Apolipoprotein A deficiency: Difference between revisions

Lipid Disorders Main Page
Overview
Causes
Classification Abetalipoproteinemia Hypobetalipoproteinemia Familial hypoalphalipoproteinemia LCAT Deficiency Chylomicron retention disease Tangier disease Familial combined hypolipidemia
Differential Diagnosis

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Revision as of 21:13, 5 December 2016

Template:Apolipoprotein A1 Deficiency

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 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.

Historical Perspective

In 1981, Vergani and Bettale described a familial syndrome with hypoalphalipoproteinemia.^[1]
- 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.
- 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.^[2]
In 1982, Karathanasis isolated and described the characteristics of the human Apo A1 gene.^[3]
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.^[4]
- 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.^[5]
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.^[6]
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.^[7]
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.^[8]
In 1998, Gillotte described the mechanism apolipoprotein mediated cellular lipid efflux.^[9]
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.^[10]

Classification

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
- ApoA1/C-III deficiency
- Isolated Apo A1 deficiency
- Apo A1 Variants

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.^[11]
Her plasma LCAT activity was normal.
Defect was a homozygous deletion of the entire APOA1/C3/A4 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.^[12]

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.^[13]
These patients had low TG, normal LDL-C and had enhanced clearance of VLDL Apo B.^[14]
The defect was a homozygous DNA re-arrangement affecting the APOA1 and APO CIII genes.

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.^[15]
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.^[16]
- 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.
- Genotyping of the kindred showed four homozygotes, four heterozygotes and two unaffected subjects.
- 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.^[17]
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.^[18]
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.^[19]

Apo A1 Variants

ApoA-I variants are heterozygous premature terminations, frameshift mutation or amino acid substitutions in the 243 amino acid Apo AI 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.
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.^[20]^[21]^[22]
Few mutations resulting in low HDL C with normal LCAT function have an increased risk of coronary artery disease at a young age.^[23]^[24]
Few mutations in Apo A1 are associated with familial visceral amyloidosis.^[25]^[26]
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.^[27]
- 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.^[28]
- 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.^[29]
- 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).^[23]
- 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.^[30]
- 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.^[22]

Demographics, Epidemiology

Worldwide, 82 Apo AI mutations have been reported in human subjects.^[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 ApoA1 gene in 10,330 population based participants in the Copenhagen City Heart study revealed^[24]:
- 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.

Natural History, Progression, Complications

Pathogenesis

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^[33]:
- Apo-AI is important for mediating the efflux of cholesterol from peripheral tissues.^[34]
- ApoA-I interacts with ABCA1 and accepts free cholesterol.^[35]^[36]
- Apo-A1 is a potent activator of LCAT, enzyme helpful in the formation of cholesterol esters.^[37]
- Delivery of cholesterol esters to the liver mediated by scavenger receptor class B type I (SR-B1).^[38]
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.^[39]
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.^[40]^[41]^[42]^[43]
The atheroprotective function of HDL C is determined by measuring the cholesterol efflux from the cells and its anti-oxidative ability.^[44]

Reverse Cholesterol Transport^[45]

Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter^[46] 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 can re-enter the HDL cycle, or be catabolized directly by the kidney or liver

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.^[45]
- Decrease in the cholesterol efflux.
- Failure of cholesterol ester formation as LCAT function is compromised in few mutations.
The changes in the reverse cholesterol transport predispose the patients to premature heart disease.

Genetics

Apolipoprotein deficiency is caused by mutation in the Apo A1 gene (11q23-q24) which codes for the apolipoprotein A1.
Mutations in the gene can lead to decreased production, impaired function or increased Apo A1 catabolism.
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.
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.

History, Symptoms

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.
Patients who are symptomatic usually present with:
- Blurry vision due to corneal opacities
- 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.

Congestive heart failure
Peripheral vascular disease - History of claudication

Cerebrovascular disease

History of stroke
History of transient ischemic attack
History of carotid endarterectomy

Less common findings in Apo A1 deficiency include:
- Ataxia
- Hearing loss
- Manifestions of amyloidosis:
  - 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.

Physical Examination

Corneal opacities, corneal arcus
Tubero-eruptive, palmar or planar xanthomas
Cerebellar ataxia
Neuro-sensory hearing loss
Hepatomegaly

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:
- Undetectable Apo A1
- HDL C less than 10mg/dl
- Normal or elevated triglyceride
- Normal or elevated LDL C

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

The gold standard for diagnosis of Apo A1 deficiency is molecular gene sequencing for identification of the mutation.

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- a 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 A IV	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 ApoA1

>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 include:

Patients with low HDL C and Apo A1 should be treated with statins for reduction 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 like PCI.

Surgical Therapy

Patients presenting with myocardial infarction should undergo PCI with stent of the blocked vessel.

Primary Prevention

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.
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.

