A 52-year-old man with familial hypercholesterolaemia is found to have severely elevated LDL cholesterol despite dietary modification. Which is the most common genetic defect responsible for familial hypercholesterolaemia type IIa?

Explanation

## Familial Hypercholesterolaemia: Genetic Basis and Classification **Key Point:** Familial hypercholesterolaemia type IIa (FH IIa) is caused by loss-of-function mutations in the LDL receptor gene in ~85% of cases, making it the most common genetic defect. ### Genetic Defects in Familial Hypercholesterolaemia | Type | Genetic Defect | Frequency | Mechanism | LDL Level | |------|----------------|-----------|-----------|----------| | **FH IIa (Most common)** | LDL receptor gene mutation (loss-of-function) | ~85% | Reduced LDL-R expression; impaired LDL clearance | 350–500 mg/dL | | FH IIb | APOB gene mutation (gain-of-function) | ~10% | Defective apoB-100; poor LDL-R binding | 250–400 mg/dL | | FH III (Rare) | PCSK9 gene mutation (gain-of-function) | ~3–5% | Increased LDLR degradation | 200–350 mg/dL | | Homozygous FH | Homozygous LDL-R mutations | <1% | Severe LDL-R deficiency | >600 mg/dL | **High-Yield:** The LDL receptor is the primary mechanism for clearing LDL from circulation. Loss-of-function mutations reduce LDL-R number or function, leading to: 1. Impaired hepatic LDL uptake 2. Accumulation of LDL in plasma 3. Increased risk of premature atherosclerosis and MI **Clinical Pearl:** Heterozygous FH (1 in 500 people) presents with total cholesterol >350 mg/dL and premature coronary artery disease (men <55 years, women <65 years). Homozygous FH (1 in 1 million) presents with MI in childhood. ### Pathophysiology of LDL-R Mutations ```mermaid flowchart TD A[LDL-R Gene Mutation<br/>Loss-of-function]:::outcome --> B[Reduced LDL-R<br/>expression on hepatocytes]:::outcome B --> C[Impaired LDL<br/>endocytosis]:::outcome C --> D[Increased plasma<br/>LDL cholesterol]:::outcome D --> E[Increased LDL<br/>oxidation & foam cell<br/>formation]:::outcome E --> F[Premature<br/>atherosclerosis]:::urgent ``` **Mnemonic:** **"LDL-R LOSS = LIPID LOSS (from circulation fails)"** — Loss-of-function mutations in LDL Receptor cause Loss of cholesterol clearance, leading to Lipid accumulation.