Apolipoprotein A deficiency: Difference between revisions

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{{Hypolipoproteinemia}}{{Apolipoprotein A1 Deficiency}}
{{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}}
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==Overview==
==Overview==
Apolipoprotien deficiency is a rare monogenic metabolic disorder resulting in undetectable Apo A1 levels and HDL C less than 20mg/dl. APOA1 gene encodes for the ApoA1 protein which is the major component of HDL C. It is synthesized in the liver and released into the circulation as very small discoid pre beta HDL, which picks up free cholesterol from the cells and macrophages. Apo A1 also activates LCAT which esterifies free cholesterol on the surface of alpha 4 HDL resulting in the formation of cholesterol esters. These two initial steps in the reverse cholesterol are dependent on a functional ApoA1 which is affected in Apo A1 deficiency. Apo A1 synthesis is affected leading to very low HDL levels. Worldwide, 82 cases and a variety of mutations are reported. The biochemical phenotype is always low Apo A1 and low HDL C. Clinical phenotype varies with each mutation and is inconsistent. Symptomatic patients usually present with corneal opacities, xanthelasma and premature heart disease. Cardiovascular risk assessment and optimizing risk factors has an important role in the management.
[[Apolipoprotien A1]] deficiency is a rare monogenic metabolic disorder resulting in undetectable [[Apo A1]] levels and [[HDL]] C less than 20mg/dl. [[APOA1]] gene encodes for the [[Apo A1]] protein which is the major component of [[HDL]] C. It is synthesized in the [[liver]] and released into the circulation as very small discoid pre beta [[HDL]], which picks up free [[cholesterol]] from the [[cells]] and [[macrophages]]. [[Apo A1]] also activates [[LCAT]] which esterifies free [[cholesterol]] on the surface of alpha 4 [[HDL]] resulting in the formation of [[cholesterol esters]]. These two initial steps in the reverse cholesterol are dependent on a functional [[Apo A1]] which is defective in [[Apo A1 deficiency]]. [[Apo A1]] [[synthesis]] is affected leading to very low [[HDL]] levels. Worldwide, 82 cases and a variety of mutations are reported. The biochemical phenotype is always a low [[Apo A1]] and low [[HDL]] C. Clinical phenotype varies with each mutation and is inconsistent. Symptomatic patients usually present with [[corneal opacities]], [[xanthelasma]] and [[premature heart disease]]. [[Cardiovascular risk]] assessment and optimizing [[risk factors]] has an important role in the management.


==Historical Perspective==
==Historical Perspective==
*In 1981, Vergani and Bettale described a familial syndrome with hypoalphalipoproteinemia.<ref name="pmid7249374">{{cite journal| author=Vergani C, Bettale G| title=Familial hypo-alpha-lipoproteinemia. | journal=Clin Chim Acta | year= 1981 | volume= 114 | issue= 1 | pages= 45-52 | pmid=7249374 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7249374  }} </ref>
*In 1981, Vergani and Bettale described a familial syndrome with hypoalphalipoproteinemia.<ref name="pmid7249374">{{cite journal| author=Vergani C, Bettale G| title=Familial hypo-alpha-lipoproteinemia. | journal=Clin Chim Acta | year= 1981 | volume= 114 | issue= 1 | pages= 45-52 | pmid=7249374 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7249374  }} </ref>
**The proband and his relatives had low levels of HDL C, Apo-A1 with normal lipase and LCAT activity.
**The proband and his relatives had low levels of [[HDL]] C, [[Apo A1]] with normal [[lipase]] and [[LCAT]] activity.
**They reported a high prevalence of premature cardiac events without other established coronary risk factors present and a shortened life expectancy on longevity analysis.
**They reported a high prevalence of [[premature cardiac events]] without the presence of other established coronary [[risk factors]] and a shortened life expectancy on [[longevity analysis]].
**Based on the biochemical data and the pedigree they have described to have an autosomal dominant inheritance.
**Based on the biochemical data and the pedigree they have described to have an [[autosomal dominant]] [[inheritance]].
*In 1982, Breslow identified the gene sequence of human Apo A1.<ref name="pmid6294659">{{cite journal| author=Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL et al.| title=Isolation and characterization of cDNA clones for human apolipoprotein A-I. | journal=Proc Natl Acad Sci U S A | year= 1982 | volume= 79 | issue= 22 | pages= 6861-5 | pmid=6294659 | doi= | pmc=347233 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6294659  }} </ref>
*In 1982, Breslow identified the gene sequence of human [[Apo A1]].<ref name="pmid6294659">{{cite journal| author=Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL et al.| title=Isolation and characterization of cDNA clones for human apolipoprotein A-I. | journal=Proc Natl Acad Sci U S A | year= 1982 | volume= 79 | issue= 22 | pages= 6861-5 | pmid=6294659 | doi= | pmc=347233 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6294659  }} </ref>
*In 1982, Karathanasis isolated and described the characteristics of the human Apo A1 gene.<ref name="pmid6413973">{{cite journal| author=Karathanasis SK, Zannis VI, Breslow JL| title=Isolation and characterization of the human apolipoprotein A-I gene. | journal=Proc Natl Acad Sci U S A | year= 1983 | volume= 80 | issue= 20 | pages= 6147-51 | pmid=6413973 | doi= | pmc=390160 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6413973  }} </ref>
*In 1982, Karathanasis isolated and described the characteristics of the human [[Apo A1]] [[gene]].<ref name="pmid6413973">{{cite journal| author=Karathanasis SK, Zannis VI, Breslow JL| title=Isolation and characterization of the human apolipoprotein A-I gene. | journal=Proc Natl Acad Sci U S A | year= 1983 | volume= 80 | issue= 20 | pages= 6147-51 | pmid=6413973 | doi= | pmc=390160 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6413973  }} </ref>
*In 1982, Daniel described cerebrovascular abnormalities and clinical status of eight children with history of familial lipoprotein disorders and evidence of thromboembolic cerebrovascular disease. Six of the eight children had low levels of plasma HDL C.<ref name="pmid7080131">{{cite journal| author=Daniels SR, Bates S, Lukin RR, Benton C, Third J, Glueck CJ| title=Cerebrovascular arteriopathy (arteriosclerosis) and ischemic childhood stroke. | journal=Stroke | year= 1982 | volume= 13 | issue= 3 | pages= 360-5 | pmid=7080131 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7080131  }} </ref>
*In 1982, Daniel described [[cerebrovascular]] abnormalities and clinical status of eight children with history of familial lipoprotein disorders and evidence of [[thromboembolic]] [[cerebrovascular disease]]. Six of the eight children had low levels of plasma [[HDL]] C.<ref name="pmid7080131">{{cite journal| author=Daniels SR, Bates S, Lukin RR, Benton C, Third J, Glueck CJ| title=Cerebrovascular arteriopathy (arteriosclerosis) and ischemic childhood stroke. | journal=Stroke | year= 1982 | volume= 13 | issue= 3 | pages= 360-5 | pmid=7080131 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7080131  }} </ref>
**They have speculated that the vascular events are due to lipoprotein-mediated endothelial damage and thrombus formation.
**They have speculated that the vascular events are due to [[lipoprotein]] mediated [[endothelial]] damage and [[thrombus]] formation.
*In 1983, Brewer reported that apoA-I mRNA codes for a precursor apolipoprotein, preproapoA-I by nucleic acid sequence analysis.<ref name="pmid6404278">{{cite journal| author=Law SW, Gray G, Brewer HB| title=cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I. | journal=Biochem Biophys Res Commun | year= 1983 | volume= 112 | issue= 1 | pages= 257-64 | pmid=6404278 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6404278  }} </ref>
*In 1983, Brewer reported that [[Apo A1]] [[mRNA]] codes for a [[precursor]] [[apolipoprotein]]-preproapoA1 by [[nucleic acid sequence analysis]].<ref name="pmid6404278">{{cite journal| author=Law SW, Gray G, Brewer HB| title=cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I. | journal=Biochem Biophys Res Commun | year= 1983 | volume= 112 | issue= 1 | pages= 257-64 | pmid=6404278 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6404278  }} </ref>
*In 1986, Borecki described the possibility of genetic heterogeneity and provided clear evidence of a major gene involved in hypolipoproteinemia after studying 64 individuals in 14 nuclear families.<ref name="pmid3953576">{{cite journal| author=Borecki IB, Rao DC, Third JL, Laskarzewski PM, Glueck CJ| title=A major gene for primary hypoalphalipoproteinemia. | journal=Am J Hum Genet | year= 1986 | volume= 38 | issue= 3 | pages= 373-81 | pmid=3953576 | doi= | pmc=1684774 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3953576  }} </ref>
*In 1986, Borecki described the possibility of genetic [[heterogeneity]] and provided clear evidence of a major gene involved in hypolipoproteinemia after studying 64 individuals in 14 nuclear families.<ref name="pmid3953576">{{cite journal| author=Borecki IB, Rao DC, Third JL, Laskarzewski PM, Glueck CJ| title=A major gene for primary hypoalphalipoproteinemia. | journal=Am J Hum Genet | year= 1986 | volume= 38 | issue= 3 | pages= 373-81 | pmid=3953576 | doi= | pmc=1684774 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3953576  }} </ref>
*In 1986, Jose described a polymorphic site on the 3' end of the Apo-A1 gene and reported that the patients with this finding had lower HDL C levels. They have also suggested the polymorphism as a useful marker for the risk of premature coronary artery disease and familial hypoalphalipoproteinemia.<ref name="pmid3081805">{{cite journal| author=Ordovas JM, Schaefer EJ, Salem D, Ward RH, Glueck CJ, Vergani C et al.| title=Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. | journal=N Engl J Med | year= 1986 | volume= 314 | issue= 11 | pages= 671-7 | pmid=3081805 | doi=10.1056/NEJM198603133141102 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3081805  }} </ref>
*In 1986, Jose described a [[polymorphic]] site on the 3' end of the [[Apo A1]] [[gene]] and reported that the patients with this finding had lower [[HDL]] C levels. They have also suggested the [[polymorphism]] as a useful marker for the risk of [[premature]] [[coronary artery disease]] and familial hypoalphalipoproteinemia.<ref name="pmid3081805">{{cite journal| author=Ordovas JM, Schaefer EJ, Salem D, Ward RH, Glueck CJ, Vergani C et al.| title=Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. | journal=N Engl J Med | year= 1986 | volume= 314 | issue= 11 | pages= 671-7 | pmid=3081805 | doi=10.1056/NEJM198603133141102 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3081805  }} </ref>
*In 1988, LiWH speculated that the gene coding for apo A-1 is a member of apolipoprotien multigene superfamily, which include genes encoding for Apo AI, Apo-A-II, Apo-C and Apo-E.<ref name="pmid3288703">{{cite journal| author=Li WH, Tanimura M, Luo CC, Datta S, Chan L| title=The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. | journal=J Lipid Res | year= 1988 | volume= 29 | issue= 3 | pages= 245-71 | pmid=3288703 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3288703  }} </ref>
*In 1988, LiWH speculated that the [[gene]] coding for [[Apo A1]] is a member of apolipoprotien multigene superfamily, which include [[genes]] encoding for [[Apo A1]], [[Apo-A II]], [[Apo C]] and [[Apo E]].<ref name="pmid3288703">{{cite journal| author=Li WH, Tanimura M, Luo CC, Datta S, Chan L| title=The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. | journal=J Lipid Res | year= 1988 | volume= 29 | issue= 3 | pages= 245-71 | pmid=3288703 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3288703  }} </ref>
*In 1998, Gillotte described the mechanism apolipoprotein mediated cellular lipid efflux.<ref name="pmid9890960">{{cite journal| author=Gillotte KL, Zaiou M, Lund-Katz S, Anantharamaiah GM, Holvoet P, Dhoest A et al.| title=Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid. | journal=J Biol Chem | year= 1999 | volume= 274 | issue= 4 | pages= 2021-8 | pmid=9890960 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9890960  }} </ref>
*In 1998, Gillotte described the mechanism [[apolipoprotein]] mediated cellular [[lipid]] [[efflux]].<ref name="pmid9890960">{{cite journal| author=Gillotte KL, Zaiou M, Lund-Katz S, Anantharamaiah GM, Holvoet P, Dhoest A et al.| title=Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid. | journal=J Biol Chem | year= 1999 | volume= 274 | issue= 4 | pages= 2021-8 | pmid=9890960 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9890960  }} </ref>
*In 2006, crystal structure of Apo A1 and the description of the electrostatic features of Apo A1 which are crucial in understanding the interactions of Apo A1 with ABCA1 and SR-B1 were described by Ajees.<ref name="pmid16452169">{{cite journal| author=Ajees AA, Anantharamaiah GM, Mishra VK, Hussain MM, Murthy HM| title=Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases. | journal=Proc Natl Acad Sci U S A | year= 2006 | volume= 103 | issue= 7 | pages= 2126-31 | pmid=16452169 | doi=10.1073/pnas.0506877103 | pmc=1413691 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16452169  }} </ref>
*In 2006, crystal structure of [[Apo A1]] and the description of the electrostatic features of [[Apo A1]] which are crucial in understanding the interactions of [[Apo A1]] with [[ABCA1]] and [[SR-B1]] were described by Ajees.<ref name="pmid16452169">{{cite journal| author=Ajees AA, Anantharamaiah GM, Mishra VK, Hussain MM, Murthy HM| title=Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases. | journal=Proc Natl Acad Sci U S A | year= 2006 | volume= 103 | issue= 7 | pages= 2126-31 | pmid=16452169 | doi=10.1073/pnas.0506877103 | pmc=1413691 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16452169  }} </ref>


