Glycogen & Lysosomal Storage Diseases
The board-tested glycogen storage diseases (Von Gierke, Pompe, Cori, McArdle) and lysosomal storage diseases (sphingolipidoses and mucopolysaccharidoses), organized by the deficient enzyme, the substrate that accumulates, and the vignette buzzwords that separate the look-alikes.
One enzyme, two disease families
Storage diseases follow a single rule: a missing enzyme blocks a pathway, so its substrate accumulates while the downstream product is lost. Two classic Step 1 families obey this. In glycogen storage diseases (GSDs), defective glycogen synthesis or breakdown causes fasting hypoglycemia, hepatomegaly, or exercise intolerance, depending on which tissue's enzyme fails. In lysosomal storage diseases (LSDs), deficient acid hydrolases let sphingolipids or mucopolysaccharides pile up inside lysosomes, damaging neurons and macrophages. Pompe disease is the crossover: a lysosomal enzyme defect that traps glycogen, so it is counted in both families.
The four high-yield GSDs
| Type | Eponym | Deficient enzyme | Classic findings |
|---|---|---|---|
| I | Von Gierke | Glucose-6-phosphatase | Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia |
| II | Pompe | Lysosomal acid α-glucosidase (acid maltase) | Hypertrophic cardiomegaly, hypotonia, macroglossia; cardiorespiratory failure in the first 1–2 yr if untreated |
| III | Cori | Debranching enzyme (amylo-α-1,6-glucosidase) | Milder Von Gierke but normal blood lactate; hepatomegaly |
| V | McArdle | Muscle glycogen phosphorylase (myophosphorylase) | Exercise intolerance, cramps, myoglobinuria, "second wind" |
- Von Gierke (I): G6-phosphatase blocks both glycogenolysis and gluconeogenesis at their final shared step → blood glucose does not rise after glucagon; treat with frequent oral glucose / cornstarch, avoid fructose & galactose (they cannot be released as free glucose and worsen lactic acidosis).
- Cori (III): debrancher defect is a milder Von Gierke — gluconeogenesis is intact so lactate is normal; accumulates limit dextrin (glycogen with short outer branches).
- McArdle (V): myophosphorylase is muscle-only, so blood glucose is normal; no rise in venous lactate with exercise, with an exaggerated ammonia rise — the classic flat-lactate ischemic forearm test.
- Pompe (II): acid maltase is lysosomal → cardiomegaly + hypotonia; blood glucose is normal (cytosolic glycogenolysis is intact). The only GSD that is also an LSD.
- Von Gierke vs Cori: both give hypoglycemia + hepatomegaly, but lactic acidosis occurs only in Von Gierke.
- Von Gierke: infant with doll-like facies (fat cheeks), thin extremities, a protuberant abdomen from massive hepatomegaly, hypoglycemic seizures, and labs showing high lactate, uric acid, and triglycerides.
- Pompe: floppy infant with feeding difficulty, macroglossia, and massive cardiomegaly on chest film progressing to cardiorespiratory failure in infancy (untreated).
- McArdle: young adult with cramps and burgundy urine (myoglobinuria) after intense exercise who improves if they push through — the "second-wind" phenomenon. Classic finding: a flat venous lactate curve with a rising ammonia on ischemic forearm exercise testing.
- "Very Poor Carbohydrate Metabolism" → types 1-2-3-5: Von Gierke, Pompe, Cori, McArdle.
- "Pompe trashes the Pump" — hypertrophic cardiomyopathy plus diaphragm/respiratory failure.
- "McArdle = Muscle" — myophosphorylase, muscle cramps, myoglobinuria.
Into the lysosome
Lysosomes hold acid hydrolases that dismantle sphingolipids and glycosaminoglycans (mucopolysaccharides). Lose one hydrolase and its substrate accumulates inside the lysosome, poisoning cells — especially neurons (neurodegeneration) and macrophages (organomegaly, foam/storage cells). The two testable subgroups are the sphingolipidoses and the mucopolysaccharidoses (MPS). Nearly all are autosomal recessive — the two exceptions, Fabry and Hunter, are X-linked recessive. Several (Tay-Sachs, Niemann-Pick, Gaucher) are enriched in Ashkenazi Jews.
Lysosomal storage diseases at a glance
| Disease | Deficient enzyme | Accumulated substrate | Hallmark clues |
|---|---|---|---|
| Tay-Sachs | Hexosaminidase A | GM2 ganglioside | Cherry-red macula, NO hepatosplenomegaly, exaggerated startle (hyperacusis); onion-skin lysosomes |
| Niemann-Pick | Sphingomyelinase | Sphingomyelin | Cherry-red macula + hepatosplenomegaly, foam cells |
| Gaucher | Glucocerebrosidase | Glucocerebroside | Most common LSD; hepatosplenomegaly, pancytopenia, bone crises/avascular necrosis, Erlenmeyer-flask femur, "crumpled tissue paper" macrophages |
| Fabry (XR) | α-galactosidase A | Ceramide trihexoside (Gb3) | Neuropathic pain, angiokeratomas, renal & cardiac disease |
| Krabbe | Galactocerebrosidase | Galactocerebroside, psychosine | Peripheral neuropathy, optic atrophy, globoid cells |
| Metachromatic leukodystrophy | Arylsulfatase A | Cerebroside sulfate (sulfatide) | Central + peripheral demyelination, ataxia, dementia |
| Hurler (MPS I) | α-L-iduronidase | Heparan & dermatan sulfate | Corneal clouding, coarse (gargoyle) facies, developmental delay |
| Hunter (MPS II, XR) | Iduronate-2-sulfatase | Heparan & dermatan sulfate | Milder, NO corneal clouding, aggressive behavior |
- All LSDs are autosomal recessive EXCEPT Fabry & Hunter (X-linked recessive).
- Cherry-red spot appears in both Tay-Sachs and Niemann-Pick; separate them by organomegaly — absent in Tay-Sachs, present in Niemann-Pick.
- Tay-SaX = no heXosaminidase A, and no hepatoSplenomegaly.
- Gaucher is the most common LSD; Gaucher cells are lipid-laden macrophages with "crumpled / wrinkled tissue paper" cytoplasm; treated with recombinant enzyme replacement therapy.
- Hurler vs Hunter: same GAGs (heparan + dermatan sulfate); Hunter is X-linked, milder, has no corneal clouding, + aggression.
- Tay-Sachs: Ashkenazi infant with progressive weakness, an exaggerated startle to sound, a cherry-red macula, and — key — no hepatosplenomegaly.
- Niemann-Pick: mimics Tay-Sachs (cherry-red spot, regression) but with hepatosplenomegaly and lipid-laden foam cells.
- Gaucher: hepatosplenomegaly, bone pain / avascular necrosis of the femoral head, thrombocytopenia, and marrow macrophages resembling crumpled tissue paper.
- Fabry: young man with burning pain in hands and feet, clusters of dark-red skin papules (angiokeratomas), progressing to renal failure and cardiac disease (X-linked).
- Hurler vs Hunter: coarse facies + developmental delay with corneal clouding = Hurler; without clouding + aggressive behavior = Hunter.
- "Tay-SaX" — deficient heXosaminidase A; and Tay-Sachs spares the organs (no hepatosplenomegaly).
- "No man picks (Niemann-Pick) his nose with his sphinger" — sphingomyelinase deficiency.
- Fabry & Hunter are the "X-men" — the two X-linked storage diseases.
- "Hunters need no goggles" — Hunter has no corneal clouding (Hurler does), and Hunters are aggressive.
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