Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is a genetic disorder in which the body is unable to remove low-density lipoprotein (LDL) cholesterol from the blood. This genetic disease has an autosomal dominant inheritance pattern. However, there are also rare cases of autosomal recessive inheritance. The onset of FH is in early childhood, and, without treatment, the condition can lead to early mortality (Bouhairie & Goldberg, 2015). FH is a highly common genetic disorder affecting cholesterol metabolism, and its symptoms include the development of cardiovascular disease, angina, atherosclerosis, cholesterol-rich deposits in tendons and skin, stroke, corneal arcus, as well as the primary feature, which is high LDL cholesterol (Zubielienė et al. 2022). The diagnosis methods of FH include the Dutch Lipid Clinic criteria as well as genetic testing (Zubielienė et al. 2022).
FH is caused by mutations to either of the apolipoprotein B (APOB), low-density lipoprotein receptor (LDLR), or proprotein convertase Subtilisin/Kexin Type 9 (PCSK9) genes (Abifadel & Boileau, 2023). FH can also be caused by multiple mutations to the APOE gene or even a mutation to the LDLR adapter protein 1 (LDLRAP1) gene for a rare autosomal recessive form of the condition (Abifadel & Boileau, 2023). These mutations, by in large, degrade the binding affinity of LDL particles to LDL receptors, causing the buildup of LDL cholesterol.
Treatment options for FH include PCSK9 inhibitors, inclisiran, statins, LDL apheresis, mipomersin and lomitapide, fibrates, and nicotinic acid (Fu et al. 2022). These treatments all fundamentally address the unwanted accumulation of LDL cholesterol. A diet low in saturated fats and cholesterol is also recommended. With regard to public health considerations, early screening is crucial for FH, especially if there is a family history of the disorder.
Some technological advancements in treating FH include the RNA-based therapies, where small interfering RNA (siRNA) inhibits PCSK9 synthesis, reducing LDL cholesterol. One such example of an siRNA that lowers cholesterol is inclisiran (Fu et al. 2022). Notably, an emerging area of RNA-based therapy is the use of antisense oligonucleotides to target the APOB gene to lower LDL cholesterol production. Additionally, the application of CRISPR-Cas9 gene editing technology has been used to repair the dysfunctional LDLR in FH. Cholesteryl ester transfer protein inhibitors are also a foreseen treatment option in the future, though impermanent (Fu et al. 2022).
References:
Abifadel, Michel, and Catherine Boileau. "Genetic and Molecular Architecture of Familial Hypercholesterolemia." Journal of Internal Medicine, vol. 293, no. 2, Feb. 2023, pp. 144–65. DOI, https://doi.org/10.1111/joim.13577. Bouhairie, V. E., and A. C. Goldberg. "Familial Hypercholesterolemia." Cardiology Clinics, vol. 33, no. 2, May 2015, pp. 169–79. ScienceDirect, https://doi.org/10.1016/j.ccl.2015.01.001. Cleveland Clinic. "Familial Hypercholesterolemia: Symptoms & Treatment." Health Library, 2024, https://my.clevelandclinic.org/health/diseases/22067-familial-hypercholesterolemia. Fu, Qiuying, et al. "Recent Advances in Gene Therapy for Familial Hypercholesterolemia: An Update Review." Journal of Clinical Medicine, vol. 11, no. 22, Nov. 2022, p. 6773. MDPI, https://doi.org/10.3390/jcm11226773. Shah, N. P., et al. "Familial Hypercholesterolemia: Diagnosis, Management, and Future Directions." Cleveland Clinic Journal of Medicine, vol. 87, no. 2, Feb. 2020, pp. 109–20. DOI, https://doi.org/10.3949/ccjm.87a.19021. Zubielienė, K., et al. "Familial Hypercholesterolemia and Its Current Diagnostics and Treatment Possibilities: A Literature Analysis." Medicina (Kaunas, Lithuania), vol. 58, no. 11, Nov. 2022, p. 1665. MDPI, https://doi.org/10.3390/medicina58111665.