Abstract 8511: A Novel Type of Homozygous Familial Hypercholesterolemia:Double Heterozygous Mutations in LDL Receptor and LDL Receptor Adaptor Protein 1 Gene

Abstract

Introduction: Autosomal recessive hypercholesterolemia (ARH), which is due to mutations in LDL receptor adaptor protein 1 (LDLRAP1) gene is extremely rare disorder. Although it is described that this defect exhibits recessive form of inheritance, several heterozygous mutation carriers in this gene are reported to show elevated LDL-C levels. There is no data exists regarding clinical impact of double heterozygous mutations in LDLR and LDLRAP1 gene, both of which are involved in the metabolism of LDL particle. Hypothesis: We assessed the hypothesis that additional mutation in LDLRAP1 gene worsen clinical phenotype of heterozygous familial hypercholesterolemia (FH) that has a single mutation in LDLR gene. Methods: We performed genetic analyses of all coding regions in the LDLRAP1 gene for our mutation determined heterozygous FH patients with mutation in LDLR gene (n=146, mean age=56.5±16.0, mean LDL-C=265.6±57.7mg/dl). Results: We identified a case with double heterozygous mutations in LDLR gene (c.2431A>T) and in LDLRAP1 gene (c.606dup). Seventy-nine-year-old Japanese female exhibits severe Achilles' tendon xanthomas, the thickness of which is as much as 24mm. She underwent coronary artery bypass graft surgery due to her three vessel disease at the age of 70. Although her coronary atherosclerosis including bypass grafts did not progress substantially for a period of 9 years on more intensive medical therapy, severe aortic valve stenosis developed to cause ventricular fibrillation. And we identified 2 other relatives with the same mutations in LDLR and LDLRAP1 gene in her family. Serum LDL-C level of these 3 subjects with double mutations was significantly higher than that of the subjects with a single LDLR mutation alone (284.0±43.5 versus 265.1±57.4, p < 0.0001). Conclusions: These results indicate that additional mutation in LDLRAP1 gene worsens clinical phenotype of heterozygous FH that has a single mutation in LDLR gene. We suggest that ARH is not a fully “recessive” disorder, and that such cases should be diagnosed as novel type of “homozygous FH”.