The Pattern
Two compartments. One fuel. Different consequences when the enzyme breaks.
Liver GSDs
Liver can't release glucose. The details of HOW differ by disease.
GSD Type Ia · Most Severe
Von Gierke Disease
Missing: Glucose-6-phosphatase (G6Pase).
The final step of BOTH glycogenolysis AND gluconeogenesis requires G6Pase to convert glucose-6-phosphate into free glucose. Without it, both pathways are dead ends. Glucose-6-P backs up and shunts into three overflow paths: glycolysis (lactic acidosis), pentose phosphate pathway (purines then uric acid), and lipogenesis (hypertriglyceridemia).
Clinical: Severe fasting hypoglycemia. Massive hepatomegaly and renomegaly. Doll-like facies from fat redistribution. No ketones despite prolonged fasting.
GSD Type III · Milder
Cori Disease
Missing: Debranching enzyme (amylo-1,6-glucosidase).
Glycogen has branches. Normal glycogenolysis chews off glucose units from the ends, but when it hits a branch point, it needs the debranching enzyme to cleave the alpha-1,6 branch so the chain can continue. Without it, glycogenolysis stalls at every branch point. Only the outer chain portions are accessible, so partial glycogen breakdown occurs.
Clinical: Milder hypoglycemia than Von Gierke (some glycogen is accessible). Hepatomegaly plus myopathy (muscle glycogen also accumulates). Normal lactate, unlike Von Gierke.
GSD Type IV · Fatal
Andersen Disease
Missing: Branching enzyme (amylo-1,4 to 1,6 transglucosidase).
Normal glycogen has many short branches, which is critical for compact storage and rapid mobilization. The branching enzyme adds those alpha-1,6 branch points during glycogen synthesis. Without it, glycogen is built as a long, poorly-branched chain resembling plant amylopectin. This abnormal glycogen is recognized as foreign by the liver, triggering a progressive inflammatory response.
Clinical: Progressive hepatic cirrhosis and liver failure. Fatal in childhood without transplant. NOT a hypoglycemia disease.
GSD Type VI · Benign
Hers Disease
Missing: Liver phosphorylase.
Liver phosphorylase is the enzyme that initiates glycogen breakdown by cleaving glucose units from the chain ends. In Hers disease, it's deficient specifically in the liver. Glycogenolysis is impaired, but gluconeogenesis still works, so hypoglycemia is mild. The course is benign.
Clinical: Mild hepatomegaly. Very mild or no hypoglycemia. Usually discovered incidentally. No significant metabolic complications.
GSD Villain Lineup
Tap to flip. Enzyme, mechanism, key clue, and board move on the back.
Missing Enzyme
Glucose-6-phosphatase (G6Pase) · blocks both glycogenolysis AND gluconeogenesis at the final step
Key Clue
Lactic acidosis + hyperuricemia + hypertriglyceridemia + NO ketones · doll-like facies, massive hepatomegaly
Why No Ketones?
G-6-P backs up into lipogenesis (makes fat, not ketones). Severe hypoglycemia but paradoxically no ketone production.
Treatment
Cornstarch (slow glucose release) · raw cornstarch q3-4h to prevent hypoglycemia
Lactic acidosis + NO ketones + infant = Von Gierke first
Missing Enzyme
Acid alpha-1,4-glucosidase (acid maltase / GAA) · lives in lysosomes
Key Clue
Massive cardiomegaly + floppy infant + macroglossia · short PR interval on ECG · normal blood glucose
Why Unique
Only GSD that is lysosomal, not cytoplasmic. Only GSD with cardiac involvement. Only GSD with approved enzyme replacement.
Treatment
Alglucosidase alfa (Myozyme/Lumizyme) · only GSD with ERT · start before cardiac damage
Floppy infant + cardiomegaly + normal glucose = Pompe
Missing Enzyme
Muscle phosphorylase (myophosphorylase) · muscle-only, liver is normal
Key Clue
Exercise cramps + myoglobinuria + "second wind" · no lactate rise on forearm ischemic exercise test · normal glucose
Second Wind
After brief rest, fatty acid oxidation + hepatic glucose release restores fuel. Patient can continue exercise. Classic board feature.
