Familial LCAT Deficiency: FLD (Fish Eye Disease)

Diseases and Disorders, Hyperlipoproteinemias

Last Updated: September 15, 2022

Introduction to Familial LCAT Deficiency, FLD

Familial LCAT deficiency (FLD) is a rare (incidence below 1:1,000,000) autosomal recessive disorder due to mutations in the LCAT gene (encoding lecithin:cholesterol ester transferase) that cause complete loss of LCAT activity. A related autosomal recessive disorder that is caused by mutations in the LCAT gene resulting in partial loss of enzyme activity is called Fish eye disease (FED).

Familial LCAT deficiency represents a disorder that is characterized by abnormalities in the levels of several different blood lipids that includes decreased levels of LDL, HDL, apoA-I, and apoA-II along with increased levels of free cholesterol, apoE, and triglycerides.

Functions of LCAT

Lecithin:cholesterol ester transferase is so named because it transfers a fatty acid from the C-2 position of a lecithin (phosphatidylcholine, PC) to the C3-OH of cholesterol, generating a cholesteryl ester and a lysolecithin. Within the blood LCAT associates almost exclusively with apolipoprotein A-I (apoA-I) which is the major activator of the enzyme. ApoA-I, released from the liver and small intestines, represents the nascent HDL.

The cholesteryl esters formed via LCAT activity are internalized into the hydrophobic core of pre-β HDL particles. As pre-β HDL particles enlarge with progressive uptake of cholesterol they become larger and spherical generating the HDL2 and HDL3 particles. LCAT has also been shown to be associated with VLDL and LDL particles but to a much lesser extent than its association with HDL. These two activities of LCAT are termed alpha-LCAT, which is specific for apoA-I-containing lipoproteins (HDL), and beta-LCAT, which is specific for apoB-100-containing lipoproteins (VLDL and LDL). Although the alpha-LCAT and beta-LCAT activities are two functional activities of the same protein they have different clearance rates from the blood.

Molecular Biology of Familial LCAT Deficiency

The LCAT gene is located on chromosome 16q22.1 and is composed of 6 exons that encode a 440 amino acid precursor protein. Expression of the LCAT is nearly exclusive to the liver. More than 80 mutations in the LCAT gene have been identified FLD and FED patients.

Clinical Features of Familial LCAT Deficiency (FLD and FED)

Individuals with FLD have characteristic abnormalities in blood lipid profiles that includes low HDL (<10 mg/dl), low apo A-I (20–30 mg/dl), low cholesteryl esters, and low LDL. The HDL particles in FLD patients, in addition to being lower than normal, are also small and resemble immature HDL. FLD patients may also experience hypertriglyceridemia, but this blood lipid abnormality does not appear in all patient. FLD patients always develop corneal opacities that give their eyes the appearance of fish eyes, hence the association with the name fish eye disease.

FLD patients will also have an abnormal lipoprotein particle in their blood called lipoprotein-X (Lp-X). Lp-X is characterized by the very low protein content of the particle (around 5%) and its predominant phospholipid (>65%) content. The protein in Lp-X is almost exclusively albumin in the inner core and apoC on the surface. Patients with FLD also develop normochromic anemia as a result of the enrichment of cholesterol in the plasma membranes of erythrocytes. Eventually FLD patient develop proteinuria and end-stage renal disease.

The abnormal Lp-X is believed to play a major role in the development of the end-stage renal disease in FLD patients. Lp-X has been shown to accumulate in the mesangial cells, endothelial cells, podocytes, and the basement membranes of the glomerular filtration apparatus of the nephrons in the kidneys. The accumulation of Lp-X causes activation of inflammation resulting in the degradation of the basement membranes leading to the observed proteinuria. The end-stage renal disease is the leading cause of mortality in FLD patients, most of whom succumb by the 4th decade of life.

Individuals who have mutations in LCAT that reduce overall LCAT activity, but do not abolish it completely (referred to as fish eye disease, FED), generally do not experience the disturbances in blood lipids nor the renal pathology seen in FLD. The primary pathology in FED is the presence of corneal opacities (fish eyes). The residual LCAT activity in FED is of the beta-LCAT type and so there is still some esterification of cholesterol in VLDL and LDL in these patients.

Treatment of LCAT Deficiency

Because renal dysfunction is the leading cause of mortality in FLD, the major focus of treatment is to manage this pathology. Patients are usually treated with angiotensin-converting enzyme (ACE) inhibitors (these drugs all have the suffix “pril”) and angiotensin II receptor blockers (ARB; these drugs all have the suffix “sartan”). A diet that is low in fat and calories and enriched in vegetables has been suggested to be beneficial in reducing the progression of renal pathology in FLD patients.

The use of a recombinant human LCAT (rhLCAT) protein has shown some promise in the treatment of patients with low HDL levels such as in FLD. This type of therapy is referred to as enzyme replacement therapy, ERT. Studies done in mice showed that intravenous injection of the recombinant protein was associated with rapid increases in HDL cholesterol (HDL-C) and increased esterification of cholesterol.