What enzyme is deficient in Andersen disease?

Andersen disease, or glycogen storage disease type IV, is caused by deficiency of the glycogen branching enzyme (amylo-alpha-1,4 to alpha-1,6 transglucosidase), encoded by the GBE1 gene and inherited in an autosomal recessive pattern. The enzyme normally creates alpha-1,6 branch points. Without it, glycogen has fewer branches and long outer chains, an amylopectin-like molecule called polyglucosan that is less soluble and injures liver and muscle cells.

What are the symptoms of Andersen disease?

In the classic and most common form, a baby who seemed normal at birth develops failure to thrive, an enlarged liver and raised liver enzymes within the first months of life, followed by progressive cirrhosis with low albumin, prolonged clotting times, portal hypertension, ascites, varices and an enlarged spleen. Hypotonia often appears by age 1 to 2. Without a liver transplant, death from liver failure usually occurs by about age 5. Rarer forms mainly affect muscle, nerves and the heart.

What is the difference between Andersen disease and Cori disease?

Andersen disease (type IV) is a branching enzyme deficiency: glycogen cannot gain new branches, so it has long unbranched outer chains and causes progressive cirrhosis in early childhood, usually with normal fasting glucose. Cori disease (type III) is a debranching enzyme deficiency: glycogen breakdown stalls at branch points, leaving short outer branches called limit dextrin, and it presents with hepatomegaly, fasting hypoglycemia and ketosis, plus muscle disease in type IIIa.

How is Andersen disease diagnosed?

Suspect it in an infant with failure to thrive, hepatomegaly and progressive liver disease without severe hypoglycemia. A liver biopsy shows enlarged hepatocytes with PAS-positive, diastase-resistant inclusions of abnormally branched glycogen (polyglucosan), fibrosis and cirrhosis. Because other rare polyglucosan disorders look similar on biopsy, the diagnosis is confirmed by finding pathogenic variants in both copies of GBE1 on genetic testing, or by showing reduced branching enzyme activity in skin fibroblasts, muscle or liver.

How is Andersen disease treated?

There is no disease-specific drug or enzyme replacement. Liver transplantation is the only treatment for the progressive liver form once liver failure develops; it corrects the liver disease, and long-term survival has been reported. However, some recipients have developed severe cardiomyopathy after transplant and died of heart failure, so heart function is checked beforehand. Supportive care covers nutrition, fat-soluble vitamins and the complications of cirrhosis. Unlike von Gierke, Cori or Hers disease, cornstarch therapy is not the main treatment.

What is adult polyglucosan body disease?

Adult polyglucosan body disease is the adult-onset form of GBE1 deficiency, also autosomal recessive. Symptoms usually begin between ages 35 and 60 with neurogenic bladder, followed by spastic, weak legs with mixed upper and lower motor neuron signs, numbness in the feet and legs, and in about half of patients a decline in cognitive function. Abnormal polyglucosan bodies build up in cells, and nerve cells are particularly vulnerable. It is rare, with about 200 diagnosed patients reported worldwide.

Andersen Disease (GSD IV): Branching Enzyme & GSD Table

Andersen disease (glycogen storage disease type IV, GSD IV) is caused by deficiency of the glycogen branching enzyme (amylo-α-1,4→α-1,6-transglucosidase), encoded by GBE1 and inherited in an autosomal recessive pattern. Without enough branching, cells build a poorly branched glycogen with long outer chains that resembles plant amylopectin (polyglucosan); it is less soluble and damages cells, above all hepatocytes and muscle. The classic and most common form is an infant who looks normal at birth and then develops failure to thrive, hepatomegaly and progressive cirrhosis; without a liver transplant, death from liver failure usually comes by age 5. Rarer forms are neuromuscular, from fatal perinatal disease to adult polyglucosan body disease. GSD IV makes up about 3% of glycogen storage diseases (roughly 1 in 600,000 to 800,000 people).

What the branching enzyme does

Glycogen is a glucose polymer: chains held together by α-1,4 bonds, with branch points made by α-1,6 bonds.

