Glycogen Storage Diseases for NEET PG: Type, Enzyme Defect and the Clue That Names It

Glycogen storage diseases (GSDs) look like a long list of numbers and eponyms, but each one is a single missing enzyme in the pathway that builds or breaks glycogen. Once you know where that enzyme sits, the organ involved and the clinical picture follow almost on their own. This guide gives you the normal pathway first, then a master table of types, enzymes, organs and clues, then the detail you need for each type.

Key Takeaways

• Liver forms present with fasting hypoglycaemia and hepatomegaly. Muscle forms present with exercise intolerance, cramps and myoglobinuria, or with fixed weakness.

• Von Gierke disease (type I) is glucose-6-phosphatase deficiency: hypoglycaemia, hepatomegaly, lactic acidosis, hyperuricaemia and hyperlipidaemia.

• Pompe disease (type II) is lysosomal acid alpha-glucosidase deficiency: cardiomegaly and hypotonia in infants, proximal weakness and respiratory failure in late-onset disease.

• McArdle disease (type V) is myophosphorylase deficiency: cramps early in exercise, then a "second wind". Tarui disease (type VII) mimics it but has no second wind and adds haemolysis.

• Cori (III) and Hers (VI) disease are milder liver forms. Lactate and uric acid are usually normal in both, which separates them from type I.

• Enzyme replacement therapy is established only for Pompe disease.

Glycogen Metabolism: The Pathway Behind Every Glycogen Storage Disease

Glycogen is a branched glucose polymer with alpha-1,4 chains and alpha-1,6 branch points (Adeva-Andany et al., BBA Clinical 2016). Learn the enzymes in the order the molecule is built and broken down, because every glycogen storage disease is one step of this sequence going wrong.

Building glycogen

Glycogenin primes the chain, and glycogen synthase extends it. The branching enzyme (GBE1) then creates the alpha-1,6 branches (BBA Clinical 2016). A synthase defect gives type 0, and a branching enzyme defect gives type IV.

Breaking glycogen down

Phosphorylase releases glucose-1-phosphate from the chain ends and stops about four residues short of a branch. The debranching enzyme (AGL) then removes those branches (BBA Clinical 2016). A separate route exists inside lysosomes, where acid alpha-glucosidase degrades glycogen. Its absence gives Pompe disease.

In the liver, the final step is glucose-6-phosphatase, which releases free glucose into blood. It is the last step of both glycogenolysis and gluconeogenesis, so losing it causes severe fasting hypoglycaemia (Orphanet J Rare Dis 2011).

Glycogen Storage Diseases Table: Type, Enzyme, Organ and Key Clue

All the types below are autosomal recessive except where marked. Read down the "key clue" column first, then try to rebuild the enzyme and organ columns from memory.

Sources: MedlinePlus Genetics type I, type 0, type III, type IV, type V, type VI, type VII, type IX, and the review Glycogen storage diseases: An update, World J Gastroenterol 2023.

Danon disease (LAMP2 defect, X-linked dominant, formerly called GSD IIb) is a cardiomyopathy-related disorder you only need to recognise by name (Heart Fail Rev 2026).

A memory aid for the eponyms

This is a memory aid, not a fact from a source. The first letters of "Very Poor Carbohydrate Metabolism" give Von Gierke, Pompe, Cori and McArdle, which are types I, II, III and V in order. Type IV, Andersen, fits as "abnormal branching", and Tarui as "muscle plus red cells".

Liver Glycogen Storage Diseases: Von Gierke, Cori, Hers and Type 0

The liver forms share fasting hypoglycaemia and hepatomegaly. The difference between them lies in how severe the hypoglycaemia is and which metabolic by-products pile up.

Von Gierke disease (type I)

Type Ia is glucose-6-phosphatase deficiency. Type Ib is a defect of the glucose-6-phosphate transporter, and Ia accounts for about 80% of GSD I and Ib for about 20% (World J Gastroenterol 2023; Orphanet J Rare Dis 2011). The incidence is about 1 per 100,000.

Because the last step of glycogenolysis and gluconeogenesis is blocked, patients develop hypoglycaemia (seizures can appear from about 3 to 4 months), marked hepatomegaly and renomegaly, a doll-like face with thin limbs, and growth delay. Platelet dysfunction gives a bleeding tendency, and gout can follow later from hyperuricaemia (MedlinePlus; Orphanet J Rare Dis 2011).

The laboratory pattern is the classic quartet: lactic acidosis, hyperuricaemia, hypertriglyceridaemia and hyperlipidaemia, with little or no glycaemic response to glucagon. Transaminases are only mildly raised.

Type Ib adds neutropenia with neutrophil dysfunction, recurrent bacterial infections, oral ulcers and a Crohn-like colitis. G-CSF treats the neutropenia. In a 112-patient multicentre study cited in the 2023 update, G-CSF could be stopped in 55% of patients who took the SGLT2 inhibitor empagliflozin (World J Gastroenterol 2023).

Long-term complications include hepatic adenomas that may turn malignant, glomerular hyperfiltration progressing to renal failure, and pancreatitis. Genetic testing of G6PC and SLC37A4 confirms most cases, so liver biopsy is rarely needed (Orphanet J Rare Dis 2011).

Management centres on avoiding fasting. Infants get frequent daytime feeds and overnight tube feeds, then uncooked cornstarch later. Fructose and galactose are restricted because they cannot be converted to glucose by this route and worsen acidosis. Allopurinol treats hyperuricaemia, an ACE inhibitor treats microalbuminuria, and a statin or fibrate treats persistent hyperlipidaemia. Liver transplant is reserved for poor control or malignant change (World J Gastroenterol 2023).