References

↑ Vergani C, Bettale G (1981). "Familial hypo-alpha-lipoproteinemia". Clin Chim Acta. 114 (1): 45–52. PMID 7249374.
↑ Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL; et al. (1982). "Isolation and characterization of cDNA clones for human apolipoprotein A-I". Proc Natl Acad Sci U S A. 79 (22): 6861–5. PMC 347233. PMID 6294659.
↑ Karathanasis SK, Zannis VI, Breslow JL (1983). "Isolation and characterization of the human apolipoprotein A-I gene". Proc Natl Acad Sci U S A. 80 (20): 6147–51. PMC 390160. PMID 6413973.
↑ Daniels SR, Bates S, Lukin RR, Benton C, Third J, Glueck CJ (1982). "Cerebrovascular arteriopathy (arteriosclerosis) and ischemic childhood stroke". Stroke. 13 (3): 360–5. PMID 7080131.
↑ Law SW, Gray G, Brewer HB (1983). "cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I". Biochem Biophys Res Commun. 112 (1): 257–64. PMID 6404278.
↑ Borecki IB, Rao DC, Third JL, Laskarzewski PM, Glueck CJ (1986). "A major gene for primary hypoalphalipoproteinemia". Am J Hum Genet. 38 (3): 373–81. PMC 1684774. PMID 3953576.
↑ Ordovas JM, Schaefer EJ, Salem D, Ward RH, Glueck CJ, Vergani C; et al. (1986). "Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia". N Engl J Med. 314 (11): 671–7. doi:10.1056/NEJM198603133141102. PMID 3081805.
↑ Li WH, Tanimura M, Luo CC, Datta S, Chan L (1988). "The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution". J Lipid Res. 29 (3): 245–71. PMID 3288703.
↑ Gillotte KL, Zaiou M, Lund-Katz S, Anantharamaiah GM, Holvoet P, Dhoest A; et al. (1999). "Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid". J Biol Chem. 274 (4): 2021–8. PMID 9890960.
↑ Ajees AA, Anantharamaiah GM, Mishra VK, Hussain MM, Murthy HM (2006). "Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases". Proc Natl Acad Sci U S A. 103 (7): 2126–31. doi:10.1073/pnas.0506877103. PMC 1413691. PMID 16452169.
↑ Schaefer EJ, Heaton WH, Wetzel MG, Brewer HB (1982). "Plasma apolipoprotein A-1 absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease". Arteriosclerosis. 2 (1): 16–26. PMID 6800349.
↑ Schaefer EJ (1984). "Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency". Arteriosclerosis. 4 (4): 303–22. PMID 6431953.
↑ Norum RA, Lakier JB, Goldstein S, Angel A, Goldberg RB, Block WD; et al. (1982). "Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease". N Engl J Med. 306 (25): 1513–9. doi:10.1056/NEJM198206243062503. PMID 7078608.
↑ Forte TM, Nichols AV, Krauss RM, Norum RA (1984). "Familial apolipoprotein AI and apolipoprotein CIII deficiency. Subclass distribution, composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis". J Clin Invest. 74 (5): 1601–13. doi:10.1172/JCI111576. PMC 425337. PMID 6501564.
↑ Matsunaga T, Hiasa Y, Yanagi H, Maeda T, Hattori N, Yamakawa K; et al. (1991). "Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene". Proc Natl Acad Sci U S A. 88 (7): 2793–7. PMC 51325. PMID 1901417.
↑ Ng DS, Leiter LA, Vezina C, Connelly PW, Hegele RA (1994). "Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia". J Clin Invest. 93 (1): 223–9. doi:10.1172/JCI116949. PMC 293756. PMID 8282791.
↑ Santos RD, Schaefer EJ, Asztalos BF, Polisecki E, Wang J, Hegele RA; et al. (2008). "Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency". J Lipid Res. 49 (2): 349–57. doi:10.1194/jlr.M700362-JLR200. PMID 17991756.
↑ Wada M, Iso T, Asztalos BF, Takama N, Nakajima T, Seta Y; et al. (2009). "Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion)". Atherosclerosis. 207 (1): 157–61. doi:10.1016/j.atherosclerosis.2009.04.018. PMID 19473658.
↑ Al-Sarraf A, Al-Ghofaili K, Sullivan DR, Wasan KM, Hegele R, Frohlich J (2010). "Complete Apo AI deficiency in an Iraqi Mandaean family: case studies and review of the literature". J Clin Lipidol. 4 (5): 420–6. doi:10.1016/j.jacl.2010.05.001. PMID 21122686.
↑ Miccoli R, Zhu Y, Daum U, Wessling J, Huang Y, Navalesi R; et al. (1997). "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". J Lipid Res. 38 (6): 1242–53. PMID 9215551.
↑ Daum U, Leren TP, Langer C, Chirazi A, Cullen P, Pritchard PH; et al. (1999). "Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers". J Lipid Res. 40 (3): 486–94. PMID 10064737.
↑ ^22.0 ^22.1 ^22.2 Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ (2015). "Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux". J Clin Lipidol. 9 (3): 390–5. doi:10.1016/j.jacl.2015.02.005. PMID 26073399.
↑ ^23.0 ^23.1 Lee EY, Klementowicz PT, Hegele RA, Asztalos BF, Schaefer EJ (2013). "HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature". J Clin Lipidol. 7 (2): 169–73. doi:10.1016/j.jacl.2012.10.011. PMC 4565164. PMID 23415437.
↑ ^24.0 ^24.1 Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A (2012). "Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach". PLoS Genet. 8 (11): e1003063. doi:10.1371/journal.pgen.1003063. PMC 3510059. PMID 23209431.
↑ Soutar AK, Hawkins PN, Vigushin DM, Tennent GA, Booth SE, Hutton T; et al. (1992). "Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis". Proc Natl Acad Sci U S A. 89 (16): 7389–93. PMC 49715. PMID 1502149.
↑ Das M, Wilson CJ, Mei X, Wales TE, Engen JR, Gursky O (2016). "Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?". J Mol Biol. 428 (2 Pt B): 449–62. doi:10.1016/j.jmb.2015.10.029. PMC 4744490. PMID 26562506.
↑ Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW (1980). "A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family". J Clin Invest. 66 (5): 892–900. doi:10.1172/JCI109956. PMC 371523. PMID 7430351.
↑ Funke H, von Eckardstein A, Pritchard PH, Karas M, Albers JJ, Assmann G (1991). "A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities". J Clin Invest. 87 (1): 371–6. doi:10.1172/JCI114997. PMC 295069. PMID 1898657.
↑ Takata K, Saku K, Ohta T, Takata M, Bai H, Jimi S; et al. (1995). "A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease". Arterioscler Thromb Vasc Biol. 15 (11): 1866–74. PMID 7583566.
↑ Anthanont P, Polisecki E, Asztalos BF, Diffenderfer MR, Barrett PH, Millar JS; et al. (2014). "A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production". Atherosclerosis. 235 (2): 470–6. doi:10.1016/j.atherosclerosis.2014.05.935. PMID 24950002.
↑ "Orphanet: Apolipoprotein A I deficiency".
↑ Yamakawa-Kobayashi K, Yanagi H, Fukayama H, Hirano C, Shimakura Y, Yamamoto N; et al. (1999). "Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey". Hum Mol Genet. 8 (2): 331–6. PMID 9931341.
↑ Lund-Katz S, Phillips MC (2010). "High density lipoprotein structure-function and role in reverse cholesterol transport". Subcell Biochem. 51: 183–227. doi:10.1007/978-90-481-8622-8_7. PMC 3215094. PMID 20213545.
↑ Hellerstein M, Turner S (2014). "Reverse cholesterol transport fluxes". Curr Opin Lipidol. 25 (1): 40–7. doi:10.1097/MOL.0000000000000050. PMID 24362356.
↑ Oram JF (2002). "ATP-binding cassette transporter A1 and cholesterol trafficking". Curr Opin Lipidol. 13 (4): 373–81. PMID 12151852.
↑ Iatan I, Bailey D, Ruel I, Hafiane A, Campbell S, Krimbou L; et al. (2011). "Membrane microdomains modulate oligomeric ABCA1 function: impact on apoAI-mediated lipid removal and phosphatidylcholine biosynthesis". J Lipid Res. 52 (11): 2043–55. doi:10.1194/jlr.M016196. PMC 3196236. PMID 21846716.
↑ Jonas A (2000). "Lecithin cholesterol acyltransferase". Biochim Biophys Acta. 1529 (1–3): 245–56. PMID 11111093.
↑ Krieger M (1999). "Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI". Annu Rev Biochem. 68: 523–58. doi:10.1146/annurev.biochem.68.1.523. PMID 10872459.
↑ Sorci-Thomas MG, Thomas MJ (2002). "The effects of altered apolipoprotein A-I structure on plasma HDL concentration". Trends Cardiovasc Med. 12 (3): 121–8. PMID 12007737.
↑ Wilson PW, Abbott RD, Castelli WP (1988). "High density lipoprotein cholesterol and mortality. The Framingham Heart Study". Arteriosclerosis. 8 (6): 737–41. PMID 3196218.
↑ Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK; et al. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMC 3284229. PMID 19903920. Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212
↑ Assmann G, Schulte H, von Eckardstein A, Huang Y (1996). "High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport". Atherosclerosis. 124 Suppl: S11–20. PMID 8831911.
↑ Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F; et al. (2004). "Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study". Lancet. 364 (9438): 937–52. doi:10.1016/S0140-6736(04)17018-9. PMID 15364185.
↑ Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE; et al. (2014). "HDL cholesterol efflux capacity and incident cardiovascular events". N Engl J Med. 371 (25): 2383–93. doi:10.1056/NEJMoa1409065. PMC 4308988. PMID 25404125.
↑ ^45.0 ^45.1 Asztalos BF, Tani M, Schaefer EJ (2011). "Metabolic and functional relevance of HDL subspecies". Curr Opin Lipidol. 22 (3): 176–85. doi:10.1097/MOL.0b013e3283468061. PMID 21537175.
↑ Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G; et al. (2009). "Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1". Biochemistry. 48 (46): 11067–74. doi:10.1021/bi901564g. PMID 19839639.
↑ Santos RD, Asztalos BF, Martinez LR, Miname MH, Polisecki E, Schaefer EJ (2008). "Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states". J Clin Lipidol. 2 (4): 237–47. doi:10.1016/j.jacl.2008.06.002. PMID 21291740.
↑ Rader DJ, deGoma EM (2012). "Approach to the patient with extremely low HDL-cholesterol". J Clin Endocrinol Metab. 97 (10): 3399–407. doi:10.1210/jc.2012-2185. PMC 3462950. PMID 23043194.

Template:WH Template:WS

[pmid7249374-1] Vergani C, Bettale G (1981). "Familial hypo-alpha-lipoproteinemia". Clin Chim Acta. 114 (1): 45–52. PMID 7249374.

[pmid6294659-2] Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL; et al. (1982). "Isolation and characterization of cDNA clones for human apolipoprotein A-I". Proc Natl Acad Sci U S A. 79 (22): 6861–5. PMC 347233. PMID 6294659.

[pmid6413973-3] Karathanasis SK, Zannis VI, Breslow JL (1983). "Isolation and characterization of the human apolipoprotein A-I gene". Proc Natl Acad Sci U S A. 80 (20): 6147–51. PMC 390160. PMID 6413973.

[pmid7080131-4] Daniels SR, Bates S, Lukin RR, Benton C, Third J, Glueck CJ (1982). "Cerebrovascular arteriopathy (arteriosclerosis) and ischemic childhood stroke". Stroke. 13 (3): 360–5. PMID 7080131.

[pmid6404278-5] Law SW, Gray G, Brewer HB (1983). "cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I". Biochem Biophys Res Commun. 112 (1): 257–64. PMID 6404278.

[pmid3953576-6] Borecki IB, Rao DC, Third JL, Laskarzewski PM, Glueck CJ (1986). "A major gene for primary hypoalphalipoproteinemia". Am J Hum Genet. 38 (3): 373–81. PMC 1684774. PMID 3953576.

[pmid3081805-7] Ordovas JM, Schaefer EJ, Salem D, Ward RH, Glueck CJ, Vergani C; et al. (1986). "Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia". N Engl J Med. 314 (11): 671–7. doi:10.1056/NEJM198603133141102. PMID 3081805.

[pmid3288703-8] Li WH, Tanimura M, Luo CC, Datta S, Chan L (1988). "The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution". J Lipid Res. 29 (3): 245–71. PMID 3288703.

[pmid9890960-9] Gillotte KL, Zaiou M, Lund-Katz S, Anantharamaiah GM, Holvoet P, Dhoest A; et al. (1999). "Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid". J Biol Chem. 274 (4): 2021–8. PMID 9890960.

[pmid16452169-10] Ajees AA, Anantharamaiah GM, Mishra VK, Hussain MM, Murthy HM (2006). "Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases". Proc Natl Acad Sci U S A. 103 (7): 2126–31. doi:10.1073/pnas.0506877103. PMC 1413691. PMID 16452169.

[pmid6800349-11] Schaefer EJ, Heaton WH, Wetzel MG, Brewer HB (1982). "Plasma apolipoprotein A-1 absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease". Arteriosclerosis. 2 (1): 16–26. PMID 6800349.

[pmid6431953-12] Schaefer EJ (1984). "Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency". Arteriosclerosis. 4 (4): 303–22. PMID 6431953.