Glycogen synthase lengthens the chains. Branching enzyme moves a segment of α-1,4-linked glucose units from the end of a chain to an α-1,6 position, starting a new branch.
Branches make glycogen more soluble and give the enzymes that build and break down glycogen more chain ends to work on.
Without branching enzyme, glycogen has fewer branch points and longer unbranched outer chains: an amylopectin-like molecule that collects as polyglucosan bodies. This less soluble material may provoke a foreign-body-type reaction; in the liver the result is cell injury, fibrosis and cirrhosis.

	Branching enzyme	Debranching enzyme
Disease	Andersen (GSD IV)	Cori or Forbes (GSD III)
Gene	GBE1	AGL
Normal job	Makes α-1,6 branches while glycogen is built	Removes branches while glycogen is broken down (4-α-glucanotransferase and α-1,6-glucosidase activities)
Abnormal glycogen	Few branches, long outer chains (amylopectin-like)	Short outer branches stuck at the branch points (limit dextrin)
Signature	Progressive cirrhosis in early childhood	Hepatomegaly with fasting hypoglycemia and ketosis; myopathy in type IIIa

Memory hook: Andersen can't Add branches; Cori can't Cut them.

The clinical spectrum of GSD IV

GBE1 variants cause a continuum, and the subtypes overlap. Residual enzyme activity partly tracks severity: under 5% in the fatal perinatal form and about 20% in the childhood neuromuscular form (MedlinePlus Genetics).

Form	Onset	Key features	Outcome
Classic (progressive) hepatic, the most common	First months of life (NORD: by about 18 months)	Failure to thrive, hepatomegaly, raised liver enzymes, then cirrhosis with low albumin, prolonged PT and PTT, portal hypertension, ascites, esophageal varices and splenomegaly; generalized hypotonia within 1-2 years	Death from liver failure usually by age 5 without a transplant
Non-progressive hepatic	Childhood	Liver dysfunction, sometimes myopathy and hypotonia, usually without cirrhosis	Survival into adulthood
Fatal perinatal neuromuscular	Before birth	Polyhydramnios, decreased fetal movement, fetal hydrops, joint contractures (arthrogryposis), severe hypotonia	Death in the newborn period
Congenital neuromuscular	At birth	Profound hypotonia, respiratory failure, dilated cardiomyopathy	Death in early infancy
Childhood neuromuscular	Late childhood or adolescence (GeneReviews: usually the second decade)	Mild-to-severe myopathy; dilated cardiomyopathy in some	Ranges from a mild lifelong course to death in the third decade
Adult polyglucosan body disease (APBD)	Usually ages 35-60	Neurogenic bladder (often the first sign), spastic gait with weakness (upper and lower motor neuron signs), distal leg sensory loss, autonomic dysfunction; cognitive problems from mild executive dysfunction to dementia (about half, per MedlinePlus)	Slowly progressive

Glucose is usually not the story. Unlike GSD I, III, VI and IX, hypoglycemia symptoms are typically absent in GSD IV. Low glucose appears mainly with liver failure (Merck lists it alongside the progressive cirrhosis; NORD calls it rare), and only a few hepatic cases have needed nutritional support for it. A von Gierke pattern (severe fasting hypoglycemia with lactic acidosis, hyperuricemia and hypertriglyceridemia) argues against GSD IV.

Diagnosis

Liver biopsy (classic hepatic form): markedly enlarged hepatocytes with PAS-positive, diastase-resistant inclusions (abnormally branched glycogen), interstitial fibrosis and cirrhosis. Normally branched glycogen is digested by diastase (amylase); polyglucosan resists it, so it still stains with PAS after diastase treatment. Electron microscopy shows fine fibrillar aggregates of amylopectin-like material.
Not specific on its own: polyglucosan also builds up in other rare disorders, including Tarui disease (GSD VII), GSD XV, Danon disease and Lafora disease, so PAS-positive, diastase-resistant material is not enough to diagnose GSD IV.
Confirmation: biallelic pathogenic GBE1 variants on molecular testing, or reduced branching enzyme activity in liver, muscle or skin fibroblasts.
Other causes of liver disease in infancy: in hereditary fructose intolerance (aldolase B deficiency), vomiting and hypoglycemia follow fructose or sucrose in the diet, as in the fructose and galactose disorders. Alpha-1 antitrypsin deficiency causes cholestatic jaundice and hepatomegaly in the first week of life, with a low serum AAT level (most severe cases are PI*ZZ). Neither shows polyglucosan on biopsy.

