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

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.

Familial hypercholesterolemia in children and the importance of early treatment

“…As a result of worldwide advancements in research in the pediatric field of familial hypercholesterolemia, there are currently more and more LLTs available and in trial to effectively treat both children with HeFH and HoFH [13]. In addition to conventional oral LLT like statins and ezetimibe, novel therapies are available if these are not sufficient to reach treatment targets or are unsuitable due to side effects.…”

“…The diagnosis familial hypercholesterolemia can be made based on clinical criteria or by genetic testing to provide a definite molecular diagnosis. If locally available, molecular genetic testing is recommended using Sanger sequencing or next-generation sequencing- based custom packages [13]. Genetic analysis can give additional insight in the severity of the specific genetic variation causing familial hypercholesterolemia and in the case of HoFH, give information on whether or not LDL receptor based therapies are an option for the individual patient [13].…”

“…If locally available, molecular genetic testing is recommended using Sanger sequencing or next-generation sequencing- based custom packages [13]. Genetic analysis can give additional insight in the severity of the specific genetic variation causing familial hypercholesterolemia and in the case of HoFH, give information on whether or not LDL receptor based therapies are an option for the individual patient [13]. A recent (2023) retrospective study from the Netherlands based on 2714 genetic test results from children with HeFH demonstrated that children having one LDL-R null genetic variant, wherein LDL-receptors exhibit no activity, have significantly higher LDL-C levels when compared to those with an LDL-R defective allele with rest activity (6.0 versus 4.9 mmol/l, P < 0.001).…”

Appropriateness of Dyslipidemia Management Strategies in Post-Acute Coronary Syndrome: A 2023 Update

“…Consequently, inclisiran has been considered an attractive therapeutic option, particularly for non-adherent patients [ 91 ]. What the impact of inclisiran on reducing lipoproteins and MACE is, has been largely investigated in the ORION/VICTORION studies [ 90 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ], which evidenced a decrease in LDL-C over 1 year of 29.5–38.7% and 29.9–46.4% after a single dose and after two doses, respectively ( p < 0.001). Moreover, Lp(a) has been shown to significantly decrease.…”

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia

“…There are four known causative genes, including the LDL receptor gene ( LDLR ), apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and LDL receptor adaptor protein 1 ( LDLRAP1 ). Among them, LDLR is by far the most common cause, the malfunction of which leads to the disruption of LDL catabolism, thus elevating LDL-C levels [ 3 ]. Currently, the prevalence of this disease is estimated to be 1 in 300 among the general population based on a meta-analysis of genetic epidemiological studies [ 4 ].…”