Question

A patient with multiple tendon xanthomas is found to have a serum cholesterol level of 398 mg/dL and an LDL level of 220 mg/dL. What is the most likely defect?

• A. Lipoprotein lipase deficiency
• B. LDL receptor defect
• C. Defective Apo B-100
• D. PCSK9 gain-of-function mutation

Hint:

In cases of familial hypercholesterolemia, look for tendon xanthomas and significantly elevated LDL levels. The defect usually lies in the LDL receptor.

Answer 1

The Correct Option is B

Step 1: Read the lipid signature first.
The patient shows isolated, very high cholesterol ($398$ mg/dL) driven by a high LDL ($220$ mg/dL), with no mention of raised triglycerides. So this is a pure hypercholesterolaemia, not a mixed or triglyceride-predominant picture. This single fact lets us discard any cause that works through triglyceride-rich particles.

Step 2: Anchor on the physical clue.
Multiple tendon xanthomas (lipid deposits in tendons, classically the Achilles and finger extensors) are the hallmark of Familial Hypercholesterolaemia (FH). Tendon xanthomas + sky-high LDL = FH until proven otherwise, so the question is really asking which molecular defect causes classic FH.

Step 3: Recall the LDL clearance pathway.
Circulating LDL is normally removed when hepatic LDL receptors bind Apo B-100 on the LDL particle and internalise it. Anything that lowers receptor number or function leaves LDL stranded in plasma, raising its level and seeding xanthomas.

Step 4: Match the defect to classic, severe FH.
The commonest and most severe cause of FH is a defect in the hepatic LDL receptor itself - fewer or non-functional receptors mean LDL cannot be cleared, so it accumulates dramatically. This fits both the lipid numbers and the tendon xanthomas.

Step 5: Rule out the partial mimics.
• Lipoprotein lipase deficiency blocks breakdown of chylomicrons/VLDL, producing hypertriglyceridaemia - the wrong lipid pattern here.
• Defective Apo B-100 (familial defective Apo B) does raise LDL because the ligand can't dock, but it is generally milder and far less common than receptor disease.
• PCSK9 gain-of-function speeds receptor degradation and raises LDL, but it too is rare and not the textbook answer for tendon-xanthoma FH.

Final answer: The most likely defect is Option 2 - an LDL receptor defect.