STEPTRACKERBIOCHEMISTRY + GENETICS + PEDIATRICS | LIPID METABOLISM | HIGH-YIELD REVIEW

Lysosomal Storage Diseases

A missing lysosomal enzyme lets one substrate pile up — sort them into sphingolipidoses and mucopolysaccharidoses, then by eye, liver and bone clues.

FOCUS ON
All AR except Fabry and Hunter (XR). Cherry-red spot: Tay-Sachs (no hepatosplenomegaly), Niemann-Pick (with HSM). Gaucher (most common): glucocerebrosidase → bone crises, HSM, pancytopenia, "crumpled tissue paper" cells. Krabbe: globoid cells, optic atrophy, neuropathy. Metachromatic leukodystrophy: arylsulfatase A → demyelination. Hurler vs Hunter: corneal clouding only in Hurler.
DISEASE
ENZYME · BUILDUP
FEATURES
CLUE
Tay-Sachs
AR · Ashkenazi
Hexosaminidase A · GM2 ganglioside
Progressive neurodegeneration from ~6 months, exaggerated startle, cherry-red spot, no hepatosplenomegaly
Onion-skin lysosomes
Niemann-Pick type A/B
AR · Ashkenazi
Sphingomyelinase · sphingomyelin
Neurodegeneration, hepatosplenomegaly, cherry-red spot, foam cells
Foamy lipid-laden macrophages
Gaucher
most common · AR
Glucocerebrosidase · glucocerebroside
Hepatosplenomegaly, pancytopenia, bone crises, avascular necrosis of femur, osteoporosis, Erlenmeyer flask femur; ↑ Parkinson risk
Gaucher cells: "crumpled tissue paper" macrophages · enzyme replacement (imiglucerase)
Fabry
XR
α-Galactosidase A · ceramide trihexoside (Gb3)
Episodic burning pain in hands/feet, angiokeratomas, hypohidrosis, corneal opacity; later CKD, cardiomyopathy, stroke
Enzyme replacement
Krabbe
AR
Galactocerebrosidase · galactocerebroside, psychosine
Infant: irritability, peripheral neuropathy, developmental regression, optic atrophy, spasticity
Globoid cells in white matter
Metachromatic leukodystrophy
AR
Arylsulfatase A · cerebroside sulfate
Central and peripheral demyelination: ataxia, dementia, neuropathy
Metachromatic granules
Hurler syndrome
MPS I · AR
α-L-iduronidase · heparan + dermatan sulfate
Developmental delay, gargoylism (coarse face), airway obstruction, corneal clouding, hepatosplenomegaly, dysostosis multiplex
Death in childhood without stem-cell transplant
Hunter syndrome
MPS II · XR
Iduronate-2-sulfatase · heparan + dermatan sulfate
Milder Hurler picture + aggressive behavior, no corneal clouding
Boys
I-cell disease (contrast)
Mannose-6-phosphate tag missing (trafficking)
Coarse face, gingival hyperplasia, restricted joints; enzymes high in plasma
See 2.04
Pompe (contrast)
Acid α-glucosidase · glycogen in lysosomes
Cardiomegaly, hypotonia
Both GSD and LSD (8.07)

Mechanism — sphingolipid breakdown chain

GM2
→
Hex ATay-Sachs
→
… Globoside → Gb3
→
α-Gal AFabry
→
Glucocerebroside
→
GlucocerebrosidaseGaucher
→
Ceramide

Side branches: sphingomyelin → (sphingomyelinase: Niemann-Pick) · galactocerebroside → (Krabbe) · sulfatides → (arylsulfatase A: MLD).

Look-alike pairs

PAIR
SHARED
DIFFERENCE
Tay-Sachs vs Niemann-Pick
Cherry-red spot, neurodegeneration
HSM only in Niemann-Pick
Hurler vs Hunter
Coarse face, HSM, MPS
Corneal clouding (Hurler); XR + aggression (Hunter)
Krabbe vs MLD
Leukodystrophy in infants
Globoid cells, optic atrophy (Krabbe)

How it's tested

COMMON CONFUSIONA cherry-red spot without hepatosplenomegaly is Tay-Sachs; with hepatosplenomegaly it is Niemann-Pick.
THE TRAPFabry and Hunter are the X-linked storage diseases — an affected boy whose maternal uncle had the same illness should make you think of them.
YOUR APPROACHSphingolipid (nerves, eyes, liver) vs mucopolysaccharide (face, bones, cornea) → organ clues → enzyme → inheritance.

If you see… think…

Ashkenazi infant, cherry-red spot, no HSM, startle → Tay-Sachs (Hex A)
Cherry-red spot + hepatosplenomegaly + foam cells → Niemann-Pick (sphingomyelinase)
Bone pain, HSM, "crumpled tissue paper" macrophages → Gaucher
Burning feet, angiokeratomas, proteinuria in a young man → Fabry
Infant with globoid cells and optic atrophy → Krabbe
Arylsulfatase A deficiency → metachromatic leukodystrophy
Coarse face + corneal clouding → Hurler (α-L-iduronidase)
Coarse face, aggressive boy, clear corneas → Hunter (XR)
Only XR lysosomal storage diseases → Fabry, Hunter
Most common lysosomal storage disease → Gaucher