==Classification==
==Classification==
*Apolipoprotein A1 deficiency can be classified based on the type of mutation and the genes affected as follows:  
*[[Apolipoprotein A1]] deficiency can be classified based on the type of [[mutation]] and the [[genes]] affected as follows:  
**Familial apolipoprotein A-I/C-III/A-IV deficiency
**Familial [[apolipoprotein A1]]/ [[Apo C III]]/[[Apo IV]] deficiency
**ApoA1/C-III deficiency
**[[ApoA1]] and [[Apo C III]] deficiency
**Isolated Apo A1 deficiency
**Isolated [[Apo A1]] deficiency
**Apo A1 Variants
**[[Apo A1]] variants
===Familial apolipoprotein A-I/C-III/A-IV deficiency===
===Familial apolipoprotein A-I/C-III/A-IV deficiency===
*In 1982, Schaefer and colleagues reported a 45 year old female proband with marked HDL deficiency, undetectable plasma ApoA-I, low-TG, normal LDL-C, corneal arcus, planar xanthomas and premature CVD. The patient had severe CVD with no other known CVD risk factors and died during coronary artery bypass surgery at age 43 years.<ref name="pmid6800349">{{cite journal| author=Schaefer EJ, Heaton WH, Wetzel MG, Brewer HB| title=Plasma apolipoprotein A-1 absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease. | journal=Arteriosclerosis | year= 1982 | volume= 2 | issue= 1 | pages= 16-26 | pmid=6800349 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6800349  }} </ref>
*In 1982, Schaefer and colleagues reported a 45 year old [[female]] [[proband]] with [[HDL]] deficiency, undetectable [[plasma]] [[Apo A1]], low [[triglyceride]], normal [[LDL]] C, [[corneal arcus]], [[planar xanthomas]] and [[premature CVD]]. The patient had severe [[CVD]] with no known [[CVD]] [[risk factors]] and died during [[coronary artery bypass]] surgery at age 43 years.<ref name="pmid6800349">{{cite journal| author=Schaefer EJ, Heaton WH, Wetzel MG, Brewer HB| title=Plasma apolipoprotein A-1 absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease. | journal=Arteriosclerosis | year= 1982 | volume= 2 | issue= 1 | pages= 16-26 | pmid=6800349 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6800349  }} </ref>
*Her plasma LCAT activity was normal.
*Her [[plasma]] [[LCAT]] activity was normal.
*Defect was a homozygous deletion of the entire APOA1/C3/A4 gene complex.  
*The defect was identified as a [[homozygous]] [[deletion]] of the entire [[APOA1]] /[[C III]]/[[A IV]] [[gene]] complex.  
*Heterozygotes had plasma HDL-C, Apo AI, Apo AIV, and Apo C-III levels that were about 50% of normal in the kindred.<ref name="pmid6431953">{{cite journal| author=Schaefer EJ| title=Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. | journal=Arteriosclerosis | year= 1984 | volume= 4 | issue= 4 | pages= 303-22 | pmid=6431953 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6431953  }} </ref>
*[[Heterozygotes]] in the [[kindred]] had 50% of normal [[plasma]] [[HDL]] C, [[Apo A1]], [[Apo AIV]], and [[Apo CIII]] levels.<ref name="pmid6431953">{{cite journal| author=Schaefer EJ| title=Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. | journal=Arteriosclerosis | year= 1984 | volume= 4 | issue= 4 | pages= 303-22 | pmid=6431953 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6431953  }} </ref>


===ApoA1/ApoC-III Deficiency===
===ApoA1/ApoC-III Deficiency===
*In 1982, Norum and colleagues described two sisters with marked HDL deficiency, undetectable plasma Apo AI, Apo C-III, planar xanthomas, and premature CVD requiring bypass surgery at ages 29 and 30 years.<ref name="pmid7078608">{{cite journal| author=Norum RA, Lakier JB, Goldstein S, Angel A, Goldberg RB, Block WD et al.| title=Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. | journal=N Engl J Med | year= 1982 | volume= 306 | issue= 25 | pages= 1513-9 | pmid=7078608 | doi=10.1056/NEJM198206243062503 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7078608  }} </ref>
*In 1982, Norum and colleagues described two sisters with [[HDL]] deficiency, undetectable plasma [[Apo A1]], [[Apo C III]], planar [[xanthomas]], and premature [[CVD]] requiring [[coronary bypass surgery]] at ages 29 and 30 years.<ref name="pmid7078608">{{cite journal| author=Norum RA, Lakier JB, Goldstein S, Angel A, Goldberg RB, Block WD et al.| title=Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. | journal=N Engl J Med | year= 1982 | volume= 306 | issue= 25 | pages= 1513-9 | pmid=7078608 | doi=10.1056/NEJM198206243062503 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7078608  }} </ref>
*These patients had low TG, normal LDL-C and had enhanced clearance of VLDL Apo B.<ref name="pmid6501564">{{cite journal| author=Forte TM, Nichols AV, Krauss RM, Norum RA| title=Familial apolipoprotein AI and apolipoprotein CIII deficiency. Subclass distribution, composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1601-13 | pmid=6501564 | doi=10.1172/JCI111576 | pmc=425337 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501564  }} </ref>
*These patients had low [[triglyceride]], normal [[LDL]]C and enhanced clearance of [[VLDL]] associated [[Apo B]].<ref name="pmid6501564">{{cite journal| author=Forte TM, Nichols AV, Krauss RM, Norum RA| title=Familial apolipoprotein AI and apolipoprotein CIII deficiency. Subclass distribution, composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1601-13 | pmid=6501564 | doi=10.1172/JCI111576 | pmc=425337 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501564  }} </ref>
*The defect was a homozygous DNA re-arrangement affecting the APOA1 and APO CIII genes.  
*The defect was identified as a [[homozygous]] [[DNA]] [[re-arrangement]] affecting the [[ApoA1]] and [[Apo CIII]] [[genes]].  


