Bit · Biochem
Lysosomal Storage Diseases (Tay-Sachs, Gaucher, Niemann-Pick, Fabry, Hurler, Hunter, Krabbe)
Seven inherited diseases of lysosomal enzyme deficiency. Each lets a specific substrate pile up in a specific cell type. The pivot is the substrate that accumulates.
Mechanism
Lysosomes degrade cellular waste. Each disease is a missing enzyme → a specific substrate accumulates → organ damage in tissues that handle that substrate:
- Sphingolipidoses (membrane lipids) — Tay-Sachs, Niemann-Pick, Gaucher, Krabbe, Fabry, Metachromatic leukodystrophy.
- Mucopolysaccharidoses (proteoglycans) — Hurler, Hunter.
Most are autosomal recessive. Two exceptions are X-linked: Fabry and Hunter.
Differentiator Table
| Disease | Enzyme | Accumulates | Clinical hallmark | Inheritance |
|---|---|---|---|---|
| Tay-Sachs | Hexosaminidase A | GM₂ ganglioside | Cherry-red macula, neurodegeneration, NO hepatosplenomegaly, Ashkenazi Jewish | AR |
| Niemann-Pick | Sphingomyelinase | Sphingomyelin | Cherry-red macula + hepatosplenomegaly + neurodegeneration; foam cells | AR |
| Gaucher (most common) | β-glucocerebrosidase | Glucocerebroside | Hepatosplenomegaly, bone crises (Erlenmeyer flask femur), pancytopenia; Gaucher cells ('crinkled paper') | AR |
| Krabbe | Galactocerebrosidase | Galactocerebroside, psychosine | Globoid cells; peripheral neuropathy, dev delay, optic atrophy | AR |
| Fabry | α-galactosidase A | Ceramide trihexoside | Peripheral neuropathy + angiokeratomas + renal failure + LVH | X-LINKED RECESSIVE |
| Metachromatic leukodystrophy | Arylsulfatase A | Sulfatides | Central + peripheral demyelination, dev regression | AR |
| Hurler (MPS I) | α-L-iduronidase | Heparan / dermatan sulfate | Coarse facies, corneal clouding, dev delay, gargoylism | AR |
| Hunter (MPS II) | Iduronate sulfatase | Heparan / dermatan sulfate | Like Hurler but milder + NO corneal clouding + aggressive behavior | X-LINKED RECESSIVE |
The Pivot
Three high-yield splits:
- Cherry-red macula? → Tay-Sachs (no HSM) vs Niemann-Pick (HSM present).
- Hepatosplenomegaly + bone crises + ↓ counts? → Gaucher (most common LSD).
- X-linked male with neuropathy + angiokeratomas + renal failure? → Fabry.
- Hurler vs Hunter: corneal clouding = Hurler; X-linked + aggressive = Hunter.
NBME-Style Stem
A 6-month-old Ashkenazi Jewish infant presents with developmental regression and exaggerated startle response. Fundoscopy shows a cherry-red spot at the macula. There is no hepatosplenomegaly. Hexosaminidase A activity is undetectable. Which of the following is the most likely diagnosis?
Concept Anchor
Each lysosomal storage disease is one broken enzyme upstream of one accumulating substrate — and the organ that handles that substrate is the organ that fails.