Apolipoprotein A deficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: Familial hypoalphalipoproteinemia, FHA, familial HDL deficiency, FHD, high density lipoprotein deficiency, HDLD

Overview

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

Historical Perspective

Classification

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

ApoA1/ApoC-III Deficiency

Apo A1 Deficiency

Apo A1 Variants

Demographics, Epidemiology

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

Pathogenesis

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

Pathophysiology

Reverse Cholesterol Transport[33]

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

Genetics

Natural History, Prognosis, Complications

History and Symptoms

Physical Examination

Physical examination findings in Apo A1 deficiency include:

Diagnosis

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

Lipid Analysis

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

2D Electrophoresis

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

Molecular Gene Sequencing

Differential Diagnosis

Familial LCAT

Deficiency

Fish Eye

Disease

Homozygous Tangier

Disease

Heterozygous Tangier

Disease

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

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

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

Distinguishing features of homozygous patients with very low or undetectable HDL C and Apo A1[47]:
Apo A/CIII/A-IV Deficiency ApoA/CIII Deficiency Apo A Deficiency
Planar Xanthomas Absent Present Present
Tubo-Eruptive Xanthomas Absent Absent Present
Premature Heart Disease Present Present Present
Triglyceride Decreased due to the absence

of Apo C III- 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 Apo A1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>5mg/dl
 
 
 
 
Undetectable or <5mg/dl
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Familial LCAT deficiency
High plasma FC:CE ratio
2D electrophoresis: Prebeta and Alpha-4, Beta mobility of LDL
 
 
 
 
Do 2D Gel Electrophoresis with Apo A1 Immunoassay
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete absence of Apo A1 containing HDL C
 
 
Only Pre-Beta HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apo A1 Deficiency
(Confirm with gene sequencing)
 
 
Homozygous Tangier Disease
(Confirm with gene sequencing)

Treatment

Medical Therapy

The mainstay of therapy for Apo A1 deficiency 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.[49]

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.

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