===Apo A1 Deficiency===
===Apo A1 Deficiency===
*In 1991, Matsunaga and colleagues described a 56-year-old Japanese woman with premature CVD, planar xanthomas, normal TG, LDL-C, marked HDL C deficiency and undetectable plasma apoA-I levels. The defect was a homozygous APOAI codon 84 nonsense mutation, resulting in a lack of normal Apo AI production.<ref name="pmid1901417">{{cite journal| author=Matsunaga T, Hiasa Y, Yanagi H, Maeda T, Hattori N, Yamakawa K et al.| title=Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. | journal=Proc Natl Acad Sci U S A | year= 1991 | volume= 88 | issue= 7 | pages= 2793-7 | pmid=1901417 | doi= | pmc=51325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1901417  }} </ref>
*In 1991, Matsunaga and colleagues described a 56-year-old Japanese woman with [[premature]] [[CVD]], planar [[xanthomas]], normal [[triglyceride]], [[LDL]] C, marked [[HDL]] C deficiency and undetectable [[plasma]] [[Apo A1]] levels. The defect was identified as a [[homozygous]] [[Apo A1]] codon 84 [[nonsense mutation]], resulting in a lack of normal [[Apo A1]] production.<ref name="pmid1901417">{{cite journal| author=Matsunaga T, Hiasa Y, Yanagi H, Maeda T, Hattori N, Yamakawa K et al.| title=Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. | journal=Proc Natl Acad Sci U S A | year= 1991 | volume= 88 | issue= 7 | pages= 2793-7 | pmid=1901417 | doi= | pmc=51325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1901417  }} </ref>
*In 1994, Ng and colleagues reported a Canadian kindred with a isolated mutation in the apolipoprotein A1 gene. The proband was a 34-year presented with bilateral retinopathy, bilateral cataracts, spinocerebellar ataxia, and tendon xanthomata.<ref name="pmid8282791">{{cite journal| author=Ng DS, Leiter LA, Vezina C, Connelly PW, Hegele RA| title=Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia. | journal=J Clin Invest | year= 1994 | volume= 93 | issue= 1 | pages= 223-9 | pmid=8282791 | doi=10.1172/JCI116949 | pmc=293756 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8282791  }} </ref>
*In 1994, Ng and colleagues reported a Canadian kindred with an isolated [[mutation]] in the [[apolipoprotein A1]] [[gene]]. The proband was a 34-year presented with bilateral [[retinopathy]], bilateral [[cataracts]], [[spinocerebellar ataxia]], and tendon [[xanthomas]].<ref name="pmid8282791">{{cite journal| author=Ng DS, Leiter LA, Vezina C, Connelly PW, Hegele RA| title=Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia. | journal=J Clin Invest | year= 1994 | volume= 93 | issue= 1 | pages= 223-9 | pmid=8282791 | doi=10.1172/JCI116949 | pmc=293756 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8282791  }} </ref>
**HDL-C was very low and Apo AI was undetectable. Genomic DNA sequencing of the proband's Apo AI gene identified a nonsense mutation at codon [-2], which was designated as Q[-2]X.  
**[[HDL C]] was very low and [[Apo A1]] was undetectable. Genomic [[DNA]] sequencing of the proband's [[Apo A1]] [[gene]] had a [[nonsense]] [[mutation]] at [[codon]] [-2], which was designated as Q[-2]X.  
**Genotyping of the kindred showed four homozygotes, four heterozygotes and two unaffected subjects.  
**Genotyping of the [[kindred]] showed four [[homozygotes]], four [[heterozygotes]] and two unaffected subjects.  
**Heterozygotes had 50% of normal HDL C and Apo-A1.
**[[Heterozygotes]] had 50% of normal [[HDL]] C and [[Apo A1]].
*In 2008, Santos reported a kindred with the similar mutation that was identified in the Canadian kindred in two homozygous brothers presenting with tubo-eruptive, planar xanthomas, corneal arcus, mild corneal opacification, HDL C <5 mg/dL, normal LDL-C and TG levels. They had no detectable Apo AI containing HDL. Multiple heterozygotes in this kindred had HDL C 50% of normal levels.<ref name="pmid17991756">{{cite journal| author=Santos RD, Schaefer EJ, Asztalos BF, Polisecki E, Wang J, Hegele RA et al.| title=Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency. | journal=J Lipid Res | year= 2008 | volume= 49 | issue= 2 | pages= 349-57 | pmid=17991756 | doi=10.1194/jlr.M700362-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17991756  }} </ref>
*In 2008, Santos reported a [[kindred]] with the similar [[mutation]] that was identified in the Canadian [[kindred]] in two [[homozygous]] brothers presenting with [[tubo-eruptive]], planar [[xanthomas]], [[corneal arcus]], mild [[corneal opacification]], [[HDL]] C <5 mg/dL, normal [[LDL]]C and [[triglyceride]] levels. They had no detectable [[Apo A1]] containing [[HDL]]. Multiple [[heterozygotes]] in this [[kindred]] had [[HDL]] C 50% of normal levels.<ref name="pmid17991756">{{cite journal| author=Santos RD, Schaefer EJ, Asztalos BF, Polisecki E, Wang J, Hegele RA et al.| title=Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency. | journal=J Lipid Res | year= 2008 | volume= 49 | issue= 2 | pages= 349-57 | pmid=17991756 | doi=10.1194/jlr.M700362-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17991756  }} </ref>
*In 2009, Wada and colleagues reported a Apo A1 mutation (apoA-I Tomioka) in  a 64year old with corneal opacities and prior history of myocardial infarction. He had marked plasma HDL C (4 mg/dl) and Apo AI (5mg/dl) deficiency. Genomic sequencing revealed a homozygous deletion of successive adenine residues in codon 138 in Apo A1 gene, resulting in a frameshift mutation.<ref name="pmid19473658">{{cite journal| author=Wada M, Iso T, Asztalos BF, Takama N, Nakajima T, Seta Y et al.| title=Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion). | journal=Atherosclerosis | year= 2009 | volume= 207 | issue= 1 | pages= 157-61 | pmid=19473658 | doi=10.1016/j.atherosclerosis.2009.04.018 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19473658  }} </ref>
*In 2009, Wada and colleagues reported a [[Apo A1]] [[mutation]] ([[ApoA-I Tomioka]]) in  a 64 year old with [[corneal opacities]] and prior history of [[myocardial infarction]]. He had marked [[plasma]] [[HDL C]] (4 mg/dl) and [[Apo A1]] (5mg/dl) deficiency. Genomic sequencing revealed a [[homozygous]] deletion of successive [[adenine]] residues in codon 138 in [[Apo A1]] [[gene]], resulting in a [[frameshift]] [[mutation]].<ref name="pmid19473658">{{cite journal| author=Wada M, Iso T, Asztalos BF, Takama N, Nakajima T, Seta Y et al.| title=Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion). | journal=Atherosclerosis | year= 2009 | volume= 207 | issue= 1 | pages= 157-61 | pmid=19473658 | doi=10.1016/j.atherosclerosis.2009.04.018 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19473658  }} </ref>
*In 2010, Al-Sarraf and colleagues reported an Iraqi kindred with two probands in 2010 with complete Apo AI deficiency, marked HDL C deficiency, normal LDL C and TG levels  caused by a homozygous nonsense mutation with a stop codon at Arg10. One proband was a 35 year old woman with xanthelasma and xanthomas with no CVD, while her 37 year old brother had planar xanthomas and sustained a myocardial infarction (MI) at age 35 years.<ref name="pmid21122686">{{cite journal| author=Al-Sarraf A, Al-Ghofaili K, Sullivan DR, Wasan KM, Hegele R, Frohlich J| title=Complete Apo AI deficiency in an Iraqi Mandaean family: case studies and review of the literature. | journal=J Clin Lipidol | year= 2010 | volume= 4 | issue= 5 | pages= 420-6 | pmid=21122686 | doi=10.1016/j.jacl.2010.05.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21122686  }} </ref>
*In 2010, Al-Sarraf and colleagues reported an Iraqi [[kindred]] with two [[probands]] in 2010 with complete [[Apo A1]] deficiency, marked [[HDL]] C deficiency, normal [[LDL]] C and [[triglyceride]] levels  caused by a [[homozygous]] [[nonsense]] [[mutation]] with a [[stop codon]] at Arg10. One [[proband]] was a 35 year old woman with [[xanthelasma]] and [[xanthomas]] with no [[CVD]], while her 37 year old brother had planar [[xanthomas]] and sustained a [[myocardial infarction]] at age 35 years.<ref name="pmid21122686">{{cite journal| author=Al-Sarraf A, Al-Ghofaili K, Sullivan DR, Wasan KM, Hegele R, Frohlich J| title=Complete Apo AI deficiency in an Iraqi Mandaean family: case studies and review of the literature. | journal=J Clin Lipidol | year= 2010 | volume= 4 | issue= 5 | pages= 420-6 | pmid=21122686 | doi=10.1016/j.jacl.2010.05.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21122686  }} </ref>


