A real-world experience of clinical, biochemical and genetic assessment of patients with homozygous familial hypercholesterolemia

Abstract

Homozygous familial hypercholesterolemia (HoFH), the severest form of familial hypercholesterolemia (FH), is characterized by very high LDL-cholesterol levels and a high frequency of coronary heart disease. The disease is caused by the presence of either a pathogenic variant at homozygous status or of two pathogenic variants at compound heterozygous status in the LDLR, APOB, PCSK9 genes. We retrospectively analyzed data of 23 HoFH patients (four children and 19 adults) identified during the genetic screening of 724 FH patients. Genetic screening was performed by sequencing FH causative genes and identifying large rearrangements of LDLR. Among the HoFH patients, four out of 23 (17.4%) were true homozygotes, whereas 19 out of 23 (82.6%) were compound heterozygotes for variants in the LDLR gene. Basal LDL-cholesterol was 12.9 ± 2.9 mmol/L. LDL-cholesterol levels decreased to 7.2 ± 1.8 mmol/L when treated with statin/ezetimibe and to 5.1 ± 3.1 mmol/L with anti-PCSK9 antibodies. Homozygous patients showed higher basal LDL-cholesterol and a poorer response to therapy compared with compound heterozygotes. Since 19 unrelated patients were identified in the Campania region (6,000,000 inhabitants) in southern Italy, the regional prevalence of HoFH was estimated to be at least 1:320,000. In conclusion, our results revealed a worse phenotype for homozygotes compared with compound heterozygotes, thereby highlighting the role of genetic screening in differentiating one genetic status from the other.