You just finished a lysosomal storage disease question, you picked “Krabbe,” and you moved on—only to realize the distractors were also plausible. That’s exactly why these questions are so high-yield: Step writers aren’t testing if you’ve memorized one disease; they’re testing whether you can map a clinical picture to an enzyme, substrate, cells involved, and imaging/pathology clues under time pressure.
Tag: Biochemistry > Lysosomal & Glycogen Storage Diseases
The Vignette (Classic Q-Bank Style)
A 4-month-old infant is brought in for irritability and progressive developmental regression. Parents report stiffness, poor feeding, and episodes of inconsolable crying. On exam, the child has hypertonia and peripheral neuropathy. MRI shows demyelination. Labs are notable for elevated CSF protein. A peripheral nerve biopsy demonstrates globoid cells.
What is the most likely enzyme deficiency?
How to Recognize Krabbe Disease in One Pass
Krabbe is a leukodystrophy (white matter disease) due to failure of myelin maintenance.
Key clinical hits
- Infantile onset (often 3–6 months)
- Irritability, developmental regression
- Hypertonia/spasticity
- Peripheral neuropathy
- Demyelination on imaging
Key pathology buzzword
- Globoid cells = multinucleated macrophages packed with unmetabolized lipids
The toxic molecule
- Psychosine (galactosylsphingosine) accumulates and is directly toxic to oligodendrocytes, driving demyelination.
Correct Answer: Krabbe Disease
Enzyme deficiency
Galactocerebrosidase (also called galactosylceramidase, GALC)
What builds up?
- Galactocerebroside
- Psychosine (most testable due to toxicity)
High-yield associations (Step-friendly)
- Autosomal recessive
- Peripheral neuropathy + central demyelination
- Globoid cells
- Presents in infancy with severe neurodegeneration
Why Every Answer Choice Matters: Systematic Distractor Breakdown
Here’s how Step likes to trap you: by offering other neurodegenerative or “storage disease” choices that share one feature (hepatosplenomegaly, neuropathy, cherry-red spot, hypotonia, etc.) but miss the pattern.
Quick comparison table (memorize the “anchors”)
| Disease | Enzyme Defect | Accumulation | Hallmark Clues |
|---|---|---|---|
| Krabbe | Galactocerebrosidase (GALC) | Psychosine, galactocerebroside | Demyelination, globoid cells, irritability, hypertonia, peripheral neuropathy |
| Metachromatic leukodystrophy | Arylsulfatase A | Cerebroside sulfate | Demyelination + peripheral neuropathy, metachromatic granules, often later onset |
| Tay-Sachs | Hexosaminidase A | GM2 ganglioside | Neurodegeneration, cherry-red spot, no hepatosplenomegaly |
| Niemann-Pick | Sphingomyelinase | Sphingomyelin | Hepatosplenomegaly, neurodegeneration, foam cells, cherry-red spot |
| Gaucher | Glucocerebrosidase | Glucocerebroside | HSM, bone crises, crumpled tissue paper macrophages |
| Pompe (GSD II) | Acid α-glucosidase | Glycogen in lysosomes | Cardiomegaly, hypertrophic cardiomyopathy, hypotonia (“floppy baby”) |
Distractor 1: Metachromatic Leukodystrophy (MLD)
Why it tempts you: It’s also a leukodystrophy with demyelination and peripheral neuropathy.
- Enzyme: Arylsulfatase A
- Accumulation: Cerebroside sulfate
- Clue: “Metachromatic granules” (sulfatide accumulation stains abnormally)
How to separate from Krabbe quickly
- Krabbe classically features globoid cells and psychosine toxicity.
- MLD is often described with ataxia/dementia and characteristic metachromatic storage material.
- Both can cause demyelination, so you need the named pathology clue.
Distractor 2: Tay-Sachs Disease
Why it tempts you: Infantile neurodegeneration is the headline.
- Enzyme: Hexosaminidase A
- Accumulation: GM2 ganglioside
- Clues:
- Cherry-red spot on macula
- No hepatosplenomegaly (classic distinction)
- Exaggerated startle response is commonly tested
Why it’s wrong for this vignette
Krabbe is about demyelination + peripheral neuropathy + globoid cells. Tay-Sachs is about neuronal GM2 accumulation, not a primary demyelinating leukodystrophy pattern.
Distractor 3: Niemann-Pick Disease (Types A/B)
Why it tempts you: It can cause neurodegeneration and a cherry-red spot.
- Enzyme: Sphingomyelinase
- Accumulation: Sphingomyelin
- Clues:
- Hepatosplenomegaly
- Foam cells
- Cherry-red spot (especially Type A)
Why it’s wrong here
The vignette emphasizes demyelination and peripheral neuropathy with globoid cells, not foam cells + prominent organomegaly.
Distractor 4: Gaucher Disease
Why it tempts you: It’s the most common lysosomal storage disease and shows up constantly.
- Enzyme: Glucocerebrosidase
- Accumulation: Glucocerebroside
- Clues:
- Hepatosplenomegaly
- Bone pain/crises, osteonecrosis
- Crumpled tissue paper macrophages
Why it’s wrong here
Gaucher’s core is reticuloendothelial system involvement (liver/spleen/bone marrow). It does not classically present as an early infantile demyelinating leukodystrophy with globoid cells.
Distractor 5: Pompe Disease (GSD II)
Why it tempts you: “Infant + regression” can point people toward a glycogen storage disease.
- Enzyme: Acid α-glucosidase (acid maltase)
- Accumulation: Glycogen in lysosomes
- Clues:
- Cardiomegaly
- Hypertrophic cardiomyopathy
- Hypotonia (“floppy baby”)
- Macroglossia can appear
Why it’s wrong here
Pompe is primarily cardiac + muscle (hypotonia), not demyelination + neuropathy (hypertonia/spasticity).
High-Yield Krabbe Facts You’ll Actually Use on Test Day
Must-know triad
- AR inheritance
- Galactocerebrosidase deficiency
- Psychosine accumulation → oligodendrocyte toxicity → demyelination
Classic presentation
- Infant with irritability, stiffness/hypertonia, regression
- Peripheral neuropathy + central demyelination
Pathology
- Globoid cells (multinucleated macrophages)
“Two leukodystrophies” mental hook
- Krabbe: GALC, globoid cells, psychosine toxicity
- MLD: Arylsulfatase A, metachromatic granules, sulfatide buildup
Your Q-Bank Takeaway Pattern
When the stem screams demyelination, don’t just think “lysosomal storage disease.” Ask:
- Is this primarily white matter (leukodystrophy) or gray matter neuronal storage?
- Is there peripheral neuropathy?
- Are there named pathology cells (globoid vs foam vs crumpled tissue paper)?
- Is there hepatosplenomegaly? (often pushes away from Tay-Sachs and toward Niemann-Pick/Gaucher)
If you do that, you won’t just get Krabbe right—you’ll delete the distractors confidently.