===Apo A1 Variants===
===Apo A1 Variants===
*ApoA-I variants are heterozygous premature terminations, frameshift mutation or amino acid substitutions in the 243 amino acid Apo AI sequence.
*[[Apo A1]] variants are [[heterozygous]] [[premature]] [[terminations]], [[frameshift]] [[mutation]] or [[amino acid]] [[substitutions]] in the 243 amino acid [[Apo A1]] sequence.
* These patients may have HDL C levels that are low or normal, plasma LCAT activity that is normal or reduced, may develop premature CVD or amyloidosis.
* These patients may have [[HDL]] C levels that are low or normal, [[plasma]] [[LCAT]] activity that is normal or reduced, may develop [[premature CVD]] or [[amyloidosis]].
* Six Heterozygous Apo A1 missense mutations with low HDL C and decreased LCAT activity are reported. They are not at increased risk of developing premature heart disease.<ref name="pmid9215551">{{cite journal| author=Miccoli R, Zhu Y, Daum U, Wessling J, Huang Y, Navalesi R et al.| title=A natural apolipoprotein A-I variant, apoA-I (L141R)Pisa, interferes with the formation of alpha-high density lipoproteins (HDL) but not with the formation of pre beta 1-HDL and influences efflux of cholesterol into plasma. | journal=J Lipid Res | year= 1997 | volume= 38 | issue= 6 | pages= 1242-53 | pmid=9215551 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9215551  }} </ref><ref name="pmid10064737">{{cite journal| author=Daum U, Leren TP, Langer C, Chirazi A, Cullen P, Pritchard PH et al.| title=Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers. | journal=J Lipid Res | year= 1999 | volume= 40 | issue= 3 | pages= 486-94 | pmid=10064737 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10064737  }} </ref><ref name="pmid26073399">{{cite journal| author=Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ| title=Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 390-5 | pmid=26073399 | doi=10.1016/j.jacl.2015.02.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073399  }} </ref>
* Six [[heterozygous]] [[Apo A1]] [[missense]] [[mutations]] with low [[HDL]] C and decreased [[LCAT]] activity are reported. They are not at increased risk of developing [[premature]] [[CVD]].<ref name="pmid9215551">{{cite journal| author=Miccoli R, Zhu Y, Daum U, Wessling J, Huang Y, Navalesi R et al.| title=A natural apolipoprotein A-I variant, apoA-I (L141R)Pisa, interferes with the formation of alpha-high density lipoproteins (HDL) but not with the formation of pre beta 1-HDL and influences efflux of cholesterol into plasma. | journal=J Lipid Res | year= 1997 | volume= 38 | issue= 6 | pages= 1242-53 | pmid=9215551 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9215551  }} </ref><ref name="pmid10064737">{{cite journal| author=Daum U, Leren TP, Langer C, Chirazi A, Cullen P, Pritchard PH et al.| title=Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers. | journal=J Lipid Res | year= 1999 | volume= 40 | issue= 3 | pages= 486-94 | pmid=10064737 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10064737  }} </ref><ref name="pmid26073399">{{cite journal| author=Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ| title=Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 390-5 | pmid=26073399 | doi=10.1016/j.jacl.2015.02.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073399  }} </ref>
*Few mutations resulting in low HDL C with normal LCAT function have an increased risk of coronary artery disease at a young age.<ref name="pmid23415437">{{cite journal| author=Lee EY, Klementowicz PT, Hegele RA, Asztalos BF, Schaefer EJ| title=HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature. | journal=J Clin Lipidol | year= 2013 | volume= 7 | issue= 2 | pages= 169-73 | pmid=23415437 | doi=10.1016/j.jacl.2012.10.011 | pmc=4565164 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23415437  }} </ref><ref name="pmid23209431">{{cite journal| author=Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A| title=Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. | journal=PLoS Genet | year= 2012 | volume= 8 | issue= 11 | pages= e1003063 | pmid=23209431 | doi=10.1371/journal.pgen.1003063 | pmc=3510059 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23209431  }} </ref>
*Few mutations resulting in low [[HDL]] C with normal [[LCAT]] function have an increased risk of [[coronary artery disease]] at a young age.<ref name="pmid23415437">{{cite journal| author=Lee EY, Klementowicz PT, Hegele RA, Asztalos BF, Schaefer EJ| title=HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature. | journal=J Clin Lipidol | year= 2013 | volume= 7 | issue= 2 | pages= 169-73 | pmid=23415437 | doi=10.1016/j.jacl.2012.10.011 | pmc=4565164 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23415437  }} </ref><ref name="pmid23209431">{{cite journal| author=Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A| title=Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. | journal=PLoS Genet | year= 2012 | volume= 8 | issue= 11 | pages= e1003063 | pmid=23209431 | doi=10.1371/journal.pgen.1003063 | pmc=3510059 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23209431  }} </ref>
*Few mutations in Apo A1 are associated with familial visceral amyloidosis.<ref name="pmid1502149">{{cite journal| author=Soutar AK, Hawkins PN, Vigushin DM, Tennent GA, Booth SE, Hutton T et al.| title=Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. | journal=Proc Natl Acad Sci U S A | year= 1992 | volume= 89 | issue= 16 | pages= 7389-93 | pmid=1502149 | doi= | pmc=49715 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1502149  }} </ref><ref name="pmid26562506">{{cite journal| author=Das M, Wilson CJ, Mei X, Wales TE, Engen JR, Gursky O| title=Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic? | journal=J Mol Biol | year= 2016 | volume= 428 | issue= 2 Pt B | pages= 449-62 | pmid=26562506 | doi=10.1016/j.jmb.2015.10.029 | pmc=4744490 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26562506  }} </ref>
*Few mutations in [[Apo A1]] are associated with [[familial visceral amyloidosis]].<ref name="pmid1502149">{{cite journal| author=Soutar AK, Hawkins PN, Vigushin DM, Tennent GA, Booth SE, Hutton T et al.| title=Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. | journal=Proc Natl Acad Sci U S A | year= 1992 | volume= 89 | issue= 16 | pages= 7389-93 | pmid=1502149 | doi= | pmc=49715 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1502149  }} </ref><ref name="pmid26562506">{{cite journal| author=Das M, Wilson CJ, Mei X, Wales TE, Engen JR, Gursky O| title=Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic? | journal=J Mol Biol | year= 2016 | volume= 428 | issue= 2 Pt B | pages= 449-62 | pmid=26562506 | doi=10.1016/j.jmb.2015.10.029 | pmc=4744490 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26562506  }} </ref>
*Below is a list of few selected Apo A1 variants which support the inconsistency in the biochemical and clinical phenotype:  
*Below is a list of few selected [[Apo A1]] variants which support the inconsistency in the biochemical and clinical phenotype:  
**In 1980, Franceschini reported significant hypertriglyceridemia and marked decrease of HDL C (7-14 mg/dl) with no signs of coronary atherosclerosis in the father, son, and daughter of an Italian family. They had normal lipoprotein lipase, LCAT activity and a reduced Apo A1 on 2D gel electrophoresis. He suggested the finding was probably due to a change in the amino acid composition and it was designated as Apo A1Milano.<ref name="pmid7430351">{{cite journal| author=Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW| title=A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. | journal=J Clin Invest | year= 1980 | volume= 66 | issue= 5 | pages= 892-900 | pmid=7430351 | doi=10.1172/JCI109956 | pmc=371523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7430351  }}</ref>
**In 1980, Franceschini reported significant [[hypertriglyceridemia]] and marked decrease of [[HDL]] C (7-14 mg/dl) with no signs of [[coronary]] [[atherosclerosis]] in the father, son, and daughter of an Italian family. They had normal [[lipoprotein lipase]], [[LCAT]] activity and a reduced [[Apo A1]] on [[2D gel electrophoresis]]. He suggested the finding was probably due to a change in the [[amino acid]] composition and it was designated as [[Apo A1 Milano]].<ref name="pmid7430351">{{cite journal| author=Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW| title=A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. | journal=J Clin Invest | year= 1980 | volume= 66 | issue= 5 | pages= 892-900 | pmid=7430351 | doi=10.1172/JCI109956 | pmc=371523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7430351  }}</ref>
**In 1991, Funke and colleagues reported a 42-year-old German patient with corneal opacification, marked HDL deficiency, apoA-I deficiency, decreased plasma LCAT activity, increased non- HDL-C and TG, and lack of CVD. Sequencing of LCAT gene was normal, but the patient was found to be homozygous for an apoA-I frameshift mutation resulting in a truncated 229 amino acid protein instead of full length apoA-I.<ref name="pmid1898657">{{cite journal| author=Funke H, von Eckardstein A, Pritchard PH, Karas M, Albers JJ, Assmann G| title=A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities. | journal=J Clin Invest | year= 1991 | volume= 87 | issue= 1 | pages= 371-6 | pmid=1898657 | doi=10.1172/JCI114997 | pmc=295069 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1898657  }} </ref>
**In 1991, Funke and colleagues reported a 42-year-old German patient with [[corneal opacification]], marked [[HDL]] deficiency, Apo A1]]deficiency, decreased plasma [[LCAT]] activity, increased non-[[HDL]] C and [[triglyceride]], and lack of [[CVD]]. Sequencing of [[LCAT]] [[gene]] was normal, but the patient was found to be [[homozygous]] for an [[Apo A1]] [[frameshift]] [[mutation]] resulting in a [[truncated]] 229 amino acid protein instead of full length [[Apo A1]].<ref name="pmid1898657">{{cite journal| author=Funke H, von Eckardstein A, Pritchard PH, Karas M, Albers JJ, Assmann G| title=A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities. | journal=J Clin Invest | year= 1991 | volume= 87 | issue= 1 | pages= 371-6 | pmid=1898657 | doi=10.1172/JCI114997 | pmc=295069 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1898657  }} </ref>
**In 1995, Takata and colleagues reported a 39-year-old Japanese man with corneal opacification, HDL-C of 6 mg/dL, Apo AI level of <3.0 mg/dL, increased LDL-C, with normal levels of plasma TG, phospholipid, Apo B, Apo C-III, and ApoE levels and no coronary artery lumen narrowing on angiography. LCAT activity was about 50% of normal. The patient was homozygous for a codon 8 nonsense mutation in exon 3 of the Apo AI gene. Heterozygotes in the family had normal HDL-C values.<ref name="pmid7583566">{{cite journal| author=Takata K, Saku K, Ohta T, Takata M, Bai H, Jimi S et al.| title=A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease. | journal=Arterioscler Thromb Vasc Biol | year= 1995 | volume= 15 | issue= 11 | pages= 1866-74 | pmid=7583566 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7583566  }} </ref>
**In 1995, Takata and colleagues reported a 39-year-old Japanese man with [[corneal opacification]], [[HDL]]C of 6 mg/dL, [[Apo A1]] level of <3.0 mg/dL, increased [[LDL]] C, with normal levels of [[plasma]] [[triglyceride]], [[phospholipid]], [[Apo B]], [[Apo C III]], and [[ApoE]] levels and no coronary artery lumen narrowing on [[angiography]]. [[LCAT]] activity was about 50% of normal. The patient was [[homozygous]] for a [[codon]] 8 [[nonsense]] [[mutation]] in exon 3 of the [[Apo A1]] [[gene]]. [[Heterozygotes]] in the family had normal [[HDL]]C levels.<ref name="pmid7583566">{{cite journal| author=Takata K, Saku K, Ohta T, Takata M, Bai H, Jimi S et al.| title=A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease. | journal=Arterioscler Thromb Vasc Biol | year= 1995 | volume= 15 | issue= 11 | pages= 1866-74 | pmid=7583566 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7583566  }} </ref>
**In 2013, reported a 61-year-old male with significant coronary heart disease from the age of 42, corneal arcus, combined hyperlipidemia, HDL C of 1 mg/dL, Apo AI of 23 mg/dL, normal LCAT acticity  and only preβ-1 and α-2 HDL particles present in his HDL particles. He had a novel heterozygous inframe insertion mutation with a duplication of nucleotides.(Apo AI Nashua).<ref name="pmid23415437">{{cite journal| author=Lee EY, Klementowicz PT, Hegele RA, Asztalos BF, Schaefer EJ| title=HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature. | journal=J Clin Lipidol | year= 2013 | volume= 7 | issue= 2 | pages= 169-73 | pmid=23415437 | doi=10.1016/j.jacl.2012.10.011 | pmc=4565164 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23415437  }} </ref>
**In 2013, reported a 61-year-old male with significant [[coronary heart disease]] from the age of 42, [[corneal arcus]], combined [[hyperlipidemia]], [[HDL]] C of 1 mg/dL, [[Apo A1]] of 23 mg/dL, normal [[LCAT]] acticity  and only pre β1 and α-2 [[HDL]] particles present on [[electrophoresis]]. He had a novel [[heterozygous]] [[inframe insertion]] [[mutation]] with a duplication of [[nucleotides]] called as [[Apo AI Nashua]].<ref name="pmid23415437">{{cite journal| author=Lee EY, Klementowicz PT, Hegele RA, Asztalos BF, Schaefer EJ| title=HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature. | journal=J Clin Lipidol | year= 2013 | volume= 7 | issue= 2 | pages= 169-73 | pmid=23415437 | doi=10.1016/j.jacl.2012.10.011 | pmc=4565164 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23415437  }} </ref>
**In 2014, Anthanont and colleagues reported a Apo A1 mutation in a  68-year-old male and two other family members with premature heart disease, corneal arcus, HDL-C 14 mg/dL,             Apo AI  57 mg/dL, normal TG, LDL C levels and a lack of very large α-1 HDL. Genotypic sequencing revealed a heterozygous nonsense mutation (Gln216termination) resulting in a truncated Apo AI containing only 215 amino acids. This mutation is designated as Apo AIMytilene. Kinetic studies showed proband Apo A1 production to be 40% of normal, cellular cholesterol efflux capacity 65% of normal, and normal LCAT activity.<ref name="pmid24950002">{{cite journal| author=Anthanont P, Polisecki E, Asztalos BF, Diffenderfer MR, Barrett PH, Millar JS et al.| title=A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production. | journal=Atherosclerosis | year= 2014 | volume= 235 | issue= 2 | pages= 470-6 | pmid=24950002 | doi=10.1016/j.atherosclerosis.2014.05.935 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24950002  }} </ref>
**In 2014, Anthanont and colleagues reported a [[Apo A1]] [[mutation]] in a  68-year-old male and two other family members with [[premature CVD]], [[corneal arcus]], [[HDL C]] 14 mg/dL, [[Apo A1]] 57 mg/dL, normal [[triglyceride]], [[LDL]] C levels and lack of very large α-1 [[HDL]]. [[Genotypic sequencing]] revealed a [[heterozygous]] [[nonsense]] [[mutation]] (Gln216termination) resulting in a [[truncated]] [[Apo A1]] containing only 215 [[amino acids]]. This mutation is designated as [[Apo AI Mytilene]]. [[Kinetic studies]] showed [[proband]] [[Apo A1]] production to be 40% of normal, cellular [[cholesterol efflux]] capacity 65% of normal, and normal [[LCAT]] activity.<ref name="pmid24950002">{{cite journal| author=Anthanont P, Polisecki E, Asztalos BF, Diffenderfer MR, Barrett PH, Millar JS et al.| title=A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production. | journal=Atherosclerosis | year= 2014 | volume= 235 | issue= 2 | pages= 470-6 | pmid=24950002 | doi=10.1016/j.atherosclerosis.2014.05.935 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24950002  }} </ref>
**In 2015, Anthanont and colleagues reported a mutation in a 68-year female and her two sons with severe HDL deficiency, mild hypertriglyceridemia, and detectable large alpha-1 and alpha-2 HDL particles by 2-dimensional gel electrophoresis. Sequencing revealed a a heterozygous missense mutation of Apo A1, designated as Apo AIBoston. They had decreased LCAT function and cholesterol efflux.<ref name="pmid26073399">{{cite journal| author=Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ| title=Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 390-5 | pmid=26073399 | doi=10.1016/j.jacl.2015.02.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073399  }} </ref>
**In 2015, Anthanont and colleagues reported a mutation in a 68-year female and her two sons with severe [[HDL]] deficiency, mild [[hypertriglyceridemia]], and detectable large alpha-1 and alpha-2 [[HDL]] particles on [[2D gel electrophoresis]]. [[Genomic sequencing]] revealed a a [[heterozygous]] [[missense]] mutation of [[Apo A1]], designated as [[Apo AI Boston]]. They had decreased [[LCAT]] function and [[cholesterol efflux]].<ref name="pmid26073399">{{cite journal| author=Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ| title=Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 390-5 | pmid=26073399 | doi=10.1016/j.jacl.2015.02.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073399  }} </ref>


