The biochemical and cardiovascular consequences of LCAT deficiency

We have recently identified 14 Italian families with LCAT deficiency, carrying 19 different mutations in the LCAT gene. All carriers of two mutant LCAT alleles (n=17) had remarkably low plasma HDL-C, apoA-I, and apoA-II levels, associated with multiple alterations in HDL structure and particle distribution, with a selective depletion of LpAI:A-II particles, a predominance of small, pre-beta-migrating HDL and a complete lack of HDL2. Unesterified cholesterol, the unesterified/total cholesterol ratio, VLDL-cholesterol, and triglycerides were significantly elevated, whereas apoB was significantly lower compared to controls. Twenty-three out of 44 carriers of one mutant LCAT allele (53%) had a low plasma HDL-C; the average plasma HDL-C and apoA-I levels were significantly lower than in controls. Plasma LCAT activity was also significantly lower than in controls. Despite the atherogenic profile, only one of the 17 carriers of two mutant LCAT alleles, a 71 y.o. man with elevated LDL-C, hypertension, and diabetes, presented with premature coronary artery disease. The evaluation of carotid intima-media thickness (IMT) showed that carriers of two mutant LCAT alleles have IMT values comparable to age-sex matched controls, despite the severe hypoalphalipoproteinemia. Carriers of one mutant LCAT allele have widely distributed IMT values, showing on average IMT values comparable to controls. 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. No premature cardiovascular disease and no increase in carotid IMT was observed, despite the hypoalphalipoproteinemia, in the Italian LCAT deficient subjects.