Test
Forearm ischemic exercise test: no lactate rise (normally goes up 3-5x). Ammonia DOES rise (amino acids still metabolized).
Second wind + no lactate rise = McArdle (V)
Missing Enzyme
Debranching enzyme (amylo-1,6-glucosidase) · glycogenolysis stalls at every branch point
Key Clue
Milder hypoglycemia + hepatomegaly + myopathy · NORMAL lactate (unlike Von Gierke) · both liver AND muscle affected
Why Milder
Only the outer chain glucose is inaccessible. Gluconeogenesis is intact (G6Pase works). So some glucose still gets to blood.
Board Discriminator
Von Gierke vs. Cori: lactate · elevated in Von Gierke, normal in Cori. Myopathy only in Cori.
Liver GSD + normal lactate + myopathy = Cori (III)
Muscle GSDs
Muscle can't use its own glycogen during exercise. Liver is fine. Glucose is normal.
GSD Type V · Classic
McArdle Disease
Missing: Muscle phosphorylase (myophosphorylase).
Skeletal muscle cannot break down its own glycogen at all. During the first 5-10 minutes of exercise, ATP from non-glycogen sources (phosphocreatine, circulating glucose) is depleted faster than it can be replaced. Cramping and myoglobinuria result from muscle cell breakdown.
Second wind: After brief rest, fatty acid oxidation ramps up in muscle AND the liver releases glucose into blood. Fuel supply is restored by non-glycogenolytic routes, and the patient can continue exercise without further pain. This is the board discriminator.
Forearm ischemic exercise test: No rise in venous lactate after forearm exercise under ischemic conditions. Normally, muscle glycogenolysis generates pyruvate then lactate. Without it, lactate doesn't rise.
GSD Type VII · McArdle Mimic
Tarui Disease
Missing: Muscle phosphofructokinase (PFK).
PFK catalyzes one of the committed steps of glycolysis (fructose-6-phosphate to fructose-1,6-bisphosphate). Without it, muscle can't run glycolysis even when glucose enters the cell, so the fuel crisis during exercise is the same as McArdle despite a different enzyme.
Distinguisher from McArdle: PFK is also expressed in red blood cells, so Tarui disease causes a compensated hemolytic anemia in addition to exercise intolerance. The forearm ischemic exercise test also shows no lactate rise, just like McArdle.
Clinical: Exercise intolerance, painful cramps, myoglobinuria. Hemolytic anemia (mild). Reticulocytosis.
Pompe Disease (GSD II)
The one GSD that lives in the lysosomes. Everything else is different because of that.
Clinical anchors: tap any image to enlarge.
GSD Type II · Lysosomal
Pompe Disease
Missing: Acid alpha-1,4-glucosidase (acid maltase, GAA).
This enzyme lives in lysosomes and degrades the small amounts of glycogen that get sequestered into lysosomes as part of normal autophagy. Without it, glycogen accumulates inside lysosomes of every tissue. The lysosomes swell, disrupt cell structure, and cause progressive organ failure.
Infantile form: Massive cardiomegaly (the biggest board clue). Profound generalized hypotonia ("floppy infant"). Macroglossia. Respiratory failure. Short PR interval + massive QRS voltage on ECG. Death within the first year without treatment. Glucose is normal.
Adult/late-onset form: Proximal myopathy that mimics limb-girdle muscular dystrophy. No cardiac involvement. Slowly progressive respiratory insufficiency. Presents in teens to adulthood. Confirmed by acid maltase activity in dried blood spot or muscle biopsy with PAS-positive vacuoles.
Treatment: Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme). The only GSD with approved ERT. Must start before irreversible cardiac damage.