==Demographics, Epidemiology==
==Demographics, Epidemiology==
*Worldwide, 82 Apo AI mutations have been reported in human subjects.<ref name="pmid26073399">{{cite journal| author=Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ| title=Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 390-5 | pmid=26073399 | doi=10.1016/j.jacl.2015.02.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073399  }} </ref>
*Worldwide, 82 [[Apo A1]] [[mutations]] have been reported.<ref name="pmid26073399">{{cite journal| author=Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ| title=Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux. | journal=J Clin Lipidol | year= 2015 | volume= 9 | issue= 3 | pages= 390-5 | pmid=26073399 | doi=10.1016/j.jacl.2015.02.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073399  }} </ref>
*The prevalence of Apo A1 deficiency is estimated to be less than 1/1,000,000 population.<ref name="urlOrphanet: Apolipoprotein A I deficiency">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=2927&Disease_Disease_Search_diseaseGroup=Apolipoprotein-A-I-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Apolipoprotein-A-I-deficiency&title=Apolipoprotein-A-I-deficiency&search=Disease_Search_Simple |title=Orphanet: Apolipoprotein A I deficiency |format= |work= |accessdate=}}</ref>
*The prevalence of [[Apo A1]] deficiency is estimated to be less than 1/1,000,000 population.<ref name="urlOrphanet: Apolipoprotein A I deficiency">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=2927&Disease_Disease_Search_diseaseGroup=Apolipoprotein-A-I-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Apolipoprotein-A-I-deficiency&title=Apolipoprotein-A-I-deficiency&search=Disease_Search_Simple |title=Orphanet: Apolipoprotein A I deficiency |format= |work= |accessdate=}}</ref>
*Apo A1 deficiency accounts for 6% of Japanese population with low HDL C.<ref name="pmid9931341">{{cite journal| author=Yamakawa-Kobayashi K, Yanagi H, Fukayama H, Hirano C, Shimakura Y, Yamamoto N et al.| title=Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey. | journal=Hum Mol Genet | year= 1999 | volume= 8 | issue= 2 | pages= 331-6 | pmid=9931341 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9931341  }} </ref>
*Apo A1 deficiency accounts for 6% of Japanese population with low [[HDL]] C.<ref name="pmid9931341">{{cite journal| author=Yamakawa-Kobayashi K, Yanagi H, Fukayama H, Hirano C, Shimakura Y, Yamamoto N et al.| title=Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey. | journal=Hum Mol Genet | year= 1999 | volume= 8 | issue= 2 | pages= 331-6 | pmid=9931341 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9931341  }} </ref>
*Genomic sequencing of ApoA1 gene in 10,330 population based participants in the Copenhagen City Heart study revealed<ref name="pmid23209431">{{cite journal| author=Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A| title=Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. | journal=PLoS Genet | year= 2012 | volume= 8 | issue= 11 | pages= e1003063 | pmid=23209431 | doi=10.1371/journal.pgen.1003063 | pmc=3510059 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23209431  }} </ref>:
*Genomic sequencing of [[Apo A1]] [[gene]] in 10,330 population based participants in the Copenhagen City Heart study revealed<ref name="pmid23209431">{{cite journal| author=Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A| title=Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. | journal=PLoS Genet | year= 2012 | volume= 8 | issue= 11 | pages= e1003063 | pmid=23209431 | doi=10.1371/journal.pgen.1003063 | pmc=3510059 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23209431  }} </ref>:
**In the study, only 0.27% of the individuals in the general population were heterozygous for non-synonymous variants which were associated with significant reductions in Apo A1 and HDL C.
**In the study, only 0.27% of the individuals in the general population were [[heterozygous]] for [[non-synonymous]] [[variants]] which were associated with significant reductions in [[Apo A1]] and [[HDL]] C.
**In the study,  only 0.41% of the population was heterozygous for variants predisposing to amyloidosis.
**In the study,  only 0.41% of the population was [[heterozygous]] for [[variants]] predisposing to [[amyloidosis]].


==Natural History, Progression, Complications==
==Pathogenesis==
[[Apolipoprotein A1]] deficiency is caused by [[mutation]] in the [[APOA1]] [[gene]] encoding [[ApoA1]] [[protein]], a major transport [[protein]] of [[reverse cholesterol transport]].


