About HoFH
HoFH is an ultra-rare, inherited genetic disorder of lipid metabolism1,2
hypercholesterolaemia-icon
HoFH is characterised by:1-4
  • Markedly elevated plasma levels of LDL-C (untreated LDL-C >10 mmol/L)
  • Premature atherosclerotic cardiovascular disease and cardiovascular morbidity and mortality
  • Cholesterol buildup:
    • around the joints and on the tendons (xanthomas)
    • in the eyes (corneal arcus) and around the eyelids (xanthelasmas)

The current estimated prevalence of HoFH is 1 in 300,000.4*

HoFH is genetic and inherited
disease-state-icon

HoFH occurs when two copies of the alleles bearing the familial hypercholesterolaemia (FH)-causing genes are inherited, one from each parent.1

Almost all inheritance patterns are semi-dominant (i.e, LDLR, APOB, and PCSK9 genes) though <1% occur as true autosomal recessive (i.e, LDLRAP1 gene)1.

1. Cuchel M et al. Eur Heart J. 2023;00:1–15; 2. Raal FJ et al. Atherosclerosis. 2018;277:483–492; 3. McGowan MP et al. J Am Heart Assoc. 2019;8:e013225; 4. Tromp TR et al. The Lancet. 2022;399:719–728;

HoFH vs HeFH
HoFH differs from HeFH1-3
Homozygous FH (HoFH) Heterozygous FH (HeFH)
Mutated gene inherited from both parents Mutated gene inherited from one parent
Occurs in 1 in 300,000 persons Occurs in 1 in 250 persons
LDL-C >10 mmol/L (untreated) LDL-C cholesterol ≥4.1 mmol/L in children
LDL-C cholesterol ≥4.9 mmol/L in adults
Likely physical symptoms, such as cholesterol deposits in the eye, tendons, knees, elbows, and/or between fingers and toes; these deposits are not always present May have physical symptoms, such as cholesterol deposits in the eye, tendons, knees, elbows and/or between fingers and toes
Treatment at time of diagnosis, no matter the age, with a specialist Treatment as early as age 8

1. Cuchel M et al. Eur Heart J. 2023;00:1–15; 2. McGowan MP et al. J Am Heart Assoc. 2019;8:e013225; 3. Joshua K. et al. JAAD Reviews, 2025, Volume 4, 149–155

MOD video
Watch the mechanism of disease video
HoFH variants

85-90% of HoFH patients have pathogenic variants in the LDLR gene1,2

HoFH is associated with pathogenic variants of several genes affecting LDL receptor (LDLR) activity2,3

The majority of LDL-C is cleared from the plasma by LDLRs located on the cellular membranes of the liver cells3

hofh-variant

Pathogenic variants in genes impairing LDLR function have also been identified in patients with HoFH:3,4

  • APOB: Gene encoding apolipoprotein B
  • LDLR: Gene encoding the low-density lipoprotein receptor
  • LDLRAP1: Gene encoding low-density lipoprotein receptor adaptor protein 1
  • PCSK9: Gene encoding proprotein convertase subtilisin/kexin type 9 protein (PCSK9)

<10% of LDLR variants have been directly studied functionally4

These pathogenic variants affect different aspects of LDLR function and can be broadly categorised into six classes:3

  • Absent synthesis of LDLR or precursor protein
  • Defective LDLR transport from the endoplasmic reticulum
  • Impaired binding to LDL
  • No LDLR/LDL internalisation because of defective clustering in clathrin-coated pits
  • No LDLR recycling
  • Failed LDLR transport to the surface of the cell membrane
LDLR-variants

Pathogenic variants cause LDLR dysfunction and reduce removal of LDL-C from the blood, leading to premature atherosclerosis and cardiovascular complications1,3-5

genetics-and-pathogenesis

LDLR-deficient pathogenic variants are associated with little or no LDL-C binding and uptake3

Flash-Image

Compared with patients who are double LDLR-defective and LDLR-defective + LDLR-deficient, patients who are double LDLR-deficient (null–null) present with:3,9-11

  • Higher LDL-C
  • Higher incidence of CVD
  • Worse prognosis
  • Reduced response to drug therapy

The majority of LDL-C is cleared from the plasma by LDLR located on the cellular membranes of the liver2

genetics and pathogenesis three

CVD-free survival in HoFH patients in the SAFEHEART registry8*

*The SAFEHEART registry is a nationwide registry that includes FH patients living in Spain. Patients are enrolled and followed up every year to record relevant changes in lipid-lowering treatment and development of cardiovascular events. The graph shows survival data from 34 HoFH patients enrolled from 2004 to 2015.

1. France M et al. Atherosclerosis. 2016;255:128–139; 2. Cuchel M et al. Eur Heart J. 2014;35:2146–2157; 3. Gidding SS et al. Circulation. 2015;132:2167–2192; 4. Cuchel M et al. Eur Heart J. 2023;00:1–15; 5. Nordestgaard BG et al. Eur Heart J. 2013;34:3478–3490; 6. Reijman MD et al. Curr Opin Lipidol. 2023 Dec 1;34(6):287-295; 7. Bertolini S et al. Atherosclerosis. 2020;312:72–78; 8. Raal FJ et al. T. JACC Adv. 2023;2(9):100648; 9. Bruckert E. Atheroscler Suppl. 2014;15:26–32; 10. Alonso R et al. J Clin Lipidol. 2016;10:953–961; 11. Sjouke B et al. Eur Heart J. 2015;36:560–565.

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