What enzyme is deficient in Cori disease?

Cori disease, also called glycogen storage disease type III or Forbes disease, is an autosomal recessive deficiency of the glycogen debranching enzyme, encoded by the AGL gene. This single protein has two activities: 4-alpha-glucanotransferase, which moves three glucose residues to a neighboring chain, and amylo-1,6-glucosidase, which releases the glucose at the branch point. Without it, glycogen phosphorylase can trim only the outer chains, and an abnormal limit dextrin accumulates in the liver and often in muscle.

How do you tell Cori disease from Von Gierke disease?

Both cause hepatomegaly, fasting hypoglycemia and hyperlipidemia in a young child, but Von Gierke disease (glucose-6-phosphatase deficiency) adds lactic acidosis, hyperuricemia and enlarged kidneys, with more severe hypoglycemia and hypertriglyceridemia. Cori disease usually has normal lactate and uric acid, ketotic hypoglycemia, very high transaminases (often about 500 U/L) and, in type IIIa, a raised CK from muscle involvement. On biopsy, Cori livers show fibrosis, while Von Gierke livers show steatosis without fibrosis.

Why is lactate normal in Cori disease?

The debranching block lies upstream of glucose-6-phosphatase, so gluconeogenesis still works. During a fast, the liver can still make glucose from glucogenic amino acids and other precursors, so lactate does not pile up the way it does in GSD I, and fat breakdown produces ketones, giving ketotic hypoglycemia. In Von Gierke disease, glucose-6-phosphatase is missing, so both glycogen breakdown and gluconeogenesis dead-end at glucose-6-phosphate, which drives lactic acidosis, hyperuricemia and hyperlipidemia. Lactate can still rise after meals in GSD III.

What is the difference between GSD IIIa and GSD IIIb?

GSD IIIa makes up about 85% of cases and affects both liver and muscle: children have the liver picture plus a raised CK, and weakness progresses slowly, often becoming prominent in the third or fourth decade; cardiac hypertrophy or cardiomyopathy develops in about 58%. GSD IIIb, about 15% of cases, affects only the liver. Both share hepatomegaly, ketotic hypoglycemia, hyperlipidemia and the long-term risk of liver fibrosis, cirrhosis and hepatocellular carcinoma.

How is Cori disease treated?

Treatment prevents hypoglycemia and supports muscle. Infants need feeds every 3-4 hours; from late in the first year, uncooked cornstarch is given several times a day, with extended-release cornstarch or overnight tube feeds for night-time lows. A high-protein diet (about 3 g/kg/day in children) supplies gluconeogenesis, excess carbohydrate is avoided, and unlike in GSD I, fructose and galactose are allowed. Patients need cardiac and liver surveillance, and liver transplantation is reserved for severe cirrhosis, liver failure or hepatocellular carcinoma.

What is limit dextrin?

Limit dextrin is the partly degraded, still-branched glycogen left behind when the debranching enzyme is missing. Glycogen phosphorylase cleaves alpha-1,4 bonds from the chain ends but stops four residues before each alpha-1,6 branch point. Normally the debranching enzyme then moves three residues to another chain and cleaves the remaining branch-point glucose. In Cori disease that step fails, so glycogen with short outer chains and intact branch points accumulates in the liver and muscle.

Cori Disease (GSD III): Debranching Enzyme vs Von Gierke

Cori disease, or glycogen storage disease type III (GSD III, also called Forbes disease or limit dextrinosis), is an autosomal recessive deficiency of the glycogen debranching enzyme, encoded by AGL, which carries both 4-α-glucanotransferase and amylo-1,6-glucosidase activity. Glycogen can be trimmed only down to its branch points, so an abnormal "limit dextrin" builds up in the liver and, in most patients, in muscle. The toddler looks like a milder Von Gierke: hepatomegaly, fasting ketotic hypoglycemia, hyperlipidemia and strikingly high transaminases, but lactate and uric acid are usually normal because gluconeogenesis still works. GSD IIIa (about 85%) adds a raised CK, slowly progressive myopathy and cardiac hypertrophy; GSD IIIb (about 15%) is liver-only.

Mechanism: glycogen stuck at the branch points

Glycogen is a tree of glucose chains joined by α-1,4 bonds, with an α-1,6 bond at each branch point.
Glycogen phosphorylase clips α-1,4 bonds from the chain ends, releasing glucose-1-phosphate, and stops 4 residues before a branch. It cannot cut α-1,6 bonds.
The debranching enzyme finishes the job with two activities on one protein:
1. 4-α-glucanotransferase moves a block of 3 glucose residues to the end of a neighboring chain.
2. Amylo-1,6-glucosidase hydrolyzes the remaining α-1,6-linked glucose, releasing free glucose.
In GSD III, phosphorylase strips only the outer chains, and the stubby, still-branched remnant (limit dextrin) accumulates. Hepatocytes swell with it, and liver fibrosis builds over time.

