Homozygous vs. Heterozygous Familial

Introduction

Familial Hypercholesterolemia (FH) is one of the most common inherited metabolic disorders, characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and dramatically increased cardiovascular risk. The disease is caused by genetic mutations that impair the clearance of LDL-C from plasma, most often involving the LDL receptor pathway.

FH occurs in two major forms:

1. Heterozygous FH (HeFH) – a milder but still serious form, resulting from inheriting one defective allele.
2. Homozygous FH (HoFH) – the rare and severe form, resulting from inheriting two defective alleles.

The clinical course, biochemical features, and treatment response differ significantly between these two forms. While heterozygous FH is relatively common and often presents in adulthood with premature cardiovascular disease, homozygous FH manifests in childhood and, if untreated, can lead to death before the age of 30.

This article provides a comprehensive comparison of clinical, genetic, and therapeutic differences between HeFH and HoFH, highlighting their pathophysiology, diagnosis, and future management strategies.

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Epidemiology

Heterozygous FH (HeFH)

• Prevalence: 1 in 200–300 individuals worldwide.
• One of the most common monogenic disorders.
• Despite its high frequency, over 90% of cases remain undiagnosed.

Homozygous FH (HoFH)

• Prevalence: 1 in 160,000–300,000 individuals.
• Much rarer but associated with extreme cardiovascular morbidity.
• Incidence is higher in regions with high consanguinity (e.g., Lebanon, South Africa, and certain communities in India).

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Genetic Basis

FH is primarily caused by mutations in genes regulating LDL metabolism. The genetic context determines whether an individual develops heterozygous or homozygous FH.

1. Heterozygous FH (HeFH)

• Caused by inheritance of one defective allele from one parent.
• The other allele is functional, allowing some residual LDL receptor activity.
• Mutations commonly involve:
  • LDLR (Low-Density Lipoprotein Receptor) – most frequent cause (~85–90% of cases).
  • APOB (Apolipoprotein B-100) – impairs LDL particle binding.
  • PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) – gain-of-function mutations increase LDLR degradation.

2. Homozygous FH (HoFH)

• Caused by inheritance of two defective alleles, one from each parent.
• Genetic possibilities:
  • True Homozygous: identical mutation inherited from both parents.
  • Compound Heterozygous: two different pathogenic mutations affecting both alleles.
  • Double Heterozygous: mutations in different FH-related genes (e.g., one LDLR, one APOB).
• Results in minimal or absent LDL receptor activity, severely impairing LDL clearance.

Genetic Consequences

• HeFH: ~50% normal LDL receptor function.
• HoFH: <5–10% LDL receptor activity, sometimes complete absence.

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Biochemical and Pathophysiological Differences

Feature	Heterozygous FH	Homozygous FH
LDL-C levels	190–400 mg/dL	>500 mg/dL (often 600–1000 mg/dL)
Receptor activity	~50% normal	<5–10% normal
Onset of atherosclerosis	Early adulthood (20s–40s)	Childhood or adolescence
Cardiovascular risk	High	Extreme, with early CAD

The difference in receptor function explains why homozygous FH patients accumulate cholesterol at a much faster rate, leading to accelerated vascular damage.

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Clinical Features

1. Heterozygous FH (HeFH)

• Typically asymptomatic during childhood.
• Clinical manifestations appear in adolescence or adulthood.
• Features include:
  • Xanthomas: tendon deposits (Achilles, extensor tendons).
  • Xanthelasmas: cholesterol-rich eyelid plaques.
  • Corneal arcus: premature corneal cholesterol deposition.
• Cardiovascular events:
  • Premature coronary artery disease (CAD).
  • Increased risk of myocardial infarction in men <55 and women <65.

2. Homozygous FH (HoFH)

• Presents in childhood with striking clinical features.
• Features include:
  • Cutaneous xanthomas by age 5–10.
  • Thickened Achilles tendons.
  • Corneal arcus in childhood.
• Cardiovascular events:
  • Severe atherosclerosis before age 20.
  • Angina or myocardial infarction during adolescence.
  • Untreated HoFH often fatal before age 30.

