A 3-year-old boy presents with hepatosplenomegaly, developmental delay, and cherry-red spot on the macula. Enzyme assay shows deficiency of hexosaminidase A. All of the following statements regarding lysosomal storage disorders are true EXCEPT:

Explanation

## Analysis of Lysosomal Storage Disorders ### Key Pathophysiology **Key Point:** Lysosomal storage disorders result from deficiency of specific hydrolytic enzymes, leading to accumulation of substrate within lysosomes across multiple organ systems. ### Evaluation of Each Statement | Statement | Accuracy | Explanation | |-----------|----------|-------------| | Gaucher disease most common | ✓ TRUE | Glucocerebroside accumulation; ~1:40,000–1:60,000 births; prevalent in Ashkenazi Jews | | Niemann-Pick type C | ✗ **FALSE** | Niemann-Pick type C involves defective **cholesterol transport** (NPC1/NPC2 genes), NOT esterification. The block is in intracellular cholesterol trafficking, not synthesis or esterification. | | Tay-Sachs GM2 accumulation | ✓ TRUE | Hexosaminidase A deficiency → GM2 ganglioside accumulation in neurons; cherry-red spot pathognomonic | | Krabbe demyelination | ✓ TRUE | Galactocerebrosidase deficiency → galactocerebroside accumulation in oligodendrocytes → CNS/PNS demyelination | ### Why Niemann-Pick Type C Is the Answer **High-Yield:** Niemann-Pick type C is fundamentally a **lysosomal cholesterol transport disorder**, not an esterification defect. The NPC1 and NPC2 proteins mediate egress of cholesterol from lysosomes to other compartments. When defective, cholesterol becomes sequestered in lysosomes and other organelles, causing secondary accumulation of sphingolipids (not primary deficiency of sphingolipid hydrolysis). **Clinical Pearl:** Niemann-Pick type C presents with vertical supranuclear gaze palsy (VSGP), ataxia, hepatosplenomegaly, and progressive neurodegeneration — a distinct phenotype from types A and B (which are sphingomyelinase deficiencies). **Mnemonic:** **NPC = Not Primary Ceramidase** — it's a trafficking disorder, not an enzyme deficiency in the classical sense. ### Correct Statements Confirmed - **Gaucher:** β-glucosidase ↓ → glucocerebroside ↑ (most common LSO) - **Tay-Sachs:** Hex-A ↓ → GM2 ganglioside ↑ (cherry-red spot, infantile neuronopathic) - **Krabbe:** Galactocerebrosidase ↓ → galactocerebroside ↑ (globoid cell leukodystrophy) [cite:Robbins 10e Ch 5]