Current Status of Familial LCAT Deficiency in Japan

Abstract

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

Keywords: Abnormal LDL; Corneal opacity; Enzyme replacement therapy; Lecithin cholesterol acyltransferase; Low HDL-cholesterol; Proteinuria.

Fig. 1. Previously identified mutations in LCAT gene

The LCAT gene is composed of six exons. Mutations identified so far are depicted according to The Human Gene Mutation Database (HGMD®) ( http://www.hgmd.cf.ac.uk/ac/index.php). Numbers of amino acid residues are expressed based on mature LCAT protein after signal peptide (24 amino acid residues) is cleaved. Mutations in red and bule are causative mutations identified in familial LCAT deficiency (FLD) and fish-eye disease (FED), respectively. The ^＊ symbol indicates a mutation reported in Japan, and the ^# symbol indicates a mutation identified in Japan as well as other countries. Mutations shown in black are variants of uncertain significance found by such as genome-wide nucleotide sequencing of clinical samples.

Fig. 2. Distribution of HDL-C in patients

Clinical levels of HDL-C available from published data (until Aug. 2019) for homozygous and compound heterozygous patients ( n = 86) and heterozygotes ( n = 141) have been collected and their distribution is shown in the figure. Note that their assay methods are not taken into consideration in the data distribution.

Fig. 3. Case with LCAT deficiency manifesting as corneal opacities and proteinuria (patient from ref. 31)

A) Corneal opacities in right eye (arrows). B) Light microscopic findings for renal biopsy (Periodic acid methenamine silver stain). Thickened with bubbly, vacuolated, and honeycomb appearance. (Bar = 10 µm) C) Electron microscopic findings for renal biopsy. Electron micrograph shows glomerular epimembranous, intramembranous, and subendothelial lipid droplets. Electron-lucent deposits with an electron-dense core can be observed in the glomerular basement membrane and mesangial matrix. (Bar = 2 µm)