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.
Highlights
Familial hypercholesterolemia (FH) is an inherited disease characterized by high levels of LDL-cholesterol (LDL-c) which leads to premature coronary heart disease (CHD)
Genetic defects causing the disease are pathogenic variants present in genes encoding proteins related to LDL particle uptake, i.e., genes encoding the LDL receptor (LDLR), the apolipoprotein B (APOB), the proprotein convertase subtilisin/kexin type 9 (PCSK9) inducing LDLR degradation, and the low-density lipoprotein receptor adapter protein 1 (LDLRAP1) mediating the interaction of LDLR with clathrin [2]
Very recent evidence has indicated that Heterozygous (HeFH) and homozygous (HoFH) could be treated with antibodies targeting Angiopoietin-like 3 (ANGPTL3) because their action mechanism is independent of LDLR activity [43]
Summary
Familial hypercholesterolemia (FH) is an inherited disease characterized by high levels of LDL-cholesterol (LDL-c) which leads to premature coronary heart disease (CHD). Based on the number of altered alleles, two forms of FH are recognizable: Heterozygous (HeFH) and homozygous (HoFH). The latter is the severest form of FH, since LDL-c levels above 13 mmol/L (500 mg/dL) are usually reported as being associated with a high frequency of premature CHD. There has been growing interest about genetic/clinical heterogeneity in relation to the therapeutic response of patients with HoFH [6,7,8,9,10,11]. A follow-up analysis was performed in order to evaluate the patients’ response to therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