Treatment and prognosis

No disease-specific drug therapy: liver transplantation is the only treatment for the progressive hepatic form once liver failure develops.
Transplant fixes the liver, not every tissue. It is effective for the liver disease, long-term survival has been reported, and many recipients never develop heart disease. But some have developed severe dilated cardiomyopathy afterward and died of heart failure, so the heart is assessed first (echocardiogram plus cardiac MRI). GeneReviews (2019) counted 6 deaths among 20 recipients, 4 from sepsis.
Supportive care from a multidisciplinary team: a dietitian experienced in pediatric liver disease, prevention of fat-soluble vitamin deficiencies, management of portal hypertension, ascites and varices (see cirrhosis and portal hypertension), and a coagulation check before surgery.
Contrast: uncooked cornstarch is the mainstay for the hypoglycemic liver GSDs (types I, III and VI), but it is not the treatment answer for Andersen disease; nutrition in GSD IV is supportive (growth, vitamins, and treating hypoglycemia if it appears).
Genetic counseling: each sibling of an affected child has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being unaffected.

Glycogen storage diseases compared

Type (eponym)	Deficient enzyme	Main tissue	Signature clues	Fasting glucose	Treatment
I (von Gierke)	Glucose-6-phosphatase	Liver, kidney	Before age 1: severe hypoglycemia, lactic acidosis, hepatomegaly; later hyperuricemia, hypertriglyceridemia, renomegaly, hepatic adenomas	Severely low	Frequent feeds, uncooked cornstarch, fructose and galactose restriction
II (Pompe)	Lysosomal acid α-glucosidase (acid maltase)	Heart, skeletal muscle	Infantile: cardiomyopathy with heart failure, severe hypotonia, macroglossia; later onset: limb-girdle and respiratory weakness	Normal	Enzyme replacement therapy
III (Cori or Forbes)	Debranching enzyme	Liver (IIIb) or liver and muscle (IIIa)	Hepatomegaly, ketosis, raised transaminases, limit dextrin; myopathy and cardiomyopathy in IIIa; fibrosis, sometimes cirrhosis	Low, milder than type I	Cornstarch, high-protein diet
IV (Andersen)	Branching enzyme	Liver; rarer neuromuscular forms	Failure to thrive, hepatosplenomegaly, progressive cirrhosis in early childhood; polyglucosan	Usually normal until liver failure	Liver transplant for liver failure
V (McArdle)	Muscle glycogen phosphorylase	Skeletal muscle	Cramps in the first minutes of exercise, second wind, myoglobinuria, high CK	Normal	Regular moderate aerobic exercise, sucrose before exercise
VI (Hers)	Liver glycogen phosphorylase	Liver	Hepatomegaly, growth retardation, mild hypoglycemia, ketosis, hyperlipidemia; benign course	Mildly low	Uncooked cornstarch

All six are autosomal recessive (the X-linked exception among GSDs is a form of phosphorylase kinase deficiency, type IX). More on each: von Gierke disease, the Pompe disease mnemonic, the Cori disease question and the McArdle disease question.

Practice question

A 14-month-old boy is evaluated for poor weight gain and a swollen abdomen. He seemed healthy at birth and fed well, but since 6 months of age he has crossed down two weight percentiles. He has a firm, enlarged liver, splenomegaly, shifting dullness and mildly decreased muscle tone. AST and ALT are raised, albumin is low and PT is prolonged. Fasting glucose, lactate, uric acid and triglycerides are normal, and an echocardiogram is normal. Liver biopsy shows markedly enlarged hepatocytes with PAS-positive, diastase-resistant cytoplasmic inclusions and early cirrhosis; electron microscopy shows fibrillar aggregates of amylopectin-like material.