==Pathogenesis==
===Pathophysiology===
===Pathophysiology===
*HDL C is synthesized and secreted from the liver and intestine as nascent very small discoid pre-β-1 HDL, conformed predominantly by apolipoprotein A-I.
*Apo-A1 is a predominant lipoprotein of HDL and plays an important role in maturation of HDL and reverse cholesterol transport by<ref name="pmid20213545">{{cite journal| author=Lund-Katz S, Phillips MC| title=High density lipoprotein structure-function and role in reverse cholesterol transport. | journal=Subcell Biochem | year= 2010 | volume= 51 | issue=  | pages= 183-227 | pmid=20213545 | doi=10.1007/978-90-481-8622-8_7 | pmc=3215094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20213545  }}</ref>:
**Apo-AI is important for mediating the efflux of cholesterol from peripheral tissues.<ref name="pmid24362356">{{cite journal| author=Hellerstein M, Turner S| title=Reverse cholesterol transport fluxes. | journal=Curr Opin Lipidol | year= 2014 | volume= 25 | issue= 1 | pages= 40-7 | pmid=24362356 | doi=10.1097/MOL.0000000000000050 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24362356  }} </ref>
**ApoA-I interacts with ABCA1 and accepts free cholesterol.<ref name="pmid12151852">{{cite journal| author=Oram JF| title=ATP-binding cassette transporter A1 and cholesterol trafficking. | journal=Curr Opin Lipidol | year= 2002 | volume= 13 | issue= 4 | pages= 373-81 | pmid=12151852 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12151852  }} </ref><ref name="pmid21846716">{{cite journal| author=Iatan I, Bailey D, Ruel I, Hafiane A, Campbell S, Krimbou L et al.| title=Membrane microdomains modulate oligomeric ABCA1 function: impact on apoAI-mediated lipid removal and phosphatidylcholine biosynthesis. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 11 | pages= 2043-55 | pmid=21846716 | doi=10.1194/jlr.M016196 | pmc=3196236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21846716  }} </ref>
**Apo-A1 is a potent activator of LCAT, enzyme helpful in the formation of cholesterol esters.<ref name="pmid11111093">{{cite journal| author=Jonas A| title=Lecithin cholesterol acyltransferase. | journal=Biochim Biophys Acta | year= 2000 | volume= 1529 | issue= 1-3 | pages= 245-56 | pmid=11111093 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11111093  }} </ref>
**Delivery of cholesterol esters to the liver mediated by scavenger receptor class B type I (SR-B1).<ref name="pmid10872459">{{cite journal| author=Krieger M| title=Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI. | journal=Annu Rev Biochem | year= 1999 | volume= 68 | issue=  | pages= 523-58 | pmid=10872459 | doi=10.1146/annurev.biochem.68.1.523 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10872459  }} </ref>
*Genetic factors regulate the circulating levels of HDL and its functionality, mutations in the Apo A1 gene affect the total plasma levels of Apo A1 leading to low undetectable HDL C.<ref name="pmid12007737">{{cite journal| author=Sorci-Thomas MG, Thomas MJ| title=The effects of altered apolipoprotein A-I structure on plasma HDL concentration. | journal=Trends Cardiovasc Med | year= 2002 | volume= 12 | issue= 3 | pages= 121-8 | pmid=12007737 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12007737  }} </ref>
*Majority of clinical and epidemiological studies like the Framingham Heart Study, Emerging Risk Factor Collaboration, Munster Heart Study, INTERHEART Study have proved an inverse relationship between HDL-C concentration and cardiovascular risk.<ref name="pmid3196218">{{cite journal| author=Wilson PW, Abbott RD, Castelli WP| title=High density lipoprotein cholesterol and mortality. The Framingham Heart Study. | journal=Arteriosclerosis | year= 1988 | volume= 8 | issue= 6 | pages= 737-41 | pmid=3196218 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3196218  }} </ref><ref name="pmid19903920">{{cite journal| author=Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK et al.| title=Major lipids, apolipoproteins, and risk of vascular disease. | journal=JAMA | year= 2009 | volume= 302 | issue= 18 | pages= 1993-2000 | pmid=19903920 | doi=10.1001/jama.2009.1619 | pmc=3284229 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19903920  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20157124 Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212] </ref><ref name="pmid8831911">{{cite journal| author=Assmann G, Schulte H, von Eckardstein A, Huang Y| title=High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. | journal=Atherosclerosis | year= 1996 | volume= 124 Suppl | issue=  | pages= S11-20 | pmid=8831911 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8831911  }} </ref><ref name="pmid15364185">{{cite journal| author=Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F et al.| title=Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. | journal=Lancet | year= 2004 | volume= 364 | issue= 9438 | pages= 937-52 | pmid=15364185 | doi=10.1016/S0140-6736(04)17018-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15364185  }} </ref>
*The atheroprotective function of HDL C is determined by measuring the cholesterol efflux from the cells and its anti-oxidative ability.<ref name="pmid25404125">{{cite journal| author=Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE et al.| title=HDL cholesterol efflux capacity and incident cardiovascular events. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 25 | pages= 2383-93 | pmid=25404125 | doi=10.1056/NEJMoa1409065 | pmc=4308988 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25404125  }} </ref>
===Reverse Cholesterol Transport<ref name="pmid21537175">{{cite journal| author=Asztalos BF, Tani M, Schaefer EJ| title=Metabolic and functional relevance of HDL subspecies. | journal=Curr Opin Lipidol | year= 2011 | volume= 22 | issue= 3 | pages= 176-85 | pmid=21537175 | doi=10.1097/MOL.0b013e3283468061 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21537175  }} </ref>===
===Reverse Cholesterol Transport<ref name="pmid21537175">{{cite journal| author=Asztalos BF, Tani M, Schaefer EJ| title=Metabolic and functional relevance of HDL subspecies. | journal=Curr Opin Lipidol | year= 2011 | volume= 22 | issue= 3 | pages= 176-85 | pmid=21537175 | doi=10.1097/MOL.0b013e3283468061 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21537175  }} </ref>===
{{Family tree/start}}
{{Family tree/start}}
{{Family tree | | | | A01 | | | |A01= Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter<ref name="pmid19839639">{{cite journal| author=Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G et al.| title=Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1. | journal=Biochemistry | year= 2009 | volume= 48 | issue= 46 | pages= 11067-74 | pmid=19839639 | doi=10.1021/bi901564g | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19839639  }} </ref> to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease resulting in only pre beta HDL on 2D electrophoresis.}}
{{Family tree | | | | A01 | | | |A01= Very small discoidal pre beta-1 [[HDL]] picks up free [[cholesterol]] from [[cells]] via [[ABCA1 transporter]]<ref name="pmid19839639">{{cite journal| author=Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G et al.| title=Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1. | journal=Biochemistry | year= 2009 | volume= 48 | issue= 46 | pages= 11067-74 | pmid=19839639 | doi=10.1021/bi901564g | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19839639  }} </ref> to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease resulting in only pre beta HDL on 2D electrophoresis.}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | B01 | | | |B01= Discoidal HDL particles are converted to medium spherical α-3 HDL and larger particles by the esterification of free cholesterol via the enzyme lecithin:cholesterol acyltransferase (LCAT) and the addition of apoA-II. }}
{{Family tree | | | | B01 | | | |B01= Discoidal [[HDL]] particles are converted to medium spherical α-3 [[HDL]] and larger particles by the [[esterification]] of free [[cholesterol]] via the [[enzyme]] [[lecithin cholesterol acyltransferase]] ([[LCAT]]) and the addition of [[ApoA II]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | C01 | | | |C01= These particles are further converted to large and very large spherical α-2 and α-1 HDL by the actions of cholesteryl ester transfer protein (CETP). CETP transfers cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride}}
{{Family tree | | | | C01 | | | |C01= These particles are further converted to large and very large spherical α-2 and α-1 [[HDL]] by the actions of [[cholesteryl ester transfer protein]] ([[CETP]]). [[CETP]] transfers [[cholesteryl ester]] from [[HDL]] to [[triglyceride]] rich [[lipoproteins]] in exchange for [[triglyceride]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | D01 | | | |D01= Very large α-1 HDL particles are donors of cholesterol to the liver, and the constituents of these particles can recycle back to form very small discoidal particles and can re-enter the HDL cycle, or be catabolized directly by the kidney or liver}}
{{Family tree | | | | D01 | | | |D01= Very large α-1 [[HDL]] particles are donors of [[cholesterol]] to the [[liver]], and the constituents of these particles can recycle back to form very small discoidal particles and re-enter the [[HDL]] cycle, or be [[catabolized]] directly by the [[kidney]] or [[liver]]}}
{{Family tree/end}}
{{Family tree/end}}
*In Apo A1 deficiency there is complete absence of Apo A1 and HDL C in homozygotes and less than 50% normal in heterozygotes, this disrupts the reverse cholesterol transport by :
*[[HDL]] C is synthesized and secreted from the [[liver]] as nascent very small discoid pre-β-1 [[HDL]], predominantly composed of [[apolipoprotein A1]].
**Change of chemical compositon in sub-populations of HDL C.<ref name="pmid21537175">{{cite journal| author=Asztalos BF, Tani M, Schaefer EJ| title=Metabolic and functional relevance of HDL subspecies. | journal=Curr Opin Lipidol | year= 2011 | volume= 22 | issue= 3 | pages= 176-85 | pmid=21537175 | doi=10.1097/MOL.0b013e3283468061 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21537175  }} </ref>
*[[Apo A1]] is a predominant [[lipoprotein]] of [[HDL]] and plays an important role in [[maturation]] of [[HDL]] and [[reverse cholesterol transport]] by<ref name="pmid20213545">{{cite journal| author=Lund-Katz S, Phillips MC| title=High density lipoprotein structure-function and role in reverse cholesterol transport. | journal=Subcell Biochem | year= 2010 | volume= 51 | issue=  | pages= 183-227 | pmid=20213545 | doi=10.1007/978-90-481-8622-8_7 | pmc=3215094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20213545  }}</ref>:
**Decrease in the cholesterol efflux.
**[[Apo A1]] is important for mediating the [[efflux]] of [[cholesterol]] from peripheral tissues.<ref name="pmid24362356">{{cite journal| author=Hellerstein M, Turner S| title=Reverse cholesterol transport fluxes. | journal=Curr Opin Lipidol | year= 2014 | volume= 25 | issue= 1 | pages= 40-7 | pmid=24362356 | doi=10.1097/MOL.0000000000000050 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24362356  }} </ref>
**Failure of cholesterol ester formation as LCAT function is compromised in few mutations.
**[[Apo A1]] interacts with ABCA1 and accepts free [[cholesterol]].<ref name="pmid12151852">{{cite journal| author=Oram JF| title=ATP-binding cassette transporter A1 and cholesterol trafficking. | journal=Curr Opin Lipidol | year= 2002 | volume= 13 | issue= 4 | pages= 373-81 | pmid=12151852 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12151852  }} </ref><ref name="pmid21846716">{{cite journal| author=Iatan I, Bailey D, Ruel I, Hafiane A, Campbell S, Krimbou L et al.| title=Membrane microdomains modulate oligomeric ABCA1 function: impact on apoAI-mediated lipid removal and phosphatidylcholine biosynthesis. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 11 | pages= 2043-55 | pmid=21846716 | doi=10.1194/jlr.M016196 | pmc=3196236 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21846716  }} </ref>
*The changes in the reverse cholesterol transport predispose the patients to premature heart disease.
**[[Apo A1]] is a potent activator of [[LCAT]], [[enzyme]] helpful in the formation of [[cholesterol esters]].<ref name="pmid11111093">{{cite journal| author=Jonas A| title=Lecithin cholesterol acyltransferase. | journal=Biochim Biophys Acta | year= 2000 | volume= 1529 | issue= 1-3 | pages= 245-56 | pmid=11111093 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11111093  }} </ref>
**Delivery of [[cholesterol esters]] to the [[liver]] is mediated by [[scavenger receptor class B type I]] ([[SR-B1]]).<ref name="pmid10872459">{{cite journal| author=Krieger M| title=Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI. | journal=Annu Rev Biochem | year= 1999 | volume= 68 | issue=  | pages= 523-58 | pmid=10872459 | doi=10.1146/annurev.biochem.68.1.523 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10872459  }} </ref>
*Genetic factors regulate the circulating levels of [[HDL]] and its [[functionality]], [[mutations]] in the [[Apo A1]] [[gene]] affect the total [[plasma ]]levels of [[Apo A1]] leading to low undetectable levels of [[HDL]] C.<ref name="pmid12007737">{{cite journal| author=Sorci-Thomas MG, Thomas MJ| title=The effects of altered apolipoprotein A-I structure on plasma HDL concentration. | journal=Trends Cardiovasc Med | year= 2002 | volume= 12 | issue= 3 | pages= 121-8 | pmid=12007737 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12007737  }} </ref>
*Majority of clinical and epidemiological studies like the [[Framingham Heart Study]], [[Emerging Risk Factor Collaboration]], [[Munster Heart Study]], [[INTERHEART Study]] have proved an inverse relationship between [[HDL]] C concentration and [[cardiovascular risk]].<ref name="pmid3196218">{{cite journal| author=Wilson PW, Abbott RD, Castelli WP| title=High density lipoprotein cholesterol and mortality. The Framingham Heart Study. | journal=Arteriosclerosis | year= 1988 | volume= 8 | issue= 6 | pages= 737-41 | pmid=3196218 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3196218  }} </ref><ref name="pmid19903920">{{cite journal| author=Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK et al.| title=Major lipids, apolipoproteins, and risk of vascular disease. | journal=JAMA | year= 2009 | volume= 302 | issue= 18 | pages= 1993-2000 | pmid=19903920 | doi=10.1001/jama.2009.1619 | pmc=3284229 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19903920  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20157124 Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212] </ref><ref name="pmid8831911">{{cite journal| author=Assmann G, Schulte H, von Eckardstein A, Huang Y| title=High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. | journal=Atherosclerosis | year= 1996 | volume= 124 Suppl | issue=  | pages= S11-20 | pmid=8831911 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8831911  }} </ref><ref name="pmid15364185">{{cite journal| author=Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F et al.| title=Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. | journal=Lancet | year= 2004 | volume= 364 | issue= 9438 | pages= 937-52 | pmid=15364185 | doi=10.1016/S0140-6736(04)17018-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15364185  }} </ref>
*The atheroprotective function of [[HDL]] C is determined by measuring the cholesterol [[efflux]] from the cells and its [[anti-oxidative]] ability.<ref name="pmid25404125">{{cite journal| author=Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE et al.| title=HDL cholesterol efflux capacity and incident cardiovascular events. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 25 | pages= 2383-93 | pmid=25404125 | doi=10.1056/NEJMoa1409065 | pmc=4308988 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25404125  }} </ref>
*In [[Apo A1]] deficiency there is complete absence of [[Apo A1]] and [[HDL]] C in [[homozygotes]] and less than 50% normal in [[heterozygotes]], this disrupts the [[reverse cholesterol transport]] by :
**Change of chemical compositon in sub-populations of [[HDL]] C.<ref name="pmid21537175">{{cite journal| author=Asztalos BF, Tani M, Schaefer EJ| title=Metabolic and functional relevance of HDL subspecies. | journal=Curr Opin Lipidol | year= 2011 | volume= 22 | issue= 3 | pages= 176-85 | pmid=21537175 | doi=10.1097/MOL.0b013e3283468061 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21537175  }} </ref>
**Decrease in the [[cholesterol efflux]].
**Failure of cholesterol ester formation as [[LCAT]] function is compromised.
*The changes in the [[reverse cholesterol transport]] predispose the patients to premature heart disease.


==== Genetics ====
==== Genetics ====
*Apolipoprotein deficiency is caused by mutation in the Apo A1 gene (11q23-q24) which codes for the apolipoprotein A1.
*[[Apolipoprotein A1]] deficiency is caused by [[mutation]] in the [[Apo A1]] [[gene]] (11q23-q24) which encodes for the [[apolipoprotein A1]].
*Mutations in the gene can lead to decreased production, impaired function or increased Apo A1 catabolism.
*Mutations in the [[gene]] result in decreased production, impaired function or increased [[Apo A1]] [[catabolism]].
*Clinical phenotype varies with individual mutation and the type.
*[[Clinical phenotype]] varies with individual [[mutation]] and the [[type]].
*Frameshift mutations, nonsense mutations, genomic rearrangements, deletions are more commonly associated with premature heart disease and undetectable ApoA1 levels.
*[[Frameshift mutations]], [[nonsense]] mutations, [[genomic rearrangements]], [[deletions]] are more commonly associated with [[premature]] [[CVD]] and undetectable [[Apo A1]] levels.
*Patients with mis-sense mutations usually have detectable plasma Apo A1 and low HDL C can present with cardiovascular symptoms, amyloidosis or are healthy patients with no signs of atherosclerosis.
*Patients with [[missense]] [[mutations]] usually have detectable plasma [[Apo A1]], low [[HDL]] C and can present with cardiovascular symptoms, [[amyloidosis]] or are healthy patients with no signs of [[atherosclerosis]].


==History, Symptoms==
==Natural History, Prognosis, Complications==
*Age of of symptom onset and age of clinical presentation varies as many patients can remain asymptomatic into adulthood. Many patients are diagnosed for the first time with a cardiovascular event at a young age.
*The age of symptom onset in patients with [[Apo A1]] deficiency and the clinical presentation varies with different [[mutations]].
*Few patients remain asymptomatic into adulthood and few individuals may present from adolescence with symptoms of [[blurred vision]] due to [[corneal opacities]] or [[cataract]], tubero-eruptive, tendinous, palmar and/or planar [[xanthomas]], [[xanthelasmas]] and [[premature CVD]] and [[carotid atherosclerosis]].
*Individuals with certain mutations present with signs such as [[cerebellar ataxia]], [[hearing loss]], proliferative [[retinopathy]] or manifestations of secondary [[amyloidosis]] such as [[hepatomegaly]], [[nephropathy]] and [[cardiomyopathy]].
*If left untreated the major complication is development of [[premature CVD]].
*Prognosis depends on occurrence of [[premature CVD]] and end-stage organ failure in individuals with [[amyloidosis]].
 
