BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, with heterozygous FH (HeFH) affecting approximately 1 in 310 individuals. FH is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which are typically twice those of unaffected individuals, and by a markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Homozygous FH (HoFH) is rarer and presents substantial phenotypic variability, with total cholesterol levels ranging from 13 to 55 mmol/L. CASE PRESENTATIONS: We report three atypical cases of HoFH, with one patient being a homozygote for the c.1775G > A (p.Gly592Glu) variant and two patients being compound heterozygotes (c.340T > A/c.1775G > A, p.Phe114Ile/p.Gly592Glu and c.761A > C/c.910G > A, p.Gln254Pro/p.Asp304Tyr). All the patients presented with relatively mild clinical phenotypes, delayed diagnoses, and no evidence of early-onset ASCVD. CONCLUSIONS: These cases underscore the clinical heterogeneity of HoFH and challenge the prevailing assumption that HoFH uniformly results in severe cardiovascular outcomes. Personalized treatment strategies are essential for improving prognoses and quality of life of affected individuals.

3rd Department of Internal Medicine Department of Endocrinology and Metabolism 1st Faculty of Medicine General University Hospital Charles University Prague Czech Republic

Experimental Medicine Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

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Goldstein JL, Kottke BA, Brown MS. Biochemical genetics of LDL receptor mutations in familial hypercholesterolemia. Prog Clin Biol Res. (1982) 103(Pt B):161–76. PubMed

Hu P, Dharmayat KI, Stevens CA, Sharabiani MT, Jones RS, Watts GF, et al. Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Circulation. (2020) 141:1742–59. 10.1161/CIRCULATIONAHA.119.044795 PubMed DOI

Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects. J Am Coll Cardiol. (2020) 75:2553–66. 10.1016/j.jacc.2020.03.057 PubMed DOI

Vrablik M, Tichý L, Freiberger T, Blaha V, Satny M, Hubacek JA. Genetics of familial hypercholesterolemia: new insights. Front Genet. (2020) 11:574474. 10.3389/fgene.2020.574474 PubMed DOI PMC

Nohara A, Tada H, Ogura M, Okazaki S, Ono K, Shimano H, et al. Homozygous familial hypercholesterolemia. J Atheroscler Thromb. (2021) 28:665–78. 10.5551/jat.RV17050 PubMed DOI PMC

Bruckert E, Kalmykova O, Bittar R, Carreau V, Béliard S, Saheb S, et al. Long-term outcome in 53 patients with homozygous familial hypercholesterolemia in a single centre in France. Atherosclerosis. (2017) 257:130–7. 10.1016/j.atherosclerosis.2017.01.015 PubMed DOI

Widhalm K, Benke IM, Fritz M, Geiger H, Helk O, Fritsch M, et al. Homozygous familial hypercholesterolemia: summarized case reports. Atherosclerosis. (2017) 257:86–9. 10.1016/j.atherosclerosis.2017.01.002 PubMed DOI

Altschmiedova T, Todorovova V, Vrablik M, Ceska R. Familial hypercholesterolemia: real-world data of 1236 patients attending a Czech lipid clinic. Front Genet. (2022) 13:849267. 10.3389/fgene.2022.849267 PubMed DOI PMC

Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L. The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. Atherosclerosis. (2012) 223:401–8. 10.1016/j.atherosclerosis.2012.05.014 PubMed DOI

Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European atherosclerosis society. Eur Heart J. (2013) 34:3478–90. 10.1093/eurheartj/eht273 PubMed DOI PMC

Sijbrands EJ, Kaprio J, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, et al. Mortality over two centuries in large pedigree with familial hypercholesterolemia: family tree mortality study. Br Med J. (2001) 322:1019–23. 10.1136/bmj.322.7293.1019 PubMed DOI PMC

Hofmaenner DA, Kleyman A, Press A, Bauer M, Singer M. The many roles of cholesterol in sepsis: a review. Am J Respir Crit Care Med. (2022) 205:388–96. 10.1164/rccm.202105-1197TR PubMed DOI PMC

Taylor R, Zhang C, George D, Kotecha S, Abdelghaffar M, Forster T, et al. Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies. EBioMedicine. (2024) 100:104981. 10.1016/j.ebiom.2024.104981 PubMed DOI PMC

Jo YS, Han K, Kim D, Yoo JE, Kim Y, Yang B, et al. Relationship between total cholesterol level and tuberculosis risk in a nationwide longitudinal cohort. Sci Rep. (2021) 11:16254. 10.1038/s41598-021-95704-1 PubMed DOI PMC

Claxton AJ, Jacobs DR, Jr., Iribarren C, Welles SL, Sidney S, Feingold KR. Association between serum total cholesterol and HIV infection in a high-risk cohort of young men. J Acquir Immune Defic Syndr Hum Retrovirol. (1998) 17:51–7. 10.1097/00042560-199801010-00008 PubMed DOI

Alothman L, Belanger AM, Ruel I, Brunham LR, Hales L, Genest J, et al. Health-related quality of life in homozygous familial hypercholesterolemia: a systematic review and meta-analysis. J Clin Lipidol. (2022) 16:52–65. 10.1016/j.jacl.2021.11.014 PubMed DOI

Tromp TR, Reijman MD, Wiegman A, Hovingh GK, Defesche JC, van Maarle MC, et al. Counseling couples at risk of having a child with homozygous familial hypercholesterolemia: clinical experience and recommendations. J Clin Lipidol. (2023) 17:291–6. 10.1016/j.jacl.2022.12.006 PubMed DOI