A 2-year-old boy of Ashkenazi Jewish descent presents with failure to thrive, massive hepatosplenomegaly, and developmental regression. Bone marrow aspirate shows large foamy histiocytes. The pathologic process marked **D** in the diagram—sphingomyelinase deficiency—is responsible for the accumulation of substrate material in these cells. Which of the following best describes the biochemical consequence and the primary clinical phenotype associated with this enzymatic defect in Niemann-Pick disease type A?

Explanation

## Why option 1 is correct Niemann-Pick disease type A (NPA) is caused by mutations in the SMPD1 gene leading to acid sphingomyelinase deficiency. This enzyme normally degrades sphingomyelin in lysosomes. When deficient, sphingomyelin accumulates in lysosomes, particularly in macrophages (forming foam cells), causing the characteristic pathology. Type A is the severe infantile neuronopathic form with onset in infancy, presenting with hepatosplenomegaly, failure to thrive, developmental regression, and progressive neurodegeneration leading to death by 3–5 years. This is the classic presentation in Ashkenazi Jewish populations, where carrier screening is routinely offered. The clinical anchor directly states this phenotype and the biochemical mechanism (Harrison 21e Ch 412). ## Why each distractor is wrong - **Option 2**: Describes Gaucher disease (glucocerebroside accumulation due to glucocerebrosidase deficiency), not Niemann-Pick disease. While both are lysosomal storage disorders with hepatosplenomegaly and foam cells, Gaucher disease has a different enzyme defect, different cell morphology ("crumpled tissue paper"), and different clinical course. Gaucher type I is non-neuronopathic and responds well to enzyme replacement therapy—not the case in NPA. - **Option 3**: Describes Niemann-Pick disease type C (NPC1/NPC2 mutations), which has a fundamentally different mechanism—a cholesterol transport defect, not sphingomyelinase deficiency. NPC presents with progressive neurodegeneration, vertical supranuclear gaze palsy (downward gaze restriction), ataxia, and dystonia, but NOT the severe infantile hepatosplenomegaly and death by 3–5 years seen in type A. This is a critical distinction tested in NEET PG. - **Option 4**: Describes Krabbe disease (galactocerebroside accumulation due to galactocerebrosidase deficiency), a different lysosomal storage disorder with infantile leukodystrophy and demyelination. Not related to sphingomyelinase deficiency. **High-Yield:** Niemann-Pick type A = sphingomyelinase deficiency + infantile neuronopathic + Ashkenazi Jewish + death by 3–5 years; type B = same enzyme defect but residual activity + visceral only + chronic; type C = DIFFERENT mechanism (cholesterol transport) + vertical supranuclear gaze palsy (key eye finding). [cite: Harrison 21e Ch 412]