[pmid7078608-13] Norum RA, Lakier JB, Goldstein S, Angel A, Goldberg RB, Block WD; et al. (1982). "Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease". N Engl J Med. 306 (25): 1513–9. doi:10.1056/NEJM198206243062503. PMID 7078608.

[pmid6501564-14] Forte TM, Nichols AV, Krauss RM, Norum RA (1984). "Familial apolipoprotein AI and apolipoprotein CIII deficiency. Subclass distribution, composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis". J Clin Invest. 74 (5): 1601–13. doi:10.1172/JCI111576. PMC 425337. PMID 6501564.

[pmid1901417-15] Matsunaga T, Hiasa Y, Yanagi H, Maeda T, Hattori N, Yamakawa K; et al. (1991). "Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene". Proc Natl Acad Sci U S A. 88 (7): 2793–7. PMC 51325. PMID 1901417.

[pmid8282791-16] Ng DS, Leiter LA, Vezina C, Connelly PW, Hegele RA (1994). "Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia". J Clin Invest. 93 (1): 223–9. doi:10.1172/JCI116949. PMC 293756. PMID 8282791.

[pmid17991756-17] Santos RD, Schaefer EJ, Asztalos BF, Polisecki E, Wang J, Hegele RA; et al. (2008). "Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency". J Lipid Res. 49 (2): 349–57. doi:10.1194/jlr.M700362-JLR200. PMID 17991756.

[pmid19473658-18] Wada M, Iso T, Asztalos BF, Takama N, Nakajima T, Seta Y; et al. (2009). "Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion)". Atherosclerosis. 207 (1): 157–61. doi:10.1016/j.atherosclerosis.2009.04.018. PMID 19473658.

[pmid21122686-19] Al-Sarraf A, Al-Ghofaili K, Sullivan DR, Wasan KM, Hegele R, Frohlich J (2010). "Complete Apo AI deficiency in an Iraqi Mandaean family: case studies and review of the literature". J Clin Lipidol. 4 (5): 420–6. doi:10.1016/j.jacl.2010.05.001. PMID 21122686.

[pmid9215551-20] Miccoli R, Zhu Y, Daum U, Wessling J, Huang Y, Navalesi R; et al. (1997). "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". J Lipid Res. 38 (6): 1242–53. PMID 9215551.

[pmid10064737-21] Daum U, Leren TP, Langer C, Chirazi A, Cullen P, Pritchard PH; et al. (1999). "Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers". J Lipid Res. 40 (3): 486–94. PMID 10064737.

[pmid26073399-22] 22.0 ^22.1 ^22.2 Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ (2015). "Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux". J Clin Lipidol. 9 (3): 390–5. doi:10.1016/j.jacl.2015.02.005. PMID 26073399.

[pmid23415437-23] 23.0 ^23.1 Lee EY, Klementowicz PT, Hegele RA, Asztalos BF, Schaefer EJ (2013). "HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature". J Clin Lipidol. 7 (2): 169–73. doi:10.1016/j.jacl.2012.10.011. PMC 4565164. PMID 23415437.

[pmid23209431-24] 24.0 ^24.1 Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A (2012). "Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach". PLoS Genet. 8 (11): e1003063. doi:10.1371/journal.pgen.1003063. PMC 3510059. PMID 23209431.

[pmid1502149-25] Soutar AK, Hawkins PN, Vigushin DM, Tennent GA, Booth SE, Hutton T; et al. (1992). "Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis". Proc Natl Acad Sci U S A. 89 (16): 7389–93. PMC 49715. PMID 1502149.

[pmid26562506-26] Das M, Wilson CJ, Mei X, Wales TE, Engen JR, Gursky O (2016). "Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?". J Mol Biol. 428 (2 Pt B): 449–62. doi:10.1016/j.jmb.2015.10.029. PMC 4744490. PMID 26562506.

[pmid7430351-27] Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW (1980). "A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family". J Clin Invest. 66 (5): 892–900. doi:10.1172/JCI109956. PMC 371523. PMID 7430351.

[pmid1898657-28] Funke H, von Eckardstein A, Pritchard PH, Karas M, Albers JJ, Assmann G (1991). "A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities". J Clin Invest. 87 (1): 371–6. doi:10.1172/JCI114997. PMC 295069. PMID 1898657.

[pmid7583566-29] Takata K, Saku K, Ohta T, Takata M, Bai H, Jimi S; et al. (1995). "A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease". Arterioscler Thromb Vasc Biol. 15 (11): 1866–74. PMID 7583566.

[pmid24950002-30] Anthanont P, Polisecki E, Asztalos BF, Diffenderfer MR, Barrett PH, Millar JS; et al. (2014). "A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production". Atherosclerosis. 235 (2): 470–6. doi:10.1016/j.atherosclerosis.2014.05.935. PMID 24950002.

[urlOrphanet:_Apolipoprotein_A_I_deficiency-31] "Orphanet: Apolipoprotein A I deficiency".

[pmid9931341-32] Yamakawa-Kobayashi K, Yanagi H, Fukayama H, Hirano C, Shimakura Y, Yamamoto N; et al. (1999). "Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey". Hum Mol Genet. 8 (2): 331–6. PMID 9931341.

[pmid20213545-33] Lund-Katz S, Phillips MC (2010). "High density lipoprotein structure-function and role in reverse cholesterol transport". Subcell Biochem. 51: 183–227. doi:10.1007/978-90-481-8622-8_7. PMC 3215094. PMID 20213545.

[pmid24362356-34] Hellerstein M, Turner S (2014). "Reverse cholesterol transport fluxes". Curr Opin Lipidol. 25 (1): 40–7. doi:10.1097/MOL.0000000000000050. PMID 24362356.

[pmid12151852-35] Oram JF (2002). "ATP-binding cassette transporter A1 and cholesterol trafficking". Curr Opin Lipidol. 13 (4): 373–81. PMID 12151852.

[pmid21846716-36] Iatan I, Bailey D, Ruel I, Hafiane A, Campbell S, Krimbou L; et al. (2011). "Membrane microdomains modulate oligomeric ABCA1 function: impact on apoAI-mediated lipid removal and phosphatidylcholine biosynthesis". J Lipid Res. 52 (11): 2043–55. doi:10.1194/jlr.M016196. PMC 3196236. PMID 21846716.

[pmid11111093-37] Jonas A (2000). "Lecithin cholesterol acyltransferase". Biochim Biophys Acta. 1529 (1–3): 245–56. PMID 11111093.

[pmid10872459-38] Krieger M (1999). "Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI". Annu Rev Biochem. 68: 523–58. doi:10.1146/annurev.biochem.68.1.523. PMID 10872459.

[pmid12007737-39] Sorci-Thomas MG, Thomas MJ (2002). "The effects of altered apolipoprotein A-I structure on plasma HDL concentration". Trends Cardiovasc Med. 12 (3): 121–8. PMID 12007737.

[pmid3196218-40] Wilson PW, Abbott RD, Castelli WP (1988). "High density lipoprotein cholesterol and mortality. The Framingham Heart Study". Arteriosclerosis. 8 (6): 737–41. PMID 3196218.

[pmid19903920-41] Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK; et al. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMC 3284229. PMID 19903920. Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212

[pmid8831911-42] Assmann G, Schulte H, von Eckardstein A, Huang Y (1996). "High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport". Atherosclerosis. 124 Suppl: S11–20. PMID 8831911.

[pmid15364185-43] Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F; et al. (2004). "Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study". Lancet. 364 (9438): 937–52. doi:10.1016/S0140-6736(04)17018-9. PMID 15364185.

[pmid25404125-44] Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE; et al. (2014). "HDL cholesterol efflux capacity and incident cardiovascular events". N Engl J Med. 371 (25): 2383–93. doi:10.1056/NEJMoa1409065. PMC 4308988. PMID 25404125.

[pmid21537175-45] 45.0 ^45.1 Asztalos BF, Tani M, Schaefer EJ (2011). "Metabolic and functional relevance of HDL subspecies". Curr Opin Lipidol. 22 (3): 176–85. doi:10.1097/MOL.0b013e3283468061. PMID 21537175.

[pmid19839639-46] Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G; et al. (2009). "Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1". Biochemistry. 48 (46): 11067–74. doi:10.1021/bi901564g. PMID 19839639.

[pmid21291740-47] Santos RD, Asztalos BF, Martinez LR, Miname MH, Polisecki E, Schaefer EJ (2008). "Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states". J Clin Lipidol. 2 (4): 237–47. doi:10.1016/j.jacl.2008.06.002. PMID 21291740.

[pmid23043194-48] Rader DJ, deGoma EM (2012). "Approach to the patient with extremely low HDL-cholesterol". J Clin Endocrinol Metab. 97 (10): 3399–407. doi:10.1210/jc.2012-2185. PMC 3462950. PMID 23043194.