Deficiency of which enzyme is most likely?

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

Answer: D, glycogen branching enzyme (Andersen disease, GSD IV). A child who was well at birth, then develops failure to thrive and progressive cirrhosis with normal fasting glucose and diastase-resistant, amylopectin-like inclusions, has a glycogen structure problem: chains that were never branched.

A. Acid α-glucosidase (Pompe disease): lysosomal glycogen storage; the infantile form brings massive cardiomegaly with heart failure, severe hypotonia and macroglossia. A normal echocardiogram and liver-led disease rule it out.
B. Aldolase B (hereditary fructose intolerance): symptoms follow fructose or sucrose intake (vomiting, hypoglycemia), with liver and kidney damage after repeated exposure. There is no dietary trigger here, and the stored material is polyglucosan.
C. Glucose-6-phosphatase (von Gierke disease): severe fasting hypoglycemia, lactic acidosis, hyperuricemia and hypertriglyceridemia before age 1. All of those are normal in this child.
E. Debranching enzyme (Cori disease): hepatomegaly with fasting hypoglycemia, ketosis and raised transaminases, plus myopathy in type IIIa. Its glycogen has short outer branches (limit dextrin), the opposite of long unbranched chains, and the presentation is led by hypoglycemia.
F. Liver glycogen phosphorylase (Hers disease): hepatomegaly, growth retardation, mild hypoglycemia and ketosis with a benign course, not progressive liver failure in infancy. A phosphorylase defect leaves more glycogen, not abnormally shaped glycogen.
G. Muscle glycogen phosphorylase (McArdle disease): a disease of skeletal muscle in older children and adults (exercise cramps, second wind, myoglobinuria), with a normal liver.

Sneaky variants: the same enzyme is the answer for a newborn with polyhydramnios, arthrogryposis and severe hypotonia (fatal perinatal neuromuscular form), and for a middle-aged adult with neurogenic bladder, spastic gait and distal leg numbness (adult polyglucosan body disease).

How USMLE tests Andersen disease

Buzzwords: long unbranched outer chains, amylopectin-like glycogen, polyglucosan bodies, PAS-positive and diastase-resistant inclusions.
Progressive cirrhosis in a toddler with a GSD and normal fasting glucose = Andersen. Severe fasting hypoglycemia with lactic acidosis = von Gierke. Hypoglycemia with ketosis, limit dextrin and a myopathy = Cori. Infant cardiomegaly and hypotonia = Pompe.
Branching vs debranching is the favorite trap: Andersen can't add branches (long chains); Cori can't remove them (short stubs). For treatment, pick liver transplant, not cornstarch.
Name traps: Andersen-Tawil syndrome is an unrelated autosomal dominant channelopathy (KCNJ2 potassium channel in about 60% of cases) with periodic paralysis, ventricular arrhythmias and long QT, and dysmorphic features. Anderson-Fabry disease is another name for Fabry disease, an X-linked α-galactosidase A deficiency.

Key takeaways

Andersen disease = GSD IV = glycogen branching enzyme deficiency (GBE1), autosomal recessive, about 3% of GSDs.
No branching → few branch points, long outer chains, amylopectin-like polyglucosan that injures cells.
Classic hepatic form: failure to thrive, hepatosplenomegaly and progressive cirrhosis in the first years; death from liver failure usually by age 5 without transplant.
Neuromuscular forms range from fatal perinatal disease to adult polyglucosan body disease (neurogenic bladder, spastic gait, neuropathy).
Hypoglycemia is typically absent until the liver fails, unlike von Gierke, Cori and Hers.
Biopsy: PAS-positive, diastase-resistant inclusions (polyglucosan resists diastase; normal glycogen does not); confirm with biallelic GBE1 variants or low enzyme activity.
Liver transplantation is the only treatment for progressive liver failure; it fixes the liver, but some recipients later develop severe cardiomyopathy, so the heart is checked first.