Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): A phenotypic comparison

Autosomal recessive hypercholesterolemia (ARH) is a rare disorder, due to complete loss of function of an adaptor protein (ARH protein) required for receptor-mediated hepatic uptake of LDL. ARH is a phenocopy of homozygous familial hypercholesterolemia (HoFH) due to mutations in LDL receptor (LDLR) gene; however, previous studies suggested that ARH phenotype is less severe than that of HoFH. To test this hypothesis we compared 42 HoFH and 42 ARH patients. LDLR and ARH genes were analysed by Southern blotting and sequencing. LDLR activity was measured in cultured fibroblasts. In ARH plasma LDL cholestrol (LDL-C) level (14.25 ± 2.29 mmol/L) was lower than in receptor-negative HoFH (21.38 ± 3.56 mmol/L) but similar to that found in receptor-defective HoFH (15.52 ± 2.39 mmol/L). The risk of coronary artery disease (CAD) was 9-fold lower in ARH patients. No ARH patients ≤20 years of age were found to have CAD as opposed to 43% of HoFH. The CAD prevalence was or tended to be lower in ARH also in the 21–40 (45% versus 86%) and 41–60 (78% versus 100%) age groups. Heterozygous ARH carriers showed higher level of LDL-C (+17%) than non-carrier family members. In conclusion the clinical phenotype of ARH is milder than that of receptor-negative HoFH and resembles that observed in receptor-defective HoFH.