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[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

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[26]

[27]

[28]

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[31]

[32]

[33]

[34]

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[36]

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@@ Line 1: / Line 1: @@
 __NOTOC__
-{{Hypolipoproteinemia}}
+{{Hypolipoproteinemia}}{{Apolipoprotein A1 Deficiency}}
 {{CMG}}; {{AE}} {{AKI}}
 {{SK}} Familial hypoalphalipoproteinemia, FHA, familial HDL deficiency, FHD, high density lipoprotein deficiency, HDLD
 ==Overview==
-Familial hypoalphalipoproteinemia is defined as a reduction in the synthesis of HDL-cholesterol or "good" cholesterol (< 35 mg/dl) for men and < 45 mg/dL for women).  Hypoalphalipoproteinemia (HA) includes a variety of conditions, ranging from mild to severe, in which concentrations of alpha-lipoproteins or high-density lipoprotein (HDL) are reduced. The etiology of HDL deficiencies ranges from secondary causes, such as smoking, to specific genetic mutations, such as Tangier disease and fish eye disease.<ref name="pmid16115486">{{cite journal |author=Pisciotta L, Calabresi L, Lupattelli G, ''et al'' |title=Combined monogenic hypercholesterolemia and hypoalphalipoproteinemia caused by mutations in LDL-R and LCAT genes |journal=Atherosclerosis |volume=182 |issue=1 |pages=153–9 |year=2005 |month=September |pmid=16115486 |doi=10.1016/j.atherosclerosis.2005.01.048 |url=http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(05)00117-6}}</ref>
+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.
-HA has no clearcut definition. An arbitrary cutoff is the 10th percentile of HDL cholesterol (HDL-C) levels. A more practical definition derives from the theoretical cardioprotective role of HDL. The US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) recently redefined the HDL-C level that constitutes a formal coronary heart disease (CHD) risk factor. The level was raised from 35 mg/dL to 40 mg/dL for both men and women. For the metabolic syndrome in which multiple mild abnormalities in lipids, waist size (abdominal circumference), blood pressure, and blood sugar increase the risk of CHD, the designated HDL-C levels that contribute to the syndrome are sex-specific. For men, a high-risk HDL-C level is still less than 40 mg/dL, but for women, the high-risk HDL-C level is less than 50 mg/dL.
-[[Category:]]
-A low HDL-C level is thought to accelerate the development of atherosclerosis because of impaired reverse cholesterol transport and possibly because of the absence of other protective effects of HDL, such as decreased oxidation of other lipoproteins.
-The common, mild forms of HA have no characteristic physical findings, but patients may have premature coronary heart or peripheral vascular disease and a family history of low HDL-C levels and premature CHD.
-Therapy to raise the concentration of HDL-C includes weight loss, smoking cessation, aerobic exercise, and pharmacological management with niacin and fibrates.
-This review addresses the pathogenesis, presenting features, diagnostic tests, therapeutic interventions, and follow-up strategies for low HDL-C levels (i.e., HA).
-==Frequency==
-===United States===
-HA is frequently found in patients with CHD. Among patients with CHD, 58% had HDL-C levels below the 10th percentile of normal values.
-===International===
-At present, the prevalence of inheritance and underlying defects in the familial disorder are unknown. However, overall, both secondary and primary HA are common.
-==Mortality / Morbidity==
-* Hypoalphalipoproteinemia is associated with an increased risk of recurrent coronary episodes and mortality caused by CHD and constitutes a significant risk factor for the development of premature (accelerated) atherosclerosis.
-* In general, approximately 14 million people in the United States have CHD, many of whom exhibit associated HA. CHD remains the most common cause of death in the industrialized world. Approximately 1.5 million acute myocardial infarctions (MIs) occur each year in the United States; of patients experiencing acute MI, 500,000 die (almost 33%). Survivors experience an ever-increasing incidence of congestive heart failure, arrhythmias, and other forms of morbidity.
-* The incidence of stroke is also quite high. An estimated 600,000 new and recurrent cases of stroke occur each year, with 160,000 deaths per year. Stroke has become a leading cause of serious long-term disability. Approximately 4.4 million stroke survivors live in the United States today, and care of these patients costs approximately $45.3 billion, in addition to a huge cost in human suffering.
-* Peripheral vascular disease also affects many individuals. Approximately 50% of patients who report claudication have peripheral vascular disease.
-==Demographics==
-===Race===
-HA has been described in persons of all races. While no particular predilection has been noted, some literature suggests a higher prevalence of HA in Asian Indians.
+==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>
+**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.
+**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, 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>
+**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 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 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 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>
-===Gender===
+==Classification==
+*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
+**ApoA1/C-III deficiency
+**Isolated Apo A1 deficiency
+**Apo A1 Variants
+===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>
+*Her plasma LCAT activity was normal.
+*Defect was a homozygous deletion of the entire APOA1/C3/A4 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>
-Women tend to have a somewhat lower frequency of HA than men. Whether this finding is a reflection of hormonal differences is not clear.
+===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>
+*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>
+*The defect was a homozygous DNA re-arrangement affecting the APOA1 and APO CIII genes.
-===Age===
+===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 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>
+**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.
+**Genotyping of the kindred showed four homozygotes, four heterozygotes and two unaffected subjects.
+**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 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 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>
-Young boys and girls have similar HDL-C levels, but after male puberty, HDL-C levels in males decrease and remain lower than those in females for all subsequent age groups.
+===Apo A1 Variants===
+*ApoA-I variants are heterozygous premature terminations, frameshift mutation or amino acid substitutions in the 243 amino acid Apo AI 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.
+* 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>
+*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>
+*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 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 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 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 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 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>
-==Pathophysiology==
+==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>
+*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>
+*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>:
+**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.
-===Plasma lipoproteins===
+==Natural History, Progression, Complications==
-Plasma lipoproteins are macromolecular complexes of lipids and proteins that are classified by density and electrophoretic mobility. The structure of all lipoproteins is the same. The nonpolar lipids (i.e., cholesterol ester, [[triglycerides]] [TGs]) reside in a core surrounded by more polar components (eg, free cholesterol, phospholipids, proteins). The protein, termed apolipoprotein (apo), plays an important role in lipoprotein metabolism. The major apolipoproteins of [[HDL]] are alpha-apolipoproteins (i.e., apo A-I, apo A-II, apo A-IV), which are soluble and can move between different classes of lipoproteins. The beta-lipoproteins are structural, are never complexed with HDL, and remain throughout the metabolism of the lipoproteins with which they are associated. Apo B-450 is associated with chylomicrons and their remnants, and apo B-100 is associated with [[very low-density lipoprotein]] ([[VLDL]]), [[VLDL]] remnants, intermediate-density lipoprotein, and [[low-density lipoprotein]] ([[LDL]]).
+==Pathogenesis==
+===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>===
-[[HDL]] plays a major role in reverse cholesterol transport, mobilizing cholesterol from the periphery to promote return to the liver. In the general population, lower-than-normal HDL-C levels are closely correlated with CHD; the risk of a coronary event is thought to increase 2% for every 1% decrease in HDL-C. However, extreme HDL deficiencies caused by rare autosomal recessive disorders, including familial HA, familial [[lecithin-cholesterol acetyltransferase]] ([[LCAT]]) deficiency, and [[Tangier disease]], do not always correlate with more frequent [[CHD]].
-===Familial hypoalphalipoproteinemia or familial apolipoprotein A-I deficiency===
+{{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 | | | | |!| | | | | }}
+{{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 | | | | 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 | | | | 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/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 :