Why lactate and urate stay normal: the block sits upstream of glucose-6-phosphatase, so gluconeogenesis is intact. During a fast, glucogenic amino acids from protein can still be turned into glucose, while fat breakdown produces ketones: ketotic hypoglycemia. In Von Gierke disease, glucose-6-phosphatase itself is missing, so both glycogen breakdown and gluconeogenesis dead-end at glucose-6-phosphate, producing lactic acidosis, hyperuricemia and hyperlipidemia. The same logic gives a diet pearl: unlike in GSD I, fructose and galactose are allowed in GSD III, because patients can still use them.

Presentation: GSD IIIa vs IIIb

Feature	GSD IIIa (about 85%): liver + muscle	GSD IIIb (about 15%): liver only
Infancy and childhood	Hepatomegaly (the presenting feature in about 98% of GSD III), failure to thrive or short stature, fasting ketotic hypoglycemia, hyperlipidemia, high transaminases	Same liver picture
Skeletal muscle	CK rises once toddlers become active; weakness progresses slowly and is often prominent by the third or fourth decade, with distal involvement (calves, peroneal muscles, hands)	No myopathy
Heart	Cardiac hypertrophy or cardiomyopathy in 58%; severe dysfunction, heart failure and sudden death are occasionally reported	Not expected; screened less often
Adolescence and adulthood	Liver signs usually fade, but fibrosis can progress to cirrhosis and hepatocellular carcinoma; adenomas in about 7%	Same liver risks

Other findings include osteopenia or osteoporosis, which are common, and polycystic ovaries in some women.

Labs: Cori vs Von Gierke

Finding	Cori (GSD III)	Von Gierke (GSD I)
Enzyme	Debranching enzyme (AGL)	Glucose-6-phosphatase (Ia) or glucose-6-phosphate translocase (Ib)
Hypoglycemia	Fasting; less severe than in GSD I	Severe; can cause seizures
Ketones	High with fasting (ketotic hypoglycemia, or ketosis with normal glucose)	Not a defining feature: ketosis marks the hepatic GSDs 0, III, VI and IX
Lactate	Usually normal (can rise after meals)	High: lactic acidosis
Uric acid	Usually normal	High
Triglycerides	High	High, and more severe than in GSD III
AST/ALT	Very high, often about 500 U/L before treatment; no other GSD raises them this much	Lower than in GSD III
CK	High in GSD IIIa	Not a feature
Liver biopsy	Hepatocytes distended by glycogen, fibrous septa and periportal fibrosis; less steatosis	Steatosis; fibrosis is not a feature
Diet	Fructose and galactose allowed; high protein	Fructose and galactose restricted
Extras	Myopathy, cardiomyopathy	Enlarged kidneys, thin arms and legs; Ib adds neutropenia and infections

Diagnosis

First-line test: molecular genetic testing for biallelic AGL variants; debranching enzyme activity in tissue if genetics is inconclusive.
Pattern before the result: a hepatic GSD with ketosis, normal lactate and urate, very high transaminases and a raised CK points to GSD IIIa.
Fasting clue: hypoglycemia after a short fast fits GSD I and III, whereas GSD VI and IX usually drop glucose only after an overnight fast. The ketotic hepatic GSDs (0, III, VI and IX) usually push β-hydroxybutyrate above 2.5 mmol/L.
Liver biopsy, if done, shows the distended hepatocytes and periportal fibrosis; GSD III livers carry more fibrosis than other GSDs.

Management

Prevent fasting: feeds every 3-4 hours in infancy; from late in the first year, uncooked cornstarch (about 1 g/kg, several doses a day); extended-release cornstarch or continuous overnight tube feeds for night-time hypoglycemia.
High-protein diet: about 3 g/kg/day in children (25% of energy in adults), since protein supplies gluconeogenesis. Avoid excess carbohydrate, which is simply stored as more glycogen.
Surveillance: NT-proBNP, CK-MB, ECG and echocardiogram every 12-24 months in GSD IIIa (every 5 years in IIIb), plus liver monitoring for adenomas, cirrhosis and hepatocellular carcinoma.
Liver transplantation is reserved for severe cirrhosis, liver failure or hepatocellular carcinoma.

The Q-bank case

A 15-month-old boy is brought in for a swollen abdomen and poor weight gain. His parents say he becomes sweaty and irritable when breakfast is late. His weight is at the 3rd percentile. The liver edge is 6 cm below the right costal margin, the spleen is not palpable, and he has mild hypotonia. Labs after a 6-hour fast:

Test	Result
Glucose	45 mg/dL
Urine ketones	Large
Lactate	Normal
Uric acid	Normal
AST / ALT	610 / 540 U/L
Triglycerides	Elevated
Creatine kinase	1,150 U/L (elevated)

A liver biopsy shows hepatocytes distended by glycogen, with periportal fibrosis; the stored glycogen has abnormally short outer branches. Deficiency of which enzyme best explains these findings?

