Lecithin cholesterol acyltransferase 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: LCAT deficiency, dyslipoproteinemic corneal dystrophy, fish eye disease, Norum disease, partial LCAT deficiency, Familial LCAT deficiency

Overview

Lecithin cholesterol acyltransferase (LCAT) is an enzyme with 2 subunits catalyzing the esterification of free cholesterol into cholesterol esters, an important step in the reverse cholesterol transport. LCAT deficiency is a monogenic autosomal recessive disease resulting from mutation in the LCAT gene on chromosome number 16. Patients with homozygous and compound heterozygous mutations are symptomatic due to the accumulation of excessive free cholesterol in the cornea, RBC cell membrane and the kidney. LCAT deficiency is classified into Familial LCAT deficiency(FLD) and Fish Eye Disease (FED) based on the degree of the enzyme function lost. The characteristic feature of these diseases is low plasma HDL C. FLD is a severe form with low HDL C and increase in LDL type protein called lipoprotein-X causing progressive renal failure, FED has a benign course with corneal opacities and low HDL C alone. Low HDL is a risk factor for development of cardiovascular disease,[1]but the risk of developing atherosclerosis and cardiovascular disease in LCAT deficiency is still not well defined and is controversial.[2][3]

Historical Perspective

Classification

LCAT deficiency is classified based on the quantity of enzyme function defective. A mutation in the LCAT gene can cause either a complete loss of function or a partial loss of function which is the basis of LCAT deficiency classification:[8]

  • Familial LCAT deficiency(FLD): Complete loss of alpha and beta LCAT function.
  • Fish Eye Disease (FED): Loss of alpha LCAT function with preserved beta function.[9]
Familial LCAT deficiency (FLD) Fish Eye Disease (FED)
Enzyme Function Completely dysfunctional Loss of alpha function only
Clinical Features Corneal opacities, anaemia

and progressive renal disease with proteinuria

Corneal opacities only;

Normal renal function

Microscopy Deposition of free cholesterol and phospholipids in cornea, RBC cell membrane and in the kidney Deposition of free cholesterol and phospholipids in the cornea
Laboratory findings Elevated free cholesterol

HDLC < 10 mg/dL[3] 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 AII

Elevated Apo E and triglycerides

Normal LDL and VLDL

Electrophoresis Pre β-1 and α-4 HDL, LDL C with β mobility due to

Lipoprotien-X

Pre β-1and α-4 HDL with normal

pre-β LDL

Treatment Preserve kidney function

Kidney transplant

Human recombinant enzyme replacement

Optimize lipid levels

Responds to statins[10]

Pathophysiology

Pathogenesis

LCAT deficiency is caused by a mutation in the LCAT gene, resulting in disruption of the reverse cholesterol transport.

LCAT Function

 
 
 
LCAT is synthesized in liver and released into circulation and is picked up by HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apo A1 activates LCAT associated with HDL, Apo E activates LCAT associated with LDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LCAT cleaves fatty acid from phosphotidylcholine
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfers fatty acid to beta hydroxyl group of free cholesterol taken up by HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Results in the formation of cholesterol esters which help in maturation of HDL C and also forms lysophosphotidylcholine
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Esterification of free cholesterol taken up by HDL C, is α-LCAT activity. Esterification of free cholesterol associated with Apo B( LDL C), is β-LCAT activity. This differentiation into alpha and beta is based on the HDL and LDL mobility on electrophoresis[11]
 
 
 

LCAT Deficiency

 
 
 
Loss of LCAT function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Loss of alpha function leads to failure of HDL maturation resulting in elevated FC, phospholipids, Apo E, pre beta HDL, and low Apo A1 and Apo A2 levels
 
 
 
Loss of beta function results in elevated FC, phospholipids, and formation of cholesterol rich multilamellar particles called Lipoprotein X [14], which are implicated in the development of glomerulopathy[15] [16].

Genetics

LCAT deficiency presents the following genetic characteristics:

Microscopy

Microscopic and histopathological examinations of tissues in LCAT deficiency will reveal the following:

Epidemiology and Demographics

  • The prevalence of Familial LCAT deficiency rare and is estimated to be less than 1/1,000,000. About 125 cases have been reported to date worldwide.[20]
  • Majority of the cases are reported in Europe, Japan and Canada.

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

The most common features of clinical presentation include annular corneal opacity, hemolytic anemia and renal disease.[23] The common presenting features include:

Physical Examination

Physical examination of patients with LCAT deficiency is remarkable for the following:

Laboratory Findings

Laboratory findings consistent with the diagnosis of Familial LCAT deficiency include:

Electrophoresis

2D gel electrophoresis in FLD is remarkable for the following:[26]

Low HDL C 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.

Treatment

Medical Therapy

The mainstay of therapy for Familial LCAT deficiency include:

While there is no definitive medical therapy to treat LCAT deficiency, the following methods can help mitigate complications and alleviate symptoms:

Surgery

  • Patients dependent on hemodialysis with worsening renal function are indicated for renal transplant.
    • Lipid abnormalities usually recur after a renal transplant .[31]

Prevention

  • There are no screening recommendations for the disease. Patients are advised regular follow up, medication compliance and monitoring of the renal function to prevent progressive decline in renal function.

References

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