+**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 in few mutations.
+*The changes in the reverse cholesterol transport predispose the patients to premature heart disease.
-Criteria for the definition of familial HAs are (1) a low HDL-C level in the presence of normal VLDL cholesterol and LDL cholesterol (LDL-C) levels, (2) an absence of diseases or factors to which HA may be secondary, and (3) the presence of a similar lipoprotein pattern in a first-degree relative.
+==== Genetics ====
+*Apolipoprotein deficiency is caused by mutation in the Apo A1 gene (11q23-q24) which codes for the apolipoprotein A1.
+*Mutations in the gene can lead to decreased production, impaired function or increased Apo A1 catabolism.
+*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.
+*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.
-Familial HA is a relatively common disorder and is frequently associated with decreased apo A-1 production or increased apo A-1 catabolism. Severe HDL deficiency can also be associated with a heterogeneous group of rare autosomal recessive lipoprotein disorders. The underlying molecular defects involve apo A-I, apo C-III, or apo A-IV. HDL in plasma is almost undetectable in persons with the familial apo A-I deficiency because of deletions of the APOA1 gene (level <10 mg/dL). Heterozygotes tend to have less severe reductions in HDL.
+==History, Symptoms==
+*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.
-Some patients with severe genetic HDL reductions manifest corneal opacities and xanthomas and have an increased risk of developing premature coronary atherosclerosis (ie, CHD). The molecular diagnosis can be made by specialized analysis, including electrophoresis of the plasma apolipoproteins and DNA analysis to determine the mutation. Because raising plasma apo A-I or HDL-C levels is usually difficult in persons with these disorders, treatment should be directed toward lowering the level of non–HDL-C.
+*Patients who are symptomatic usually present with:
+**Blurry vision due to corneal opacities
-In some patients, this condition occurs as a result of certain nonsense mutations that affect the generation of the apo A-I molecule. These mutations are a very rare cause of low HDL-C levels (usually 15-30 mg/dL). An example is APOA1 Milano, inherited as autosomal dominant trait, which is not associated with an increased risk of premature CHD despite low HDL levels. Other than corneal opacities, most of these patients do not exhibit many clinical sequelae related to the APOA1 mutations. Certain other APOA1 mutations have been found in association with systemic amyloidosis, and the mutant APOA1 gene has been located within the amyloid plaque.
+**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.
-===Familial lecithin-cholesterol acyltransferase (LCAT) deficiency===
-This is a very rare [[autosomal recessive]] disorder characterized by corneal opacities, normochromic [[anemia]], and [[renal failure]] in young adults. Approximately 30 types and a number of mutations have been reported. [[LCAT]] deficiency results in decreased esterification of [[cholesterol]] to cholesteryl esters on [[HDL]] particles. This, in turn, results in an accumulation of free cholesterol on lipoprotein particles and in peripheral tissues, such as the [[cornea]], [[red blood cell]]s, renal glomeruli, and vascular walls. At present, no effective method has been found to increase the plasma [[LCAT]] levels; therefore, therapy is limited to (1) dietary restriction of fat to prevent the development of complications and (2) management of complications (e.g., renal transplant for advanced [[renal disease]]).
-Two kinds of genetic [[LCAT]] deficiencies have been reported. The first is complete (or classic) [[LCAT]] deficiency. Complete [[LCAT]] deficiency is manifested by [[anemia]], increasing [[proteinuria]], and [[renal failure]]. The diagnosis can be made based on results of [[LCAT]] quantification and [[cholesterol]] esterification activity in the plasma in certain specialized laboratories. The second is partial [[LCAT]] deficiency (fish eye disease). Partial [[LCAT]] deficiency has known clinical sequelae. Progressive corneal opacification, very low plasma levels of [[HDL-C]] (usually <10 mg/dL), and variable hypertriglyceridemia are characteristic of partial and classic [[LCAT]] deficiency.
-The risk of atherosclerosis is not usually associated with an increased risk of [[CHD]]. Similarly, [[LCAT]]-deficient animal models do not demonstrate an increased prevalence of atherosclerosis.
-===Tangier disease===
-[[Tangier disease]] is an autosomal codominant disorder that causes a complete absence or extreme deficiency of HDL. LDL-C levels are also usually reduced. The disease is characterized by the presence of orange [[tonsil]]s, [[peripheral neuropathy]], [[splenomegaly]], discoloration of the rectal mucosa, [[hepatomegaly]], opacities, premature [[CHD]], and other abnormalities. Although the underlying mutation is not yet well defined, in some subjects the condition is caused by mutations of the ATP-binding cassette transporter 1, which is involved in the passage of cholesterol from within the cells to outside the cells (efflux). Cholesteryl esters are deposited in the reticuloendothelial system. Patients with [[Tangier disease]] also may exhibit accelerated HDL catabolism. Their [[HDL-C]] levels are usually lower than 5 mg/dL. Their '''apo A-I''' levels are also very low. This condition has no specific treatment.
-===Components of plasma high-density lipoprotein===
-Plasma [[HDL]] is a small, spherical, dense lipid-protein complex that consists of half lipid and half protein. The major lipids are phospholipid, [[cholesterol]], cholesteryl esters, and [[TG]]s. The major proteins include apo A-I (molecular weight, 28,000) and apo A-II (molecular weight, 17,000). Other minor but important proteins are apo E and apo C, including apo C-I, apo C-II, and apo C-III. HDL particles are heterogeneous. They can be classified into larger, less dense HDL2 or smaller, more dense HDL3. Most [[HDL]] is normally present as HDL3. However, individual variability in [[HDL]] levels in humans is usually due to different amounts of HDL2.
-Reverse cholesterol transport system
-[[HDL]] removes [[cholesterol]] from the peripheral tissues, such as fibroblasts and [[macrophage]]s, and it is esterified by [[LCAT]]. The cholesteryl ester thus produced is transferred from the [[HDL]] to apo B–containing lipoproteins, such as [[VLDL]], intermediate-density lipoprotein, and [[LDL]], by a key protein termed cholesteryl ester transport protein in the liver. The [[HDL]] itself becomes enriched with [[TG]]s and subsequently becomes hydrolyzed by hepatic [[lipase]]. By this mechanism, the [[HDL]] finally becomes smaller again and is ready to scavenge more [[cholesterol]]. This pathway is called the reverse [[cholesterol]] transport system.
-Therefore, HA represents a clinical condition in which the reverse [[cholesterol]] transport system functions suboptimally, causing an increased tendency to develop atherosclerotic lesions.
-==Variant apolipoproteins==
-The variant '''apo A-I Milano''' and the less well known variants '''apo A-I Marburg''', '''apo A-I Giessen''', '''apo A-I Munster''', and '''apo A-I Paris''' cause HA but do not seem to increase the risk of atherosclerosis.
-==Causes==
-HA may be caused by familial or primary and secondary disorders that are associated with low plasma [[HDL-C]] levels.
-* '''Familial or primary causes''': Decreased or absent synthesis of '''apo A-I''' due to a gene defect is the cause of '''apo A-I'''/'''apo C-III''' and '''apo A-I'''/'''apo C-III'''/'''apo A-IV deficiency'''. However, the etiology of the low levels of [[HDL]] is unclear for most of the remaining familial HAs. Increased catabolism, decreased synthesis, and altered equilibration of [[HDL]] between intravascular and extravascular spaces have all been suggested as underlying causes of low plasma [[HDL]] levels. Whatever the cause, these disorders are associated with altered [[HDL]] composition and altered equilibration of [[cholesterol]] among the various lipoprotein classes.
-:* Familial apo A-I deficiency and structural mutations
-:* Familial [[LCAT]] deficiency
-:* [[Tangier disease]]
-:* Miscellaneous
-:*:* Familial [[HDL]] deficiency
-:*:* Familial apo A-I and apo C-III deficiency (formerly known as apo A-I absence)
-:*:* Familial deficiency of '''apo A-I''' and '''apo C-III'''
-:*:* Fish eye disease (partial [[LCAT]] deficiency)
-:*:* Familial HA
-:*:* Apo A-I variants ('''apo A-I Milano''', '''apo A-I Marburg''', '''apo A-I Giessen''', '''apo A-I Munster''')
-* '''Secondary causes'''
-:* [[Obesity]]
-:* Physical inactivity
-:* Type 2 diabetes
-:* [[Cigarette smoking]]
-:* End-stage renal disease
-:* [[Hypertriglyceridemia]]
-:* [[Probucol]]
-:* [[Androgen]]s
-:* [[Progestin]]s
-:* High-dose [[thiazide diuretic]]s
-:* High-dose [[beta-blocker]]s
-:* Very low-fat diet
-:* Dysglobulinemia
-:* Severe liver disease
-:* [[Malabsorption]]
-:* [[Malnutrition]]
-:* Severe inflammatory disease
-* Miscellaneous: Data in the literature suggest that some cases of HA involve an increase in [[thromboxane B2]] together with an increased risk of atherosclerosis. Satta et al described a 32-year-old man who revealed clinical and biochemical features strongly indicative of this pathology.
-==Diagnosis==
-==History and Symptoms==
-Persons with low HDL-C levels, except those with a deficiency syndrome, have no symptoms specific to the condition. However, they may have a history of premature atherosclerosis and a history consistent with [[CHD]], [[peripheral artery disease]], or other such conditions.
-* Premature atherosclerosis
-:* [[Coronary heart disease]] - History of [[angina]] or [[MI]] when younger than 60 years, history of premature [[heart disease]] in siblings and first-degree relatives, sequelae of [[MI]]
