early in infancy and progression to neurological symptoms which begin in the 1st or 2nd decade. Usually benign, few patients may present with steatorrhea. Early onset of symptoms with diarrhea and failure to thrive. Benign
Complications Neurologic degeneration, Anemia, Blindness None
Prognosis A familial syndrome of longevity has been observed in the benign forms of HBL and many patients live over the age of 85.[27] Poorly documented evidence on prognosis.[28] Good

Diagnosis

History, Symptoms and Physical Examination

Hypobetalipoproteinemias present with varying severity of similar symptoms based on the type of mutation as follows:

Homozygous Familial

Hypobetalipoproteinemia

Heterozygous Familial

Hypobetalipoproteinemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Age of Presentation Infancy Asymptomatic 2 months to 1 year Asymptomatic
History and Symptoms
Physical Examination Hepatomegaly Normal Physical Exam

Laboratory Results

Definitive gold standard for diagnosis is gene sequencing for APOB, MTTP, SAR1B, ANGPTL3 to see the exact mutation. Laboratory findings consistent with the diagnosis of hypobetalipoproteinemias include as follows:

Homozygous Familial

Hypobetalipoproteinemia

Heterozygous Familial

Hypobetalipoproteinemia

Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

Lipid analysis
  • LDL C is one third of normal value and not 50% of expected for age and sex.
  • Due to decreased production and increased catabolism of VLDL apo B-100.[34] This causes decreased secretion of triglycerides and low LDL C levels.[35]
Other findings
  • Mild elevation of LFTs
  • None
Abetalipoprotienemia Familial Homozygous

Hypobetalipoproteinemia

Familial Heterozygous

Hypobetalipoproteinemia

PCSK9 deficiency Chylomicron Retention

Disease

Familial Combined

Hypolipidemia

LDL C ↓↓↓ (0) ↓↓↓ ↓↓ ↓↓
Apo B ↓↓↓( 0) ↓↓↓ N ↓↓ N
TG ↓↓↓ ↓↓↓ N
TC ↓↓↓ ↓↓↓ ↓↓
HDL ↓↓ ↓↓ N N ↓↓ ↓↓
VLDL ↓↓ ↓↓ N ↓↓
Apo A1 ↓↓ ↓↓ N ↓↓ N

Approach to patient with Low LDL C

 
 
 
 
 
Low LDL C <5th percentile
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out secondary causes of low LDL
Anemia
Criticial illness
Chronic inflammation
Chronic liver disease
Hyperthyroidism
Infection
Malabsorption
Malignancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Once secondary causes are ruled out consider primary diseases based on analysis of Lipid profile
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal Triglycerides
 
 
 
 
Low Triglycerides
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chlyomicron retention disease
(Confirm with gene sequencing)
 
 
 
 
Screen the lipid profile of the patient's parents
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal Parental Lipid Profile
 
 
If Parental Lipid Profile <50% of Normal on:
*LDL
*Total Cholesterol
*Triglycerides
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abetalipoproteinemia
(Confirm with gene sequencing)
 
 
Familial Homozygous hypobetalipoproteinemia
(Confirm with gene sequencing)

Treatment

Medical Therapy

  • The mainstay of management of familial hypobetalipoproteinemia include early diagnosis and early initiation of low fat diet and fat soluble vitamin supplementation in all symptomatic patients, with yearly follow up to assess the growth and nutritional status, diet compliance, neurological function, lipid panel.
  • FHBL heterozygous patients with elevated liver enzyme, regular ultrasound imaging is recommended to monitor for progression of fatty liver to cirrhosis or hepatocellular carcinoma.[40]

Chylomicron Retention Disease Management

  • If the patient is diagnosed early in the course of the disease diet modification and oral supplementation of vitamins improved outcomes.[32]
    • Low-fat diet
    • Vegetable oil enriched in essential fatty acids ± Enriched in medium-chain triglycerides
    • Vitamin E (hydrosoluble form): 50 IU/kg/d
    • Vitamin A: 15,000 IU/d (adjust according to plasma levels)
    • Vitamin D: 800-1200 IU/kg/d or 100,000 IU/2 month if < 5 y old, and 600,000 IU/2 month if > 5 y old
    • Vitamin K: 15 mg/week (adjust according to INR and plasma levels)
  • If patient is diagnosed late and with neurological disease, combined oral and parental supplementation is recommended:
Follow up

Surgical Therapy

  • No surgical options are available.

