Lecithin cholesterol acyltransferase deficiency

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

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

Historical Perspective

• In 1962, Glomset identified an enzyme (plasma fatty acid transferase) which transfers fatty acid onto free cholesterol to make a cholesterol ester. This helps in the formation of a mature HDL particle a crucial step in reverse cholesterol transport .
• In 1967, Norum and Gjone described a disease for the first time in a patient from Norway with features of normochromic anemia, protienuria and corneal lipid deposits.
• In 1967, Norum and Gjone reported that two sisters of the affected patient had similar presentation along with low levels of cholesterol esters and lysolecithin in the serum, with increased total body cholesterol, triglyceride and phospholipid. Foam cells in the bone marrow and glomerulus were demonstrated on microscopy. Patients had absent hepatomegaly and normal tonsils differentiating it from liver disease causing the defect in esterification and Tangier disease. Low serum cholesterol esters were attributed to the LCAT enzyme deficiency.
• In 1986, McLean and colleagues reported the complete gene sequence and sites expression of Lecithin cholesterol acyl transferase gene(LCAT). The location of the gene is identified to be on q21-22 region of chromosome 16 and is synthesized mainly in the liver.

Pathophysiology

Pathogenesis

LCAT Function

• Majority of the enzyme is associated with HDL C, very small amount with LDL C.

LCAT synthesized in liver and released into circulation and is picked up by HDL C

Apo A1 activates LCAT

LCAT cleaves fatty acid from phosphotidylcholine

Transfers fatty acid to beta hydroxyl group of free cholesterol(FC) 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 FC taken up by HDL C, is Alpha LCAT activity. Esterification of FC associated with Apo B ( LDL C), is β-LCAT activity. This differntiation into alpha and beta is based on the HDL and LDL mobility on electrophoresis

• LCAT helps in reverse cholesterol transport by:
  • Cholesterol esters due to the hydrophobic nature occupy the core of the lipoprotien, which prevent the backflow of cholesterol into the cells.
  • LCAT promotes unidirectional efflux of free cholesterol from the cells via ABCA1 and scavenger receptor type B-I (SR-BI) by creating a concentration gradient.

LCAT Deficiency

Loss of LCAT function

Loss of alpha function leads to failure HDL maturation resulting in elevated FC, phospholipids, Apo E and 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 particle called Lipoprotien X , which are implicated in the development of glomerulopathy.

Genetics

• Autosomal Recessive.
• LCAT gene is on chromosome 16.
• Expression of clinical features and severity of disease in homozygous patients depends on the type and locus of the mutation.

Classification

Severity of the disease is a direct result of the enzyme deficiency. Mutation can cause either a complete loss of function or a partial loss of function, based on which LCAT deficiency can be classified into:

• Familial LCAT deficiency: Complete loss of alpha and beta LCAT function.
• Fish Eye Disease: Loss of alpha LCAT function and preserved beta fucntion.

	Familial LCAT deficiency	Fish Eye Disease
Enzyme Defect	Complete loss	Loss of alpha function only
Clinical Features	Corneal opacities, anaemia and progressive renal disease with protienuria	Corneal opacities only Normal renal function
Microscopy	Deposition of FC and phospholipids in cornea and RBC membrane. Lipoprotien-X deposition in the glomerulus.	Deposition of FC and phospolipids in the cornea.
Laboratory findings	Elevated Free cholesterol Very low HDL C Low Apo A1 and Apo A2 Elevated Apo E Low LDL C	Elevated free cholesterol Very low HDL C Low Apo A1 and Apo A2 Elevated Apo E Normal LDL and VLDL