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Diagnosis

Clinical Criteria

HeFH

• Dutch Lipid Clinic Network (DLCN) and Simon Broome criteria are commonly used.
• LDL-C >190 mg/dL plus family history of premature CAD strongly suggests FH.

HoFH

• LDL-C levels often >500 mg/dL, sometimes exceeding 1000 mg/dL.
• Early physical signs (childhood xanthomas).
• Family history often includes both parents with hypercholesterolemia.

Genetic Testing

• Confirms diagnosis and distinguishes HeFH from HoFH.
• Essential for cascade screening in families.

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Cardiovascular Risk and Outcomes

Heterozygous FH

• Lifetime risk of CAD is 10–20 times higher than in the general population.
• Men often present with myocardial infarction in their 40s; women in their 50s.
• Without treatment, half of men develop CAD by age 50.

Homozygous FH

• Risk of CAD is extreme.
• Aortic valve stenosis and supravalvular aortic stenosis are common due to lipid deposition.
• Untreated patients often die of myocardial infarction before age 30.

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Management

1. Lifestyle Modifications

• Recommended for both HeFH and HoFH.
• Includes diet low in saturated fats and cholesterol, exercise, and avoidance of smoking.
• Alone, however, lifestyle changes are insufficient.

2. Pharmacological Therapy

HeFH

• Statins are first-line; reduce LDL-C by 30–50%.
• Ezetimibe as add-on therapy.
• PCSK9 inhibitors (evolocumab, alirocumab): highly effective in reducing LDL-C by an additional 50–60%.
• Most patients achieve target LDL-C levels with combination therapy.

HoFH

• Statins have limited effect due to absent LDL receptor activity.
• Ezetimibe provides modest benefit.
• PCSK9 inhibitors are often ineffective in patients with complete receptor deficiency.
• Additional therapies include:
  • Lomitapide: inhibits ApoB synthesis, reducing LDL production.
  • Mipomersen: antisense oligonucleotide targeting ApoB mRNA.
  • Evinacumab: monoclonal antibody targeting ANGPTL3, independent of LDLR function.

3. LDL Apheresis

• Used in severe HeFH and essential in HoFH.
• Removes LDL particles directly from blood.
• Requires weekly or biweekly sessions.

4. Gene Therapy and Future Options

• Gene editing (CRISPR-Cas9) and viral vector–mediated correction are in development.
• Mitochondrial transplantation and siRNA-based therapies (inclisiran) are being explored.

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Case Studies

Case 1: Heterozygous FH

• 35-year-old male, LDL-C 270 mg/dL, Achilles xanthomas.
• Family history: father died of myocardial infarction at 50.
• Started on high-dose statin + ezetimibe + PCSK9 inhibitor.
• LDL-C reduced to 90 mg/dL, cardiovascular risk controlled.

Case 2: Homozygous FH

• 12-year-old girl, LDL-C 680 mg/dL, cutaneous xanthomas since age 6.
• Already developed supravalvular aortic stenosis.
• On lomitapide therapy plus biweekly LDL apheresis.
• Life expectancy improved, though risk of early CAD remains high.

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Psychosocial and Public Health Perspectives

• Underdiagnosis is the greatest challenge. Many families are unaware of their FH status until a catastrophic cardiac event occurs.
• Cascade screening is vital to detect FH in relatives early.
• Psychological burden: children diagnosed with HoFH often face lifestyle restrictions and frequent hospital visits.
• Public health interventions:
  • Nationwide cholesterol screening programs.
  • Education campaigns about genetic cardiovascular diseases.
  • Genetic counseling for affected families.

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Research and Future Directions

1. Gene Editing
   • CRISPR-Cas9 approaches may one day provide a permanent cure by correcting LDLR mutations.
2. RNA-Based Therapies
   • Inclisiran (siRNA therapy) silences PCSK9 production with twice-yearly dosing.
3. Novel Biologics
   • Monoclonal antibodies against ANGPTL3 (e.g., evinacumab) offer LDLR-independent cholesterol reduction.
4. Precision Medicine
   • Tailoring treatment based on genotype, LDLR activity, and phenotype.