Cori disease (type III)

Cori disease is debranching enzyme (AGL) deficiency. Phosphorylase cannot trim the outer chains down to the branch point, so abnormal glycogen with short outer branches, called limit dextrin, accumulates (World J Gastroenterol 2023).

About 85% of patients have type IIIa (liver and muscle, including heart) and about 15% have IIIb (liver only) (MedlinePlus). Children have hepatomegaly, hypoglycaemia, hyperlipidaemia and raised transaminases. Hepatomegaly often regresses after puberty, but fibrosis can progress to cirrhosis. In IIIa, expect myopathy, raised CK and cardiomyopathy.

Gluconeogenesis is intact, so the hypoglycaemia is ketotic and milder than in type I. Lactate and uric acid are usually normal, which is the quickest way to separate III from I (World J Gastroenterol 2023). Unlike type I, sucrose, fructose and lactose are not contraindicated. There is no enzyme replacement therapy for type III (Heart Fail Rev 2026).

Hers disease (type VI) and type IX

Hers disease is liver phosphorylase (PYGL) deficiency. It causes hepatomegaly, mild fasting hypoglycaemia with raised ketones and slow growth, though adult height is usually normal. The course is generally benign and improves with age. Lactate, uric acid and CK are normal (MedlinePlus; World J Gastroenterol 2023).

Type IX is phosphorylase kinase deficiency, the enzyme that activates glycogen phosphorylase. Clinically it overlaps with type VI. PHKA2 (liver, X-linked) is the most common form, whereas PHKG2 (liver, autosomal recessive) is more severe with a higher risk of fibrosis and cirrhosis (MedlinePlus). Type IX is the only X-linked entry in the core table.

Type 0

Type 0 is a defect of glycogen synthesis, not breakdown, so liver glycogen is very low. Type 0a gives early-morning ketotic hypoglycaemia without hepatomegaly, which contrasts with type I. After meals, lactate and lipids can rise and postprandial hyperglycaemia is possible. Diagnosis is by GYS2 analysis, and management uses frequent protein-rich meals, bedtime uncooked cornstarch and complex carbohydrates (MedlinePlus).

Pompe Disease: A Glycogen Storage Disease That Is Also a Lysosomal Storage Disease

Pompe disease (type II) is deficiency of lysosomal acid alpha-glucosidase (GAA, acid maltase), so glycogen accumulates inside lysosomes. It is both a glycogenosis and a lysosomal storage disorder (MedlinePlus).

Hypoglycaemia is not a feature, which separates Pompe from the liver forms. Biopsy shows vacuolated, PAS-positive lysosomes in muscle (Heart Fail Rev 2026).

Infantile and late-onset forms

The infantile (classic) form shows hypotonia, hepatomegaly, feeding difficulty and cardiomegaly with massive left ventricular hypertrophy. Untreated, death commonly occurs within the first two years. The ECG shows a short PR interval with very large QRS voltages (Heart Fail Rev 2026).

Late-onset disease is milder and less cardiac. It presents with proximal weakness and respiratory insufficiency from childhood to adulthood. Birth prevalence is 1.0 per 100,000 for infantile-onset and 2.4 per 100,000 for late-onset disease (Heart Fail Rev 2026).

Diagnosis and treatment

Diagnosis combines acid alpha-glucosidase enzyme activity with GAA genetic analysis. Treatment is enzyme replacement therapy with recombinant human GAA. Alglucosidase alfa was the first, approved in 2006 (Biomolecules 2020). Starting early improves survival and cardiac function in infantile-onset disease. Newer options are avalglucosidase alfa and cipaglucosidase alfa given with miglustat (Heart Fail Rev 2026). CRIM-negative patients respond less well because of antibodies (Biomolecules 2020).

Another memory aid: Pompe "trashes the pump", a reminder of the cardiomegaly.

Andersen Disease: The Branching Enzyme Defect

Andersen disease (type IV) is branching enzyme (GBE1) deficiency. The glycogen formed is amylopectin-like polyglucosan with few branches and long outer chains. It is PAS-positive and diastase-resistant, a finding reported in one review (World J Gastroenterol 2023).

In the classic progressive hepatic form, infants are normal at birth and then develop hepatomegaly, progressive cirrhosis, portal hypertension and ascites (MedlinePlus). Without transplant, liver failure develops by about age 5 (Heart Fail Rev 2026). Hypoglycaemia is typically a late sign here, unlike in type I.

Other forms exist: fatal perinatal neuromuscular, congenital muscular, non-progressive hepatic and childhood neuromuscular. Cardiomyopathy is hypertrophic and may progress to dilated. The incidence is about 1 per 600,000 to 800,000. Diagnosis rests on liver biopsy, enzyme assay and GBE1 analysis, and there is no enzyme replacement therapy. Liver transplant is the option for progressive liver disease.

McArdle and Tarui Disease: Muscle Glycogen Storage Diseases

The muscle forms of glycogen storage disease cause exercise intolerance with rhabdomyolysis, or fixed weakness without it (Biomolecules 2024). McArdle and Tarui disease are the two to compare directly.

McArdle disease (type V)

McArdle disease is myophosphorylase (PYGM) deficiency confined to muscle. Patients get fatigue, pain and cramps early in exercise that ease with rest. The "second wind" follows: after a short rest, or about 8 to 10 minutes of sustained aerobic exercise, symptoms settle and heart rate falls (MedlinePlus; Orphanet J Rare Dis 2015).

About half of patients develop rhabdomyolysis with myoglobinuria (red or brown urine), which can damage the kidneys. Resting CK is raised in nearly all patients (BMC Genomics 2017).

The forearm exercise test shows a blunted lactate rise (under about threefold) with a normal ammonia rise. The non-ischaