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Review
. 2023 Mar 7;14(3):669.
doi: 10.3390/genes14030669.

How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment

Sibbeliene E van den Bosch  1 , Willemijn E Corpeleijn  1 , Barbara A Hutten  2 , Albert Wiegman  1
Affiliations
Review

How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment

Sibbeliene E van den Bosch et al. Genes (Basel). .

Abstract

Familial hypercholesterolemia (FH) is a hereditary disorder that causes severely elevated low-density lipoprotein (LDL-C) levels, which leads to an increased risk for premature cardiovascular disease. A variety of genetic variants can cause FH, namely variants in the genes for the LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and/or LDL-receptor adaptor protein 1 (LDLRAP1). Variants can exist in a heterozygous form (HeFH) or the more severe homozygous form (HoFH). If affected individuals are diagnosed early (through screening), they benefit tremendously from early initiation of lipid-lowering therapy, such as statins, and cardiovascular imaging to detect possible atherosclerosis. Over the last years, due to intensive research on the genetic basis of LDL-C metabolism, novel, promising therapies have been developed to reduce LDL-C levels and subsequently reduce cardiovascular risk. Results from studies on therapies focused on inhibiting PCSK9, a protein responsible for degradation of the LDLR, are impressive. As the effect of PCSK9 inhibitors (PCSK9-i) is dependent of residual LDLR activity, this medication is less potent in patients without functional LDLR (e.g., null/null variant). Novel therapies that are expected to become available in the near future focused on inhibition of another major regulatory protein in lipid metabolism (angiopoietin-like 3 (ANGPTL3)) might dramatically reduce the frequency of apheresis in children with HoFH, independently of their residual LDLR. At present, another independent risk factor for premature cardiovascular disease, elevated levels of lipoprotein(a) (Lp(a)), cannot be effectively treated with medication. Further understanding of the genetic basis of Lp(a) metabolism, however, offers a possibility for the development of novel therapies.

Keywords: cholesterol; familial hypercholesterolemia; genetic screening; lipid-lowering therapy; lipids.

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Conflict of interest statement

A.W. reports research support from pharmaceutical trials of lipid modification agents from Amgen, Regeneron, and Novartis and is a member of the safety board at Amryt. B.A.H. and A.W. received a research grant from Silence Therapeutics. All other authors declare no competing interests.

Figures

Figure 1
Figure 1
Overview of key aspects of timing of screening, diagnostic criteria (genetic and clinical), treatment, and options for screening for subclinical atherosclerosis as stated by the EAS. Children suspected for HeFH or HoFH need to be screened from 5 years of age and from birth onwards, respectively. When genetic confirmation is not possible, clinical diagnostic criteria can be used based on LDL-C levels, family history, or patient’s characteristics. In both HeFH and HoFH, lifestyle changes are needed from diagnosis, while the start and type of treatment differ between HeFH and HoFH and depend on age and LDL-C levels. Screening for subclinical atherosclerosis is possible in HeFH (in research setting) but recommended in HoFH.
Figure 2
Figure 2
Genetic diagnosis and conventional/novel treatment options for children with FH.
See this image and copyright information in PMC

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