==History and Symptoms==
*Age of of symptom onset and age of clinical presentation varies as many patients can remain asymptomatic into adulthood. Majority of  patients are diagnosed for the first time with a [[cardiovascular event]] at a young age.
*Patients who are symptomatic usually present with:
*Patients who are symptomatic usually present with:
**Blurry vision due to corneal opacities
**Blurry vision due to [[corneal opacities]]
**Yellowish orange lumps in the skin, palms and feet
**Yellowish orange lumps in the skin, palms and feet
* [[Coronary heart disease]] - History of [[angina]] or [[MI]] when younger than 60 years, history of premature [[heart disease]] in siblings and first-degree relatives.
**[[Coronary heart disease]] - History of [[angina]] or [[MI]] when younger than 60 years, history of premature [[heart disease]] in siblings and first-degree relatives.
:* [[Congestive heart failure]]
***[[Congestive heart failure]]
:* Peripheral vascular disease - History of [[claudication]]
***Peripheral vascular disease - History of [[claudication]]
* [[Cerebrovascular disease]]
**[[Cerebrovascular disease]]
:* History of [[stroke]]
***History of [[stroke]]
:* History of [[transient ischemic attack]]
***History of [[transient ischemic attack]]
:* History of [[carotid endarterectomy]]
***History of [[carotid endarterectomy]]
*Less common findings in Apo A1 deficiency include:
*Less common symptoms in [[Apo A1 deficiency]] include:
**Ataxia
**[[Ataxia]]
**Hearing loss
**[[Hearing loss]]
**Manifestions of amyloidosis:  
**Manifestions of [[amyloidosis]]:  
***Nephropathy presents with hematuria, generalized body swelling, shortness of breath on exertion.
***[[Nephropathy]] presents with [[hematuria]], generalized body swelling, [[shortness of breath]] on [[exertion]].
***Cardiomyopathy can present with chest pain, shortness of breath on exertion, syncope, pedal edema.
***[[Cardiomyopathy]] can present with [[chest pain]], [[shortness of breath]] on [[exertion]], [[syncope]], [[pedal edema]].


==Physical Examination==
==Physical Examination==
*Corneal opacities, corneal arcus
Physical examination findings in [[Apo A1]] deficiency include:
*Tubero-eruptive,  palmar or planar xanthomas
*[[Corneal]] opacities, [[Arcus senilis cornea|corneal arcus]]
*Cerebellar ataxia
*Tubero-eruptive,  palmar or planar [[xanthomas]]
*Neuro-sensory hearing loss
*[[Cerebellar ataxia]]
*Hepatomegaly
*[[Sensorineural]] [[hearing loss]]
*[[Hepatomegaly]]


==Diagnosis==
==Diagnosis==
*Apo A1 deficiency is diagnosed by combination undectectable Apo A1 and HDL C levels.
*[[Apo A1]] deficiency is diagnosed by combination undectectable [[Apo A1]] and [[HDL]] C levels.
===Lipid Analysis===
===Lipid Analysis===
*Laboratory features consistent with the diagnosis of Apo A1 deficiency include:
*Laboratory features consistent with the diagnosis of [[Apo A1]] deficiency include:
**Undetectable Apo A1
**Undetectable [[Apo A1]]
**HDL C less than 10mg/dl
**[[HDL C]] less than 10mg/dl
**Normal or elevated triglyceride
**Normal or elevated [[triglyceride]]
**Normal or elevated LDL C
**Normal or elevated [[LDL]] C


===2D Electrophoresis===
===2D Electrophoresis===
*2D gel electrophoresis with anti-apo A1 immunoblotting is very useful in differentiating the diseases with low HDL C. It is based on the distribution of Apo A1 in different sub-populations of HDL C.
*[[2D gel electrophoresis]] with anti-apo A1 [[immunoblotting]] is very useful in differentiating the diseases with low [[HDL]] C. It is based on the distribution of [[Apo A1]] in different sub-populations of [[HDL]] C.
*The normal values and distribution of Apo A1 in HDL C are as follows:
*The normal values and distribution of [[Apo A1]] in [[HDL]] C are as follows:
**Normal Plasma Apo A1 is 140mg/dl
**Normal [[plasma]] [[Apo A1]] is 140mg/dl
**10% is found in small discoidal pre beta HDL and alpha-1 HDL C.
**10% is found in small discoidal pre beta [[HDL]] and alpha-1 [[HDL]] C.
**90% is found in alpha-2 and alpha-3 HDL C.
**90% is found in alpha-2 and alpha-3 [[HDL]] C.
*In Apo A1 deficiency, a total absence of Apo A1 containing HDL C is demonstrated on 2D electrophoresis.
*In Apo A1 deficiency, a total absence of [[Apo A1]] containing HDL C is demonstrated on 2D [[electrophoresis]].


===Molecular Gene Sequencing===
===Molecular Gene Sequencing===
*The gold standard for diagnosis of Apo A1 deficiency is molecular gene sequencing for identification of the mutation.
*The gold standard for diagnosis of [[Apo A1]] deficiency is molecular [[gene sequencing]] for identification of the [[mutation]].


==Differential Diagnosis==
==Differential Diagnosis==
<small>
{| class="wikitable"
{| class="wikitable"
!
!
Line 260: Line 269:
|Lack of Apo A1 containing HDL particles.
|Lack of Apo A1 containing HDL particles.
|}
|}
 
</small>
====== Distinguishing features of homozygous patients with very low or undetectable HDL C and Apo A1<ref name="pmid21291740">{{cite journal| author=Santos RD, Asztalos BF, Martinez LR, Miname MH, Polisecki E, Schaefer EJ| title=Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. | journal=J Clin Lipidol | year= 2008 | volume= 2 | issue= 4 | pages= 237-47 | pmid=21291740 | doi=10.1016/j.jacl.2008.06.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21291740  }}</ref>: ======
====== Distinguishing features of homozygous patients with very low or undetectable HDL C and Apo A1<ref name="pmid21291740">{{cite journal| author=Santos RD, Asztalos BF, Martinez LR, Miname MH, Polisecki E, Schaefer EJ| title=Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. | journal=J Clin Lipidol | year= 2008 | volume= 2 | issue= 4 | pages= 237-47 | pmid=21291740 | doi=10.1016/j.jacl.2008.06.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21291740  }}</ref>: ======
{| class="wikitable"
{| class="wikitable"
Line 268: Line 277:
!Apo A Deficiency
!Apo A Deficiency
|-
|-
|Planar Xanthomas
|Planar [[Xanthomas]]
|Absent  
|Absent  
|Present  
|Present  
|Present
|Present
|-
|-
|Tubo-Eruptive Xanthomas  
|Tubo-Eruptive [[Xanthomas]]
|Absent  
|Absent  
|Absent  
|Absent  
Line 283: Line 292:
|Present
|Present
|-
|-
|Triglyceride  
|[[Triglyceride]]
|Decreased due to the absence  
|Decreased due to the absence of [[Apo C III]](lipolysis inhibitor)
of Apo C III- a lipolysis inhibitor  
|Decreased  
|Decreased  
|Normal
|Normal
|-
|-
|LDL C  
|[[LDL]] C  
|Normal  
|Normal  
|Normal  
|Normal  
|Normal
|Normal
|-
|-
|HDL C  
|[[HDL]] C  
|Less than 5mg/dl
|Less than 5mg/dl
|Less than 5mg/dl
|Less than 5mg/dl
|Less than 5mg/dl
|Less than 5mg/dl
|-
|-
|Apo A1
|[[Apo A1]]
|Undetectable
|Undetectable
|Undetectable
|Undetectable
|Undetectable
|Undetectable
|-
|-
|Apo C III  
|[[Apo C III]]
|Undetectable
|Undetectable
|Undetectable
|Undetectable
|Normal
|Normal
|-
|-
|Apo A IV
|[[Apo AIV]]
|Undetectable  
|Undetectable  
|Normal  
|Normal  
Line 316: Line 324:


==Approch to a patient with low HDL C<ref name="pmid23043194">{{cite journal| author=Rader DJ, deGoma EM| title=Approach to the patient with extremely low HDL-cholesterol. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 10 | pages= 3399-407 | pmid=23043194 | doi=10.1210/jc.2012-2185 | pmc=3462950 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23043194  }} </ref>==
==Approch to a patient with low HDL C<ref name="pmid23043194">{{cite journal| author=Rader DJ, deGoma EM| title=Approach to the patient with extremely low HDL-cholesterol. | journal=J Clin Endocrinol Metab | year= 2012 | volume= 97 | issue= 10 | pages= 3399-407 | pmid=23043194 | doi=10.1210/jc.2012-2185 | pmc=3462950 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23043194  }} </ref>==
<small>
{{Family tree/start}}
{{Family tree/start}}
{{Family tree | | | | | | A01 | | | |A01= HDL <20mg/dl in the absence of severe hypertriglyceridemia}}
{{Family tree | | | | | | A01 | | | |A01= HDL <20mg/dl in the absence of severe [[hypertriglyceridemia]]}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | C01 | | | |C01= Rule out secondary causes of low HDL C<br>Paraproteinemia from multiple myeloma<br>Anabolic steriod use<br>Fibrate use<br>Thiazolidinedione use}}
{{Family tree | | | | | | C01 | | | |C01= Rule out secondary causes of low [[HDL]] C<br>[[Paraproteinemia]] from [[multiple myeloma]]<br>[[Anabolic steriod]] use<br>[[Fibrate]] use<br>[[Thiazolidinedione]] use}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | E01 | | | |E01= Consider Monogenic primary disorders<br>Order ApoA1}}
{{Family tree | | | | | | E01 | | | |E01= Consider Monogenic primary disorders<br>Order [[Apo A1]]}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | |,|-|-|-|^|-|-|.|}}
{{Family tree | | |,|-|-|-|^|-|-|.|}}
{{Family tree | |F01| | | | |F02| |F01= >5mg/dl| F02= Undetectable or <5mg/dl}}
{{Family tree | |F01| | | | |F02| |F01= >5mg/dl| F02= Undetectable or <5mg/dl}}
{{Family tree | | |!| | | | | | |!| | | | | | }}
{{Family tree | | |!| | | | | | |!| | | | | | }}
{{Family tree | |G01| | | | |G02| | | |G01=Familial LCAT deficiency <br>High plasma FC:CE ratio<br>2D electrophoresis: Prebeta and Alpha-4, Beta mobility of LDL|G02= Do 2D Gel Electrophoresis with Apo A1 Immunoassay}}
{{Family tree | |G01| | | | |G02| | | |G01=Familial [[LCAT]] deficiency <br>High [[plasma]] FC:CE ratio<br>[[2D electrophoresis]]: Prebeta and Alpha-4, Beta mobility of [[LDL]]|G02= Do [[2D Gel Electrophoresis]] with [[Apo A1]] Immunoassay}}
{{Family tree | | | | | | | | | |!| | | | }}
{{Family tree | | | | | | | | | |!| | | | }}
{{Family tree | | | | | | | |,|-|^|-|-|.| }}
{{Family tree | | | | | | | |,|-|^|-|-|.| }}
{{Family tree | | | | | | | H01| | |H02|H01= Complete absence of Apo A1 containing HDL C|H02= Only Pre-Beta HDL C}}
{{Family tree | | | | | | | H01| | |H02|H01= Complete absence of [[Apo A1]] containing [[HDL]] C|H02= Only Pre-Beta [[HDL]] C}}
{{Family tree | | | | | | | |!| | | | |!| }}
{{Family tree | | | | | | | |!| | | | |!| }}
{{Family tree | | | | | | |I01| | |I02|I01=Apo A1 Deficiency<br><SMALL>(Confirm with gene sequencing)</SMALL>|I02=Homozygous Tangier Disease<br><SMALL>(Confirm with gene sequencing)</SMALL>}}
{{Family tree | | | | | | |I01| | |I02|I01=[[Apo A1]] Deficiency<br><SMALL>(Confirm with [[gene sequencing]])</SMALL>|I02=[[Homozygous]] [[Tangier Disease]]<br><SMALL>(Confirm with [[gene sequencing]])</SMALL>}}
{{Family tree/end}}
{{Family tree/end}}
</small>


