A 35-year-old man presents to the cardiology clinic with a history of myocardial infarction at age 32. On examination, he has prominent xanthomas on his Achilles tendons and extensor tendons of the hands, and corneal arcus. His fasting lipid profile shows total cholesterol 520 mg/dL, LDL-C 420 mg/dL, and triglycerides 140 mg/dL. His father had an MI at age 48, and his 8-year-old son has been found to have elevated LDL-C on screening. The condition marked **B** in the diagram is suspected. Which of the following best describes the primary molecular defect in this patient's condition?
A. Defective apolipoprotein B-100 structure impairing ligand binding to the LDL receptor
B. Defective synthesis or function of the LDL receptor on hepatocytes, preventing normal clearance of LDL particles from circulation
C. Loss-of-function mutation in LDLRAP1 preventing adaptor-mediated endocytosis of LDL receptor complexes
D. Gain-of-function mutation in PCSK9 leading to accelerated degradation of LDL receptors in the endosome
Explanation
Why Option 1 is correct
The condition marked B (Heterozygous Familial Hypercholesterolemia) is caused primarily by mutations in the LDLR gene on chromosome 19p13, accounting for 85–90% of all FH cases. These mutations result in defective synthesis, trafficking, or function of the LDL receptor, impairing hepatic clearance of LDL particles and causing severely elevated LDL-C (typically 190–450 mg/dL in heterozygotes). The clinical presentation—premature CAD (MI at age 32), tendon xanthomas, corneal arcus, and vertical transmission (father affected, son screening-positive)—is pathognomonic for heterozygous FH due to LDLR dysfunction. This is the most common monogenic form (1 in 220–250 prevalence) and the anchor of the diagnosis in this case.
Why each distractor is wrong
Option 2 (PCSK9 gain-of-function): While gain-of-function PCSK9 mutations do cause FH by accelerating LDLR degradation, they account for only ~1–3% of FH cases and are much less common than LDLR mutations. The question stem explicitly anchors on B (Heterozygous FH), which is predominantly LDLR-driven.
Option 3 (APOB mutations): Defective apolipoprotein B-100 (familial defective apoB) causes FH in only ~5% of cases and is the second most common form. It does not explain the full clinical picture as well as LDLR deficiency and is not the primary mechanism in heterozygous FH.
Option 4 (LDLRAP1 loss-of-function): LDLRAP1 mutations cause a rare autosomal recessive form of FH (ARH syndrome), not the autosomal dominant heterozygous FH depicted in B. This is an incorrect inheritance pattern for the condition presented.