A. Glucose-6-phosphatase B. Lysosomal acid α-glucosidase C. Glycogen debranching enzyme D. Glycogen branching enzyme E. Liver glycogen phosphorylase F. Muscle glycogen phosphorylase

Answer: C. Glycogen debranching enzyme (GSD IIIa, Cori disease). Every clue fits: limit dextrin on biopsy, liver plus muscle involvement (high CK, hypotonia), ketotic hypoglycemia after a short fast with normal lactate and urate, transaminases in the 500s, and fibrosis rather than fat.

A. Glucose-6-phosphatase (Von Gierke, GSD Ia): the closest look-alike, with hepatomegaly, fasting hypoglycemia and hyperlipidemia. But GSD I brings lactic acidosis and hyperuricemia, enlarged kidneys, thin arms and legs, and a fatty liver without fibrosis; ketotic hypoglycemia and a high CK do not fit. Review: Von Gierke disease.
B. Lysosomal acid α-glucosidase (Pompe, GSD II): the only lysosomal GSD. Infantile Pompe means hypotonia, heart disease and hepatomegaly, with death from heart failure in the first year if untreated; cytosolic glycogen breakdown still works, so fasting hypoglycemia is not part of it. See the Pompe mnemonic.
D. Glycogen branching enzyme (Andersen, GSD IV): the abnormal glycogen (polyglucosan) has too few branch points and long outer chains, the opposite of the short outer branches in this biopsy. The classic hepatic form brings faltering growth and hepatomegaly in infancy, then cirrhosis, with death from liver failure in early childhood. See Andersen disease.
E. Liver glycogen phosphorylase (Hers, GSD VI): also hepatomegaly, ketotic fasting hypoglycemia and slow growth, but milder; it improves with age, glucose usually falls only after an overnight fast, and the defect is in the liver isoform, so a high CK points away from it. The liver form of phosphorylase kinase deficiency (GSD IX) would look similar.
F. Muscle glycogen phosphorylase (McArdle, GSD V): muscle-only. Symptoms usually start in the teens or twenties: cramps and fatigue in the first minutes of exercise, a "second wind" after brief rest, and rhabdomyolysis with red-brown urine in about half. No hepatomegaly or fasting hypoglycemia. Details: McArdle disease.

How USMLE tests it: the GSD lineup

Type (eponym)	Enzyme	Clincher
I (Von Gierke)	Glucose-6-phosphatase	Severe hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hepatomegaly and enlarged kidneys; Ib adds neutropenia
II (Pompe)	Lysosomal acid α-glucosidase (acid maltase)	Floppy infant with heart disease; the only lysosomal GSD
III (Cori, Forbes)	Debranching enzyme	Ketotic hypoglycemia, AST/ALT near 500, high CK, limit dextrin
IV (Andersen)	Branching enzyme	Polyglucosan; cirrhosis and liver failure in early childhood
V (McArdle)	Muscle phosphorylase	Early-exercise cramps, second wind, myoglobinuria; no rise in venous lactate with forearm exercise
VI (Hers)	Liver phosphorylase	Mild Cori look-alike without myopathy; improves with age
VII (Tarui)	Phosphofructokinase	McArdle-like cramps and rhabdomyolysis plus hemolysis
IX	Phosphorylase kinase	Mostly liver; X-linked (PHKA2) or autosomal recessive (PHKB, PHKG2); improves with age

Cori disease is not the Cori cycle. The Cori cycle recycles lactate from muscle and red cells into glucose in the liver; it has nothing to do with the debranching enzyme.
Limit dextrin = debrancher (III); polyglucosan = brancher (IV). "Branching" and "debranching" in the same answer list is a deliberate trap.
Liver + muscle = GSD III (IIIa); muscle = V and VII (VII also causes hemolysis); heart and skeletal muscle with lysosomal storage = II; liver only = I, IIIb, VI and most IX.
Normal lactate argues strongly against GSD I, not against GSD III, and a raised CK separates IIIa from the liver forms of VI and IX.

Key takeaways

Cori disease = GSD III = debranching enzyme (AGL) deficiency, autosomal recessive; limit dextrin accumulates.
Liver picture: hepatomegaly, fasting ketotic hypoglycemia, hyperlipidemia and AST/ALT often about 500 U/L.
Normal lactate and uric acid (gluconeogenesis intact) separate it from Von Gierke.
GSD IIIa (about 85%) adds a high CK, myopathy and cardiac hypertrophy; IIIb (about 15%) is liver-only.
Diagnose with AGL gene testing; treat with frequent feeds, uncooked cornstarch and a high-protein diet, with fructose and galactose allowed.
In adulthood, watch for cirrhosis, hepatocellular carcinoma and cardiomyopathy.