A 7-year-old girl has hepatosplenomegaly noticed in infancy, progressive cognitive decline, dystonia, and a striking inability to make voluntary vertical saccades while oculocephalic reflexes remain intact. Bone marrow shows foamy cells. Biochemical testing shows normal acid sphingomyelinase activity. What is the underlying defect?
- A Deficiency of acid sphingomyelinase
- B Defective intracellular cholesterol trafficking due to NPC1 mutation ✓
- C Deficiency of beta-glucocerebrosidase
- D Deficiency of hexosaminidase A
Correct answer: B. Defective intracellular cholesterol trafficking due to NPC1 mutation
Explanation
Niemann-Pick disease type C is caused by mutations in NPC1 (or rarely NPC2) impairing unesterified cholesterol transport out of late endosomes and lysosomes. Its hallmark is vertical supranuclear gaze palsy with visceral storage and progressive neurodegeneration, and sphingomyelinase activity is normal, distinguishing it from types A and B. Beta-glucocerebrosidase deficiency causes Gaucher disease, which lacks gaze palsy, and hexosaminidase A deficiency causes Tay-Sachs disease with a cherry-red spot and no hepatosplenomegaly.
Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.