1. Glycogen is in LYSOSOMES, not cytoplasm.
2. Massive cardiomegaly in infants is unique to Pompe.
3. The only GSD with approved enzyme replacement therapy.
4. Adult form mimics muscular dystrophy, not a metabolic crisis.
5. Glucose is normal because the liver's cytoplasmic glycogen metabolism is intact.
GSD Clinical Decision Tree
Commit at each fork before the reveal. Same logic the clinical medicine test.
Comparison Table
Every GSD. One view. Scroll horizontally on mobile.
| Disease | GSD # | Missing Enzyme | Tissue | Key Finding | Distinguisher |
|---|---|---|---|---|---|
| Von Gierke | Ia | Glucose-6-phosphatase | Liver + Kidney | Severe fasting hypoglycemia + massive hepatomegaly | Lactic acidosis + hyperuricemia + hypertriglyceridemia + NO ketones |
| Pompe | II | Acid alpha-glucosidase (acid maltase) | Lysosomes (all tissues) | Cardiomegaly + floppy infant | Lysosomal glycogen. ERT available. Normal glucose. Adult form: proximal myopathy. |
| Cori | III | Debranching enzyme (amylo-1,6-glucosidase) | Liver + Muscle | Milder hypoglycemia + hepatomegaly + myopathy | Normal lactate (unlike Von Gierke). Partial glycogenolysis works. |
| Andersen | IV | Branching enzyme (amylo-1,4 to 1,6 transglucosidase) | Liver | Progressive cirrhosis, liver failure | Abnormal long-chain glycogen (amylopectin-like). Fatal in childhood. No hypoglycemia. |
| McArdle | V | Muscle phosphorylase (myophosphorylase) | Skeletal muscle | Exercise cramps + myoglobinuria | "Second wind". No hypoglycemia. No lactate rise on forearm ischemic test. |
| Hers | VI | Liver phosphorylase | Liver | Mild hepatomegaly | Benign. Very mild or no hypoglycemia. Incidental finding. |
| Tarui | VII | Phosphofructokinase (PFK) | Muscle + RBCs | Exercise cramps + myoglobinuria | Like McArdle but also hemolytic anemia. RBCs also lack PFK. |
Quiz
Five clinical clinical vignettes. Original vignettes. Pick your answer before reading the explanation.
A 6-month-old girl is brought in because of poor feeding and failure to thrive. Physical exam reveals massive hepatomegaly and mild hypotonia. Fasting glucose is 28 mg/dL. Labs show elevated lactic acid, elevated uric acid, and elevated triglycerides. Urine shows no ketones.
Which enzyme deficiency explains ALL of these lab findings?Von Gierke disease (GSD Ia). G6Pase is required for the final step of BOTH glycogenolysis and gluconeogenesis. Without it, glucose-6-phosphate cannot be converted to free glucose. G6P shunts into glycolysis (lactic acidosis), pentose phosphate pathway (purines to uric acid), and lipogenesis (hypertriglyceridemia).
Break it down: Debranching enzyme deficiency (Cori, GSD III) gives milder hypoglycemia and normal lactate. Liver phosphorylase (Hers, GSD VI) causes mild benign hepatomegaly without the metabolic overflow. Branching enzyme (Andersen, GSD IV) causes cirrhosis, not hypoglycemia.
A 19-year-old male presents with muscle cramps and dark brown urine that appear within 30 minutes of playing basketball. He has no symptoms at rest. Laboratory studies show elevated creatine kinase and myoglobin in the urine. He notes that if he rests briefly after the cramps start, he can often continue exercising without further pain.
What is the underlying mechanism of his "second wind" phenomenon?McArdle disease (GSD V). Muscle phosphorylase is absent, so skeletal muscle cannot break down its own glycogen. During the first minutes of exercise, available ATP from phosphocreatine and circulating glucose is consumed, causing cramps. The "second wind" occurs because after a brief rest, the liver increases glucose output and fatty acid oxidation ramps up in muscle. Both of these fuel sources bypass the glycogenolysis block entirely.