Prevention

Primary Prevention

  • As the set of the diseases are rare there are no primary preventive measures.

Secondary Prevention

  • Regular follow up to look for complications and strict adherence to therapy has shown to prevent progression of the disease.

References

  1. 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.
  2. ANDERSON CM, TOWNLEY RR, JOHANSEN P (1961). "Unusual causes of steatorrhoea in infancy and childhood". Med J Aust. 48(2): 617–22. PMID 13861205.
  3. Roy CC, Levy E, Green PH, Sniderman A, Letarte J, Buts JP; et al. (1987). "Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B. Chylomicron retention disease". Gastroenterology. 92 (2): 390–9. PMID 3792776.
  4. 4.0 4.1 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.
  5. Arca M, Minicocci I, Maranghi M (2013). "The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism". Curr Opin Lipidol. 24 (4): 313–20. doi:10.1097/MOL.0b013e3283630cf0. PMID 23839332.
  6. Conklin D, Gilbertson D, Taft DW, Maurer MF, Whitmore TE, Smith DL; et al. (1999). "Identification of a mammalian angiopoietin-related protein expressed specifically in liver". Genomics. 62 (3): 477–82. doi:10.1006/geno.1999.6041. PMID 10644446.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 15.0 15.1 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 21.0 21.1 21.2 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.
  22. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH (2006). "Sequence variations in PCSK9, low LDL, and protection against coronary heart disease". N Engl J Med. 354 (12): 1264–72. doi:10.1056/NEJMoa054013. PMID 16554528.
  23. De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Shapiro MD. PMID 26561704. Missing or empty |title= (help)
  24. Cefalù AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N; et al. (2013). "A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia". Arterioscler Thromb Vasc Biol. 33 (8): 2021–5. doi:10.1161/ATVBAHA.112.301101. PMC 3870266. PMID 23723369.
  25. Lacaille F, Bratos M, Bouma ME, Jos J, Schmitz J, Rey J (1989). "[Anderson's disease. Clinical and morphologic study of 7 cases]". Arch Fr Pediatr. 46 (7): 491–8. PMID 2596948.
  26. Zamel R, Khan R, Pollex RL, Hegele RA (2008). "Abetalipoproteinemia: two case reports and literature review". Orphanet J Rare Dis. 3: 19. doi:10.1186/1750-1172-3-19. PMC 2467409. PMID 18611256.
  27. "Orphanet: Hypobetalipoproteinemia".
  28. "Orphanet: Chylomicron retention disease".
  29. 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.
  30. 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.
  31. 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.
  32. 32.0 32.1 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.
  33. Lee J, Hegele RA (2014). "Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management". J Inherit Metab Dis. 37 (3): 333–9. doi:10.1007/s10545-013-9665-4. PMID 24288038.
  34. 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.
  35. 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.
  36. Georges A, Bonneau J, Bonnefont-Rousselot D, Champigneulle J, Rabès JP, Abifadel M; et al. (2011). "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)". Orphanet J Rare Dis. 6: 1. doi:10.1186/1750-1172-6-1. PMC 3029219. PMID 21235735.
  37. 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.
  38. Dannoura AH, Berriot-Varoqueaux N, Amati P, Abadie V, Verthier N, Schmitz J; et al. (1999). "Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes". Arterioscler Thromb Vasc Biol. 19 (10): 2494–508. PMID 10521380.
  39. Gusarova V, Brodsky JL, Fisher EA (2003). "Apolipoprotein B100 exit from the endoplasmic reticulum (ER) is COPII-dependent, and its lipidation to very low density lipoprotein occurs post-ER". J Biol Chem. 278 (48): 48051–8. doi:10.1074/jbc.M306898200. PMID 12960170.
  40. Welty FK (2014). "Hypobetalipoproteinemia and abetalipoproteinemia". Curr Opin Lipidol. 25 (3): 161–8. doi:10.1097/MOL.0000000000000072. PMC 4465983. PMID 24751931.

Template:WikiDoc Sources Template:WH