 :* [[Congestive heart failure]]
 :* Peripheral vascular disease - History of [[claudication]]
@@ Line 140: / Line 125: @@
 :* History of [[transient ischemic attack]]
 :* History of [[carotid endarterectomy]]
-* [[Xanthomas]] (tendinous, [[cutaneous]])
+*Less common findings in Apo A1 deficiency include:
-* History consistent with secondary causes
+**Ataxia
-:* [[Cigarette smoking]]
+**Hearing loss
-:* Physical inactivity
+**Manifestions of amyloidosis:
-:* [[Hypertriglyceridemia]]
+***Nephropathy presents with hematuria, generalized body swelling, shortness of breath on exertion.
-:* Renal disease
+***Cardiomyopathy can present with chest pain, shortness of breath on exertion, syncope, pedal edema.
-:* [[Obesity]]
-:* Medications
-:* [[Androgens]]
-:* [[Progestins]]
-:* [[Probucol]]
-:* High-dose [[thiazides]]
-:* High-dose [[beta-blocker]]s
-* Corneal opacification
-==Physical Examination Findings==
+==Physical Examination==
-Persons with the common low HDL syndromes have no specific physical findings. If atherosclerosis is present, the examination may reveal findings consistent with the affected arterial bed. These findings may include the following:
+*Corneal opacities, corneal arcus
+*Tubero-eruptive,  palmar or planar xanthomas
+*Cerebellar ataxia
+*Neuro-sensory hearing loss
+*Hepatomegaly
-* [[Tendon]] [[xanthomas]]
+==Diagnosis==
-* Cutaneous [[xanthomas]]
+*Apo A1 deficiency is diagnosed by combination undectectable Apo A1 and HDL C levels.
-* Findings of ischemic [[CHD]] or [[peripheral vascular disease]]
+===Lipid Analysis===
-:* [[S4]] gallop consistent with ischemic left ventricular dysfunction
+*Laboratory features consistent with the diagnosis of Apo A1 deficiency include:
-:* Signs of congestive heart failure, such as raised jugular distension, crackles at lung bases, edema, and hepatomegaly
+**Undetectable Apo A1
-:* [[Arrhythmias]]
+**HDL C less than 10mg/dl
-* Corneal opacification
+**Normal or elevated triglyceride
+**Normal or elevated LDL C
-===Laboratory Studies===
-* Routine blood tests: Included among these is a chemistry profile.
-* Additional tests: These include [[liver function tests]] and a [[thyroid]] profile.
-* Plasma fasting lipid profile: After a 12-hour fast, plasma samples are obtained for lipid analysis. Total [[cholesterol]] and [[TG]] levels are measured by enzymatic methods. The [[LDL-C]] level is determined in the supernatant after plasma precipitation with magnesium chloride–phosphotungstic acid. [[LDL-C]] levels are estimated using the formula proposed by DeLong et al. Values obtained include [[LDL]], [[HDL]], total [[cholesterol]], and [[TG]] levels.
-* Plasma lipid subfractions: '''Apo A-I'', '''apo A-II''', '''apo B''', and '''lipoprotein Lp(a)''' are measured with nephelometric assays using antibodies for '''apo A-I''', '''apo B''', and '''lipoprotein Lp(a)''' and by immunoassays for '''apo A-II'''. Subfractions include '''apo A''', '''apo A-I''', '''apo A-II''', '''apo A-III''', '''apo B''', '''apo C''', '''and apo E'''.
-===Imaging Studies===
-* Whether imaging studies are needed depends on the clinical manifestations of HA.
-* Patients with corneal opacification may require ophthalmoscopic examination and corneal or intraocular imaging.
-* Patients with premature coronary atherosclerosis may need the following:
-===Chest x-ray===
-A [[chest x-ray]] film may show alteration in the size of the cardiac silhouette; calcification or congestion of the lung fields, including interstitial edema; and [[Kerley B lines]], indicating [[congestive heart failure]].
-===Echocardiogram===
-Ultrasound images of the heart (2-dimensional images) can show chamber size alterations, regional wall motion abnormalities, and valvular regurgitations consistent with the presence of atherosclerosis.
+===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.
-===Nuclear (radionuclide) stress test===
+===Molecular Gene Sequencing===
+*The gold standard for diagnosis of Apo A1 deficiency is molecular gene sequencing for identification of the mutation.
-The quantity of blood that flows to different parts of the [[myocardium]] can be evaluated with a nuclear (gamma single-photon emission computed tomography) camera as a hot spot (good flow) or cold spot (diminished flow) by using a radioactive isotope, such as [[thallium]], [[sestamibi]], or tetrofosmin, once with exercise and then without.
+==Differential Diagnosis==
+{| class="wikitable"
+!
+!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
-If a patient cannot exercise, pharmacologic agents (e.g., [[adenosine]] [Adenocard], [[dipyridamole]] [Persantine], [[dobutamine]] [Dobutrex]) can be used to stimulate the heart muscle for the stress test. This test is expensive but non-invasive, and its accuracy is quite high (>93%).
+*Dense central corneal opacity
-===Stress echocardiography===
+*Relapsing and remitting course of neuropathy
+|Asymptomatic
+|
+*Corneal Opacities
+*Tuboeruptive, Planar and palmar Xanthomas
+*Premature Heart Disease
+|-
+|Lipid Panel
+|
+*Elevated Free cholesterol
-Instead of using a radionuclide agent, echocardiographic (ultrasound) images can be obtained immediately following incremental exercise on the [[exercise stress test|treadmill]] or following the administration of [[intravenous]] [[dobutamine]]. In this test, the ventricular wall motion during stress is compared with that at rest. Wall motion decreases during stress in a [[coronary artery]] that has significant obstruction.
+*HDL-C < 10 mg/dL
-===Electron beam (ultrafast) CT scan===
+*Low Apo A1 and Apo AII
-This new test is noninvasive but somewhat controversial. By measuring the amount of calcium deposited in the plaques of coronary arteries, it can detect even 10-20% blockages, which other tests may not reveal. The only recommendations for such insignificant blockages are lifestyle changes and risk-factor modification. Also, because elderly people frequently have calcium in their coronary arteries without significant narrowing, electron beam CT is of limited value for persons in this age group. The advantage of electron beam CT is in screening young people with one or more heart disease risk factors in a noninvasive manner.
+*Elevated Apo E and Triglycerides
-===Coronary angiography===
+*Low LDL C
+|
+*Elevated free cholesterol
-Performed in the hospital, this test involves intravenous placement of long, thin, specifically designed catheters into the opening of the coronary arteries, starting from either the groin ([[femoral artery]]) or the arm ([[brachial artery]]).
+*HDL C < 27 mg/dL
-Once the catheter reaches the opening of the [[coronary artery]], a small amount of radiographic iodine dye is injected, which makes the coronary arteries visible on x-ray film. Pictures of the coronary arteries are recorded for later review. The images show the diameter of the coronary arteries and any blockages narrowing them.
+*Apo A1＜30mg/dl and low Apo A2
-[[Coronary angiography]] is an invasive test. In experienced hands, the risk of complications is less than 1%. It is the only test that helps a cardiologist to determine precisely whether to treat a patient using bypass surgery, through-the-skin intervention ([[percutaneous coronary intervention]]s) such as angioplasty or stent placement, or medicines alone.
+*Elevated Apo E and Triglycerides
-* Some imaging studies may be included in the workup for exploring secondary causes of HA.
+*Normal LDL and VLDL
+|
+*HDL < 5% of normal
-===Other Tests===
+*Apo A1 < 1% of normal
-* [[Electrocardiogram]]
-:* The 12-lead resting [[ECG]] tracings are obtained by placing 6 limb and 6 chest electrodes on the patient.
-:* [[ECG]] findings consistent with the presence of coronary atherosclerosis may include [[ST-segment]] shift or T-wave changes.
-* [[Exercise stress test|treadmill]]
-:* The presence of physiologically significant atherosclerotic plaque in one or more major coronary arteries may be detected by stressing the heart with continuous [[ECG]] monitoring.
-:* The patient walks on a treadmill while [[ECG]] heart monitoring wires are placed on the chest and tracings are recorded at 2- to 3-minute intervals. The speed and elevation are gradually increased.
-:* The [[exercise stress test|treadmill stress test]] has a predictive accuracy of 60-70%. Sometimes, its readings may be falsely abnormal in people with baseline ECG changes, electrolyte abnormalities, electrical conduction abnormalities, digitalis use, enlarged heart, or mitral valve problems.
-* Evaluation of [[HDL]] subfractions
-* Measurement of the LCAT enzymatic activity
-* Apo A-I, apo A-II, and [[HDL]] subfractions
-* Genetic studies, including chromosomal studies
-:* Reported in 1986, Ordovas et al identified a PstI restriction-endonuclease site adjacent to the human APOA1 gene at its 3' end that is polymorphic.
-:* The absence and presence of this site, as determined by genomic blotting analysis of PstI-digested chromosomal DNA with the use of an APOA1 gene probe, were associated with 3.3-kilobase (kb) and 2.2-kb hybridization bands, respectively.
-:* The 3.3-kb band appeared in 4.1% of 123 randomly selected control subjects and in 3.3% of 30 subjects with no angiographic evidence of coronary artery disease. In contrast, among 88 subjects who had severe coronary disease when younger than 60 years, as documented by angiography, the 3.3-kb band occurred in 32% (p <0.001). It was also found in 8 of 12 index cases (p <0.001) of kindreds with familial HA.
-* [[Thromboxane A2]] levels
-* Decreased erythrocyte osmotic fragility
-:* Frohlich et al in 1990 and Godin et al in 1988 described erythrocyte membrane abnormalities.
-:* The observed changes in a number of structural and functional properties of erythrocytes in this disorder are indistinguishable from those previously described in homozygotes for LCAT deficiency.