Break it down: Glycolysis can run on incoming glucose but still can't supplement from glycogen. GLUT4 translocation is intact in McArdle, meaning glucose can enter the cell, but the total fuel delivery from the liver is limited and delayed. Pyruvate carboxylase is a gluconeogenic enzyme in liver and doesn't apply here.
An 8-month-old boy has had progressive difficulty feeding and breathing since birth. His heart rate is 156 bpm. Chest X-ray shows massive cardiomegaly. He is profoundly hypotonic. ECG shows short PR interval and massive QRS complexes. Glucose is normal between feedings. Liver is normal size.
Enzyme replacement with which agent addresses the primary defect?Pompe disease (GSD II). The massive cardiomegaly in a floppy infant with hypotonia and normal glucose is the pathognomonic presentation. Acid alpha-1,4-glucosidase (acid maltase) deficiency causes glycogen accumulation in lysosomes of all tissues, with the heart and skeletal muscle most severely affected. Alglucosidase alfa (Lumizyme/Myozyme) is the approved enzyme replacement therapy.
Break it down: Imiglucerase treats Gaucher disease (glucocerebroside accumulation). Idursulfase treats Hunter syndrome (MPS II, iduronate sulfatase deficiency). Laronidase treats Hurler syndrome (MPS I, alpha-L-iduronidase deficiency). The normal glucose and cardiac-predominant presentation with normal liver size distinguish Pompe from all liver-based GSDs.
A 3-year-old boy has had hepatomegaly since infancy. He recently developed ascites and is found to have elevated liver enzymes. Liver biopsy shows cirrhosis with PAS-positive inclusions in hepatocytes. Analysis reveals an abnormal branching pattern in stored glycogen: the chains are unusually long and poorly branched.
Which enzyme is deficient in this condition?Andersen disease (GSD IV). Branching enzyme deficiency results in glycogen with abnormally long, poorly-branched chains that resemble plant amylopectin. This structurally abnormal glycogen is treated as a foreign body by the liver, triggering progressive inflammation, fibrosis, and cirrhosis. Liver failure in childhood is the result without transplant.
Break it down: Muscle phosphorylase (McArdle, GSD V) causes exercise intolerance with myoglobinuria, not cirrhosis. Glucose-6-phosphatase (Von Gierke) causes severe hypoglycemia and massive hepatomegaly, but NOT cirrhosis. Debranching enzyme (Cori, GSD III) causes partial glycogenolysis with milder liver disease, myopathy, and normal lactate.
A 24-year-old woman is evaluated for recurrent muscle cramps and tea-colored urine after jogging. Vital signs are normal at rest. Physical examination is unremarkable except for mild scleral icterus. Laboratory studies show hemoglobin 10.8 g/dL (12.0 to 15.5), reticulocyte count 4.2% (0.5 to 2.5), indirect bilirubin 2.8 mg/dL (0.1 to 1.0), and creatine kinase 420 U/L (30 to 200) after a recent run. A forearm ischemic exercise test shows no rise in venous lactate but a normal ammonia rise.
Which enzyme deficiency best explains BOTH the exercise intolerance and the hemolytic anemia?Tarui disease (GSD VII). PFK catalyzes a committed glycolysis step in muscle and erythrocytes. Without it, muscle cannot run glycolysis during exertion (same cramp and myoglobinuria pattern as McArdle, same no lactate rise on forearm ischemic exercise test). RBCs also lack PFK, causing a compensated hemolytic anemia with reticulocytosis and indirect hyperbilirubinemia.
Break it down: McArdle (A) has the same exercise test but no hemolysis. Cori (C) causes liver hypoglycemia and myopathy, not exercise cramps with hemolytic anemia. Von Gierke (D) is a severe infantile liver GSD with metabolic overflow, not an adult exercise disorder.
clinical Walkthrough
Original clinical vignettes. Shuffle remix, never-repeat, full Chicago explanations with revealBeat teaching chains.