Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare metabolic disease with lipid deposition in several organs. The authors report a man with hypertension and proteinuria. Renal biopsy revealed glomerular changes, including peculiar thrombus-like deposits, consistent with LCAT deficiency. He was found to be compound heterozygous for two mutations of the LCAT gene. He received a kidney graft from his father. The authors also describe LCAT deficiency-related lesions in the explanted native kidneys and in biopsies at 2 days, 6 weeks, and 1 year after transplantation. The morphology of this disease is characteristic, and the diagnosis should be suspected from the ultrastructural findings.
OBJECTIVE: To better understand the role of lecithin:cholesterol acyltransferase (LCAT) in lipoprotein metabolism through the genetic and biochemical characterization of families carrying mutations in the LCAT gene. METHODS AND RESULTS: Thirteen families carrying 17 different mutations in the LCAT gene were identified by Lipid Clinics and Departments of Nephrology throughout Italy. DNA analysis of 82 family members identified 15 carriers of 2 mutant LCAT alleles, 11 with familial LCAT deficiency (FLD) and 4 with fish-eye disease (FED). Forty-four individuals carried 1 mutant LCAT allele, and 23 had a normal genotype. Plasma unesterified cholesterol, unesterified/total cholesterol ratio, triglycerides, very-low-density lipoprotein cholesterol, and pre-beta high-density lipoprotein (LDL) were elevated, and high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, LpA-I, LpA-I:A-II, cholesterol esterification rate, LCAT activity and concentration, and LDL and HDL3 particle size were reduced in a gene-dose-dependent manner in carriers of mutant LCAT alleles. No differences were found in the lipid/lipoprotein profile of FLD and FED cases, except for higher plasma unesterified cholesterol and unesterified/total cholesterol ratio in the former. CONCLUSIONS: In a large series of subjects carrying mutations in the LCAT gene, the inheritance of a mutated LCAT genotype causes a gene-dose-dependent alteration in the plasma lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.