-:* Thus, in both of these disorders, an abnormality of plasma LCAT activity possibly causes functional and structural changes in the erythrocyte membrane, either directly or indirectly.
-==Procedures==
+*LDL < 40% of normal
-* Patients with HA need monitoring for the development of premature atherosclerosis. Some procedures that may be useful include the following:
+|
-:* Noninvasive cardiac procedures
+*HDL C, Apo A1 and  LDL 50% less than normal.
-:*:* Stress-nuclear testing
+|
-:*:* Rest and stress echocardiography
+*Undetectable Apo A1
-:*:* Electron beam computed tomography
+*HDL C less than 10mg/dl
-:*:* [[Cardiac catheterization]] and [[coronary angiography]]
+*Normal or low Apo AII
-:*:* [[Percutaneous coronary intervention]]s
+*LDL C normal
-:*:* Coronary artery bypass grafting surgery
+*Triglyceride normal or elevated
-:* Carotid atherosclerosis
+|-
-:*:* Carotid Doppler studies
+|2D Gel Electrophoresis
-:*:* Carotid artery angiograms
+|Pre β-1 and α-4 HDL, LDL with  β mobility due to Lipoprotien-X
-:*:* Carotid endarterectomy
+|Pre β-1and α-4 HDL with normal pre-β LDL.
-:* Peripheral vascular and renal vascular disease
+|Only preβ-1 HDL present
-:*:* [[Ankle-Brachial Index]]
+|
-:*:* Peripheral arterial angiography
+*Lack of large α-1 and α-2 HDL particles
-:*:* Percutaneous interventions
+*Normal preβ-1 HDL
-:*:* Peripheral vascular bypass surgery
+|Lack of Apo A1 containing HDL particles.
+|}
-===Histologic Findings===
+====== 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"
+!
+!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- a 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 A IV
+|Undetectable
+|Normal
+|Normal
+|}
-In 1988, Godin et al described a case of erythrocyte membrane abnormalities in a 16-year-old boy with HA resembling fish eye disease. The proband's erythrocytes had markedly decreased osmotic fragility, with target cells observed in the peripheral film. Analysis of the patient's erythrocyte membrane lipids revealed normal cholesterol and phospholipid content but a marked increase in phosphatidylcholine with concomitant decreases in phosphatidylethanolamine and [[sphingomyelin]].
+==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>==
+{{Family tree/start}}
-Of the erythrocyte membrane enzymes examined, acetylcholinesterase and superoxide dismutase activities were decreased, while those of [[Na+/K+-ATPase]], [[catalase]], and [[glutathione reductase]] were normal. In this patient, chromium Cr 51–labeled erythrocyte survival was slightly decreased. The observed changes in a number of structural and functional properties of erythrocytes in this disorder are indistinguishable from those described in homozygotes for familial LCAT deficiency.
+{{Family tree | | | | | | A01 | | | |A01= HDL <20mg/dl in the absence of severe hypertriglyceridemia}}
+{{Family tree | | | | | | |!| | | | | }}
-In 1989, Satta et al noted that the data in the literature suggest that cases of HA involve an increase in [[thromboxane B2]] together with an increased risk of atherosclerosis. A detailed examination of a 32-year-old man revealed clinical and biochemical features strongly indicative of that pathology. The case presented several unusual features, including
+{{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}}
-# Marked infiltration of the skin and mesenteric lymph nodes by histiocytic lipids, with [[hyperplasia]] sufficient to induce acute intestinal occlusion and
+{{Family tree | | | | | | |!| | | | | }}
-# An in vivo [[thromboxane B2]] generation curve, subsequently inhibited by [[aspirin]], that was comparable to the curves of the control subjects.
+{{Family tree | | | | | | |!| | | | | }}
+{{Family tree | | | | | | E01 | | | |E01= Consider Monogenic primary disorders<br>Order ApoA1}}
+{{Family tree | | | | | | |!| | | | | }}
+{{Family tree | | |,|-|-|-|^|-|-|.|}}
+{{Family tree | |F01| | | | |F02| |F01= >5mg/dl| F02= Undetectable or <5mg/dl}}
+{{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 | | | | | | | | | |!| | | | }}
+{{Family tree | | | | | | | |,|-|^|-|-|.| }}
+{{Family tree | | | | | | | H01| | |H02|H01= Complete absence of Apo A1 containing HDL C|H02= Only Pre-Beta HDL C}}
+{{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/end}}
 ==Treatment==
+===Medical Therapy===
+The mainstay of therapy for Apo A1 deficiency include:
+*Patients with low HDL C and Apo A1 should be treated with statins for reduction 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 like PCI.
-Currently, clinical trial results suggest that raising [[HDL]] levels reduces risk. However, the evidence does not support a recommendation of therapy for HA. Additionally, drugs available for cholesterol management do not raise [[HDL-C]] levels as much as desired. However, physicians should pay reasonable attention to low [[HDL-C]] levels and their management.
+===Surgical Therapy===
+*Patients presenting with myocardial infarction should undergo PCI with stent of the blocked vessel.
-According to NCEP ATP III guidelines, the primary goal of therapy is to lower [[LDL-C]] levels. Once the [[LDL]] target is reached, emphasize therapeutic lifestyle changes, such as weight management and increased exercise, especially if the patient has a metabolic syndrome.
-If [[TG]] levels are lower than 200 mg/dL (i.e., isolated HA), drugs for raising [[HDL]] (e.g., [[fibrates]], [[nicotinic acid]]) can be considered. [[Statin]]s have only a modest effect. Treatment for isolated low [[HDL-C]] levels is reserved mostly for individuals with established [[CHD]] and for patients with risk factors for [[CHD]].
-==Pharmacotherapy==
-Most individuals are diagnosed with HA based on the results of a routine lipid profile measurement. This finding of a low [[HDL-C]] level can be useful as an independent factor in assessing coronary artery disease risk and further management. Recently, the third report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood [[Cholesterol]] in Adults ATP III published its guidelines on the US National Heart, Lung and Blood Institute Web site (see www.nhlbi.org) and in the Journal of the American Medical Association. In these guidelines, the importance of [[HDL-C]] was emphasized and the level of [[HDL]] considered to be a significant risk factor was changed from less than 35 mg/dL to less than 40 mg/dL.
-The basic purpose of the management of HA and related lipid abnormalities is to reduce the risk of atherosclerosis, which is the main mechanism of increased morbidity and mortality. With regard to HA, the panel stated "Low [[HDL-C]] is a strong independent predictor of [[Coronary heart disease]] ([[CHD]]). In ATP III, low [[HDL-C]] is defined categorically as a level <40 mg/dl, a change from the level of <35 mg/dl in ATP II (published in 1993). In the present guidelines, low [[HDL-C]] both modifies the goal for [[LDL]]-lowering therapy and is used as a risk factor to estimate 10-year risk for [[CHD]]."
-According to the ATP III document, "Low [[HDL]] cholesterol levels have several causes, many of which are associated with insulin resistance, i.e., elevated triglycerides, overweight, and obesity, physical inactivity, and type 2 diabetes. Other causes are cigarette smoking, very high carbohydrate intake (>60% of calories), and certain drugs (e.g., [[beta-blocker]]s, anabolic steroids, and progestational agents)."
-* Management strategy: As specified in the current NCEP guidelines, "ATP III does not specify a goal for [[HDL]] raising. Although clinical trial results suggest that raising [[HDL]] will reduce risk, the evidence is insufficient to specify a goal of therapy. Furthermore, currently available drugs do not robustly raise HDL cholesterol. Nonetheless, a low HDL should receive clinical attention and management according to the following sequence:"
-:* LDL is the primary target. "In all persons with low [[HDL]] cholesterol, the primary goal of therapy is to lower [[LDL]] (low density lipoprotein) cholesterol. ATP III guidelines should be followed to achieve the [[LDL]] cholesterol goal."
-:* Metabolic syndrome is the second target. "After the LDL goal has been reached, emphasis shifts to weight reduction and increased physical activity (when the metabolic syndrome is present). Metabolic syndrome is diagnosed when three or more of the following risk factors are present: 1. Abdominal obesity, with waist circumference of >102 cm or >40" for men, and >88 cm or >35" for women, 2. Triglycerides equal to or >150 mg/dl, 3. [[HDL]] cholesterol <40 mg/dl for men, and <50 mg/dl for women, 4. Blood pressure equal to or >130 systolic, and equal to or >85 mm hg diastolic, and 5. Fasting glucose equal to or >110 mg/dl)."
-:* Association with hypertriglyceridemia needs attention. "When a low [[HDL]] cholesterol is associated with high triglycerides (200-499 mg/dl), secondary priority goes to achieving the non-[[HDL]] cholesterol goal. For example, 1. In the patients with established [[CHD]], or [[CHD]] risk equivalent (10-year risk for CHD >20%), the '[[LDL]]' goal is <100 mg/dl; or the 'non-[[HDL]] cholesterol' goal is <130 mg/dl. 2. In persons with multiple (2+) risk factors and 10-year risk of equal to or less than 20%, the '[[LDL]]' goal is <130 mg/dl; while the 'non-[[HDL]]' goal is <160 mg/dl. 3. In persons with 0-1 risk factor, the '[[LDL]]' goal is <160 mg/dl; and that for the 'non-HDL' is <190 mg/dl."
-:* Managing isolated low [[HDL]] cholesterol: "If the [[triglyceride]]s are <200 mg/dl (isolated low-[[HDL]] cholesterol), drugs for raising [[HDL]] ([[fibrates]] or [[nicotinic acid]]) can be considered. Statins have only modest effect. Treatment for isolated low [[HDL]] cholesterol is mostly reserved for persons with [[CHD]] and [[CHD]] risk equivalents."
-* Identify persons who eat a very low-fat diet. A low [[HDL-C]] level in this setting is rarely associated with increased risk for premature [[CHD]].
