A 52-year-old man with a family history of premature coronary artery disease presents with xanthomas on his Achilles tendons and eyelids. Lipid profile shows total cholesterol 480 mg/dL, LDL 420 mg/dL, HDL 35 mg/dL, and triglycerides 150 mg/dL. What is the most common genetic defect responsible for this presentation?

## Familial Hypercholesterolaemia (FH) — Most Common Monogenic Dyslipidaemia ### Clinical Presentation The patient exhibits classic features of **heterozygous familial hypercholesterolaemia (FH)**: - Tendon xanthomas (Achilles, extensor tendons) - Corneal arcus / eyelid xanthomas - Severely elevated LDL cholesterol (>300 mg/dL) - Premature coronary artery disease in family - Normal or near-normal triglycerides ### Genetic Basis of FH | Feature | Heterozygous FH | Homozygous FH | |---------|-----------------|---------------| | **Prevalence** | 1 in 300–500 | 1 in 160,000–1,000,000 | | **LDL-C level** | 300–600 mg/dL | >600 mg/dL | | **Xanthomas** | Present (adult) | Present (childhood) | | **CAD onset** | 30s–50s | <20 years | | **Genetic defect** | **LDL receptor mutation** (most common, ~90%) | Homozygous LDL-R or apoB-100 | **Key Point:** Mutations in the **LDL receptor gene** account for ~90% of familial hypercholesterolaemia cases. The LDL receptor is responsible for clearance of LDL particles from the circulation via receptor-mediated endocytosis in hepatocytes. Loss of function → impaired LDL clearance → severe hypercholesterolaemia. ### Pathophysiology ```mermaid flowchart TD A[LDL Receptor Gene Mutation]:::outcome --> B[Reduced LDL Receptor Expression]:::outcome B --> C[Impaired LDL Particle Uptake by Liver]:::outcome C --> D[Accumulation of LDL in Circulation]:::outcome D --> E[Elevated Plasma LDL-C]:::outcome E --> F[Deposition in Tendons & Arteries]:::outcome F --> G[Xanthomas & Premature CAD]:::urgent ``` ### Why LDL Receptor Mutation is Most Common **High-Yield:** The LDL receptor is the primary mechanism for hepatic clearance of LDL particles. Mutations cause a gene dosage effect: - **Heterozygotes:** 50% reduction in LDL-R → 2–3× elevation in LDL-C - **Homozygotes:** Near-total absence of LDL-R → 6–10× elevation in LDL-C Other genetic causes (ApoB-100, PCSK9 gain-of-function) are much rarer (<10% of FH cases). ### Clinical Pearl Tendon xanthomas are **pathognomonic** for FH and distinguish it from secondary hypercholesterolaemia. They reflect chronic LDL deposition in connective tissue and are virtually absent in other dyslipidemias. [cite:Harrison 21e Ch 397]