==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
The mainstay of therapy for Apo A1 deficiency include:
The mainstay of therapy for Apo A1 deficiency includes:
*Patients with low HDL C and Apo A1 should be treated with statins for reduction of LDL C.
*Patients with low [[HDL]] C and [[Apo A1]] should be treated with [[statins]] for optimizing the level of [[LDL]] C.
*Patients with Apo A1 variants do not develop clinical sequelae generally to need specific treatment.
*Patients with [[Apo A1]] variants do not develop clinical sequelae generally to need specific treatment.
*Apo A1 infusion therapy is the future of treatment, which helps in  improving the cholesterol efflux and reduce the plaque burden in patients who undergo interventions like PCI.<ref name="pmid27659879">{{cite journal| author=Gibson CM, Korjian S, Tricoci P, Daaboul Y, Alexander JH, Steg PG et al.| title=Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction. | journal=Am Heart J | year= 2016 | volume= 180 | issue=  | pages= 22-8 | pmid=27659879 | doi=10.1016/j.ahj.2016.06.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27659879  }}</ref>
*[[Apo A1]] infusion therapy is the future of treatment, which helps in  improving the [[cholesterol efflux]] and reduce the plaque burden in patients who undergo interventions for [[CAD]].<ref name="pmid27659879">{{cite journal| author=Gibson CM, Korjian S, Tricoci P, Daaboul Y, Alexander JH, Steg PG et al.| title=Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction. | journal=Am Heart J | year= 2016 | volume= 180 | issue=  | pages= 22-8 | pmid=27659879 | doi=10.1016/j.ahj.2016.06.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27659879  }}</ref>


===Surgical Therapy===
===Surgical Therapy===
*Patients presenting with myocardial infarction should undergo PCI with stent of the blocked vessel.
*Patients presenting with [[myocardial infarction]] should undergo [[coronary bypass]] or [[PCI]] with stent.


== Primary Prevention ==
== Primary Prevention ==
*Assessment of cardiovascular risk in patients diagnosed with Apo A1 deficiency and Apo A1 variants.
*Assessment of cardiovascular risk in patients diagnosed with [[Apo A1]] deficiency and [[Apo A1]] variants.
*The goal of LDL C should be targeted below 70mg/dl according to the ATP III guidelines with high intensity statin therapy.
*The goal of [[LDL]] C should be targeted below 70mg/dl according to the ATP III guidelines with high intensity statin therapy.
*All the traditional risk factors of CVD should be identified and addressed.
*All the traditional risk factors of CVD should be identified and addressed.
*Sub-clinical atherosclerosis can be identified by imaging with coronary artery calcium or carotid media thickness assessment which helps in guiding the lipid lowering therapy and assess the cardiovascular risk.
*Sub-clinical [[atherosclerosis]] can be identified by imaging with [[coronary artery calcium]] or [[carotid media thickness]] assessment which helps in guiding the [[lipid lowering therapy]] and assess the [[cardiovascular]] risk.


==References==
==References==

Latest revision as of 17:11, 4 April 2017

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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 hypoalphalipoproteinemia, FHA, familial HDL deficiency, FHD, high density lipoprotein deficiency, HDLD

Overview

Apolipoprotien A1 deficiency is a rare monogenic metabolic disorder resulting in undetectable Apo A1 levels and HDL C less than 20mg/dl. APOA1 gene encodes for the Apo A1 protein which is the major component of HDL C. It is synthesized in the liver and released into the circulation as very small discoid pre beta HDL, which picks up free cholesterol from the cells and macrophages. Apo A1 also activates LCAT which esterifies free cholesterol on the surface of alpha 4 HDL resulting in the formation of cholesterol esters. These two initial steps in the reverse cholesterol are dependent on a functional Apo A1 which is defective in Apo A1 deficiency. Apo A1 synthesis is affected leading to very low HDL levels. Worldwide, 82 cases and a variety of mutations are reported. The biochemical phenotype is always a low Apo A1 and low HDL C. Clinical phenotype varies with each mutation and is inconsistent. Symptomatic patients usually present with corneal opacities, xanthelasma and premature heart disease. Cardiovascular risk assessment and optimizing risk factors has an important role in the management.

Historical Perspective

Classification

Familial apolipoprotein A-I/C-III/A-IV deficiency

ApoA1/ApoC-III Deficiency

Apo A1 Deficiency

Apo A1 Variants

Demographics, Epidemiology

  • Worldwide, 82 Apo A1 mutations have been reported.[22]
  • The prevalence of Apo A1 deficiency is estimated to be less than 1/1,000,000 population.[31]
  • Apo A1 deficiency accounts for 6% of Japanese population with low HDL C.[32]
  • Genomic sequencing of Apo A1 gene in 10,330 population based participants in the Copenhagen City Heart study revealed[24]:

Pathogenesis

Apolipoprotein A1 deficiency is caused by mutation in the APOA1 gene encoding ApoA1 protein, a major transport protein of reverse cholesterol transport.

Pathophysiology

Reverse Cholesterol Transport[33]

 
 
 
Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter[34] to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease resulting in only pre beta HDL on 2D electrophoresis.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discoidal HDL particles are converted to medium spherical α-3 HDL and larger particles by the esterification of free cholesterol via the enzyme lecithin cholesterol acyltransferase (LCAT) and the addition of ApoA II
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These particles are further converted to large and very large spherical α-2 and α-1 HDL by the actions of cholesteryl ester transfer protein (CETP). CETP transfers cholesteryl ester from HDL to triglyceride rich lipoproteins in exchange for triglyceride
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very large α-1 HDL particles are donors of cholesterol to the liver, and the constituents of these particles can recycle back to form very small discoidal particles and re-enter the HDL cycle, or be catabolized directly by the kidney or liver
 
 
 

Genetics

Natural History, Prognosis, Complications

History and Symptoms

Physical Examination

Physical examination findings in Apo A1 deficiency include:

Diagnosis

  • Apo A1 deficiency is diagnosed by combination undectectable Apo A1 and HDL C levels.

Lipid Analysis

  • Laboratory features consistent with the diagnosis of Apo A1 deficiency include:

2D Electrophoresis

  • 2D gel electrophoresis with anti-apo A1 immunoblotting is very useful in differentiating the diseases with low HDL C. It is based on the distribution of Apo A1 in different sub-populations of HDL C.
  • The normal values and distribution of Apo A1 in HDL C are as follows:
    • Normal plasma Apo A1 is 140mg/dl
    • 10% is found in small discoidal pre beta HDL and alpha-1 HDL C.
    • 90% is found in alpha-2 and alpha-3 HDL C.
  • In Apo A1 deficiency, a total absence of Apo A1 containing HDL C is demonstrated on 2D electrophoresis.

Molecular Gene Sequencing

Differential Diagnosis

Familial LCAT

Deficiency

Fish Eye

Disease

Homozygous Tangier

Disease

Heterozygous Tangier

Disease

Apo A1 Deficiency
Gene Defect LCAT LCAT ABCA1 ABCA1 Apo A1
Inheritance Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Dominant
Pathogenesis
  • Loss of alpha and beta LCAT function
  • Failure of cholesterol ester formation.
Loss of alpha function only

Pre beta-1 HDL fails to picks up free cholesterol from cells due to mutation in ABCA1 transporter.

Similar to homozygous Defective synthesis of Apo A1 resulting in failure of maturation of HDL and defective reverse cholesterol transport.
Clinical Features
  • Annular corneal opacity
  • Anaemia
  • Progressive renal disease with proteinuria
  • Corneal opacities only
  • Normal renal function
  • Large yellow-orange tonsils
  • Dense central corneal opacity
  • Relapsing and remitting course of neuropathy
Asymptomatic
  • Corneal Opacities
  • Tuboeruptive, Planar and palmar Xanthomas
  • Premature Heart Disease
Lipid Panel
  • Elevated Free cholesterol
  • HDL-C < 10 mg/dL
  • Low Apo A1 and Apo AII
  • Elevated Apo E and Triglycerides
  • Low LDL C
  • Elevated free cholesterol
  • HDL C < 27 mg/dL
  • Apo A1<30mg/dl and low Apo A2
  • Elevated Apo E and Triglycerides
  • Normal LDL and VLDL
  • HDL < 5% of normal
  • Apo A1 < 1% of normal
  • LDL < 40% of normal
  • HDL C, Apo A1 and LDL 50% less than normal.
  • Undetectable Apo A1
  • HDL C less than 10mg/dl
  • Normal or low Apo AII
  • LDL C normal
  • Triglyceride normal or elevated
2D Gel Electrophoresis Pre β-1 and α-4 HDL, LDL with β mobility due to Lipoprotien-X Pre β-1and α-4 HDL with normal pre-β LDL. Only preβ-1 HDL present
  • Lack of large α-1 and α-2 HDL particles
  • Normal preβ-1 HDL
Lack of Apo A1 containing HDL particles.

Distinguishing features of homozygous patients with very low or undetectable HDL C and Apo A1[47]:
Apo A/CIII/A-IV Deficiency ApoA/CIII Deficiency Apo A Deficiency
Planar Xanthomas Absent Present Present
Tubo-Eruptive Xanthomas Absent Absent Present
Premature Heart Disease Present Present Present
Triglyceride Decreased due to the absence of Apo C III(lipolysis inhibitor) Decreased Normal
LDL C Normal Normal Normal
HDL C Less than 5mg/dl Less than 5mg/dl Less than 5mg/dl
Apo A1 Undetectable Undetectable Undetectable
Apo C III Undetectable Undetectable Normal
Apo AIV Undetectable Normal Normal

Approch to a patient with low HDL C[48]

 
 
 
 
 
HDL <20mg/dl in the absence of severe hypertriglyceridemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out secondary causes of low HDL C
Paraproteinemia from multiple myeloma
Anabolic steriod use
Fibrate use
Thiazolidinedione use
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consider Monogenic primary disorders
Order Apo A1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>5mg/dl
 
 
 
 
Undetectable or <5mg/dl
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Familial LCAT deficiency
High plasma FC:CE ratio
2D electrophoresis: Prebeta and Alpha-4, Beta mobility of LDL
 
 
 
 
Do 2D Gel Electrophoresis with Apo A1 Immunoassay
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete absence of Apo A1 containing HDL C
 
 
Only Pre-Beta HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apo A1 Deficiency
(Confirm with gene sequencing)
 
 
Homozygous Tangier Disease
(Confirm with gene sequencing)

Treatment

Medical Therapy

The mainstay of therapy for Apo A1 deficiency includes:

  • Patients with low HDL C and Apo A1 should be treated with statins for optimizing the level of LDL C.
  • Patients with Apo A1 variants do not develop clinical sequelae generally to need specific treatment.
  • Apo A1 infusion therapy is the future of treatment, which helps in improving the cholesterol efflux and reduce the plaque burden in patients who undergo interventions for CAD.[49]

Surgical Therapy

Primary Prevention

References

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  49. Gibson CM, Korjian S, Tricoci P, Daaboul Y, Alexander JH, Steg PG; et al. (2016). "Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction". Am Heart J. 180: 22–8. doi:10.1016/j.ahj.2016.06.017. PMID 27659879.


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