-* Identify and correct secondary factors. Instruct patients who smoke to stop smoking, tell persons who are overweight to manage their weight, and encourage individuals who are sedentary to engage in regular exercise. Whenever possible, eliminate medications associated with low [[HDL-C]] levels. Control diabetes optimally, and aggressively treat [[LDL-C]], regardless of the [[HDL-C]] levels.
-* Consider [[estrogen replacement therapy]] for postmenopausal women because this can substantially raise [[HDL-C]] levels.
-* Whether to use pharmacologic agents to raise the HDL-C level in otherwise healthy persons is unclear because no published clinical trials are available that demonstrate a benefit. Nonetheless, individuals at high risk require further assessment for CHD risk, with an evaluation including a family history, measurements of [[apolipoprotein]] and [[lipoprotein Lp(a)]], and electron beam computed tomography.
-:* Niacin is the most effective agent currently available. However, many patients with isolated HA do not respond well to niacin. Most patients who receive [[niacin]] also have high [[LDL-C]] levels that are being managed pharmacologically, and niacin is added to raise their [[HDL-C]] level if it is low.
-:* [[Gemfibrozil]] and [[fenofibrate]] modestly raise the [[HDL-C]] level. They are most effective in the setting of concomitant hypertriglyceridemia.
-:* Statins only mildly raise [[HDL-C]] levels. They are not recommended for this purpose alone.
-:* [[Alcohol]] tends to raise some [[HDL]] subfractions. However, no clinical trial data are available to demonstrate any positive role for raising [[HDL]] levels with [[alcohol]] in order to reduce cardiovascular events in patients with [[CHD]].
-==HDL Raising Therapies==
+== Primary Prevention ==
+*Assessment of cardiovascular risk in patients diagnosed with Apo A1 deficiency and Apo A1 variants.
-Low [[HDL]] levels often reflect a genetic abnormality, although they can also be pushed downward by a high blood level of [[triglyceride]]s or by [[cigarette smoking]], inactivity, [[hypertension]], or a diet very high in carbohydrates or polyunsaturated fats.
+*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.
-===CETP Inhibition Therapy===
+*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.
-Another pharmacologic approach geared towards raising [[HDL]] levels involves inhibiting cholesteryl ester transfer protein (CETP).  The CETP helps exchange cholesterol between lipoproteins and can transfer it from [[HDL]] to the [[LDL]] and [[VLDL]]. Individuals with a genetic mutation that causes loss of all CETP activity have very high levels of [[HDL]] cholesterol. They appear to be at lower risk of coronary disease. A small study in 2004 involving CETP inhibitor, [[Torcetrapib]], showed that the drug markedly increased [[HDL]] levels and decreased [[LDL]] levels when taken alone and also when taken in combination with a statin. The increases in [[HDL]] levels were much higher than can be achieved with existing lipid drugs. Although this points researchers in a promising direction,therapy with [[torcetrapib]] needs to be tested in a larger population, and shown not only to increase [[HDL]] levels, but also to prevent heart problems through outcome studies.
-===HDL-infusion therapy===
-[[HDL]]-infusion therapy studied in a group of 40 Italian villagers led to the discovery of a rare type of [[HDL]] that seemed to protect against heart disease even when the levels of HDL were not very high. These people had a protein in their [[HDL]], now called '''apo A-I Milano''', that seemed to be better at stimulating the removal of cholesterol from plaques than did [[HDL]] containing the normal protein, called '''apo A-I'''. Researchers recently tested whether a synthetic version of '''apo A-I Milano''' (recombinant ApoA-1 Milano/ phospho-lipid complexes, ETC-216) infused into the blood of people who didn’t naturally have this protein would have the same effect. The small trial randomly assigned 47 people who had recently had [[heart attack]]s to receive either a placebo or a low or high dose of thischemical. Through ultrasounds of the arteries, researchers found that from the beginning to the end of the five-week trial, the plaque in the treatment groups shrank by 4%, while that of the placebo group increased by a small amount. Although these are exciting results, a larger trial with such synthetic [[HDL]] infusion therapy is needed.
-===Estrogen replacement or hormone replacement therapy (HRT)===
-Raises [[HDL]] by about 8% in postmenopausal women, but its use is controversial, and is not recommended for [[CAD]] prevention due to demonstrated lack of benefit and possible risk of increased [[thrombosis]]. The heart and estrogen progestin replacement study (HERS) found no net decrease in secondary prevention of [[CHD]] events over 4 years. Events increased 50% with [[HRT]] during year 1 but then progressively decreased to 33% lower by study end. The early increase may have resulted from pro-thrombotic and/or pro-inflammatory effects of [[HRT]], while the later decrease may have reflected the 8% increase in [[HDL-C]] and/or other antiatherosclerotic mechanisms. Results of [[HRT]] in primary prevention await completion of the Women's Health Initiative in 2007.
-===Fish Oil Capsules===
-Since dietary modification to increase the consumption of cold-water fish (e.g., salmon) rich in polyunsaturated fats may help to raise [[HDL]], capsules containing omega-3 fatty acids (1.48 grams of docosahexaenoic acid and 1.88 grams of eicosa-pentaenoic acid) have been studied in small trials. In a recent study in patients with familial combined hyperlipidemia, treatment with this formulation for 8 weeks increased HDL by 8%, particularly the more buoyant HDL-2 subfraction. levels of the antioxidant [[HDL]]-associated enzyme paraoxonase were also increased by 10%.
-None of these [[HDL]]-raising therapies have been studied in the Asian Indians. And, therefore, no particular treatment recommendations can be made at this juncture. The treatment strategies, nonetheless, appear well suited for this subpopulation with high prevalence of hypoalphalipoproteinemia (Low [[HDL-cholesterol]]).
-==Surgical Therapy==
-HA may not require any surgical intervention. However, its association with and promotion of atherosclerosis may require a variety of surgical interventions, as follows:
-* [[Cardiac catheterization]], [[coronary angiography]], and various [[percutaneous intervention]]s for [[CHD]]
-* [[Coronary bypass grafting surgery]] for patients with [[CHD]]
-* Percutaneous interventions and bypass procedures for peripheral vascular disease
-* [[Carotid endarterectomy]] for carotid disease
-* Gastric stapling and other related intestinal surgeries for weight reduction and management of the [[metabolic syndrome]]
-==Additional Consultations==
-Always consider secondary causes of low [[HDL]] levels, especially medications, smoking habits, dietary patterns, and physical activity. Patients with elevated [[TG]] levels (>500 mg/dL) commonly have low [[HDL-C]] levels; address [[hypertriglyceridemia]] first in such patients. Patients with moderately reduced [[HDL]] levels (20-35 mg/dL) usually have secondary causes that should be addressed. Individuals with severely reduced [[HDL]] levels (<20 mg/dL) may have a specific genetic etiology, such as [[LCAT]] deficiency, [[Tangier disease]], or mutations in '''apo A-I'''. Ironically, these disorders are not commonly associated with an increased risk of [[atherosclerosis]]. Refer patients who may possibly have one of these diagnoses to a specialized lipid center for advanced management. Consultation with the following specialists may be required:
-* Lipidologist
-* Endocrinologist
-* Cardiologist
-* Vascular specialist
-* Cardiovascular surgeon
-* Dietitian
-==Diet Requirements==
-Very low-fat diets are associated with low [[HDL-C]] levels. However, because no data are available that show reduction of the risk of [[CHD]] upon raising the [[HDL-C]] levels, no particular dietary interventions are needed for this specific purpose. In fact, increasing the fat content in the patient's diet is not recommended. Dietary management should follow the NCEP guidelines for lowering frequently associated [[LDL-C]], which is the primary target in lipid management, and lowering of [[LDL]] levels has been demonstrated to reduce [[CHD]] morbidity and mortality in multiple randomized clinical trials.
-* The NCEP has recommended a therapeutic lifestyle change diet, which should be incorporated in the treatment of all patients. The following are recommendations:
-:* Patients should reduce their intake of saturated fats to less than 7% of total calories (energy). [[Cholesterol]] intake should be reduced to less than 200 mg/d. Keep trans fatty acids (the [[HDL]]-lowering, LDL-raising fats) to a minimum. Polyunsaturated fats should constitute up to 10% of total energy intake and monounsaturated fats up to 20% of total energy intake. Total fat intake, therefore, should be in the range of 25-35% of total energy intake.
-:* Carbohydrates (complex carbohydrates from grains, whole grains, fruits, and vegetables) should constitute 50-60% of total energy intake.
-:* Patients should consume 20-30 g/d of fiber.
-:* The [[protein]] content should be approximately 15% of total energy intake.
-:* The total amount of energy consumed must be balanced in terms of energy intake and expenditure to maintain desirable body weight and to prevent weight gain.
-==Daily Physical Activity==
-Strongly encourage increased physical activity, especially in persons with sedentary habits. According to the NCEP guidelines, daily activity and energy expenditure should include at least moderate physical activity, expending approximately 840 kJ/d.
 ==References==
 {{Reflist|2}}
-{{Lipopedia}}
-[[Category:Cardiology]]
 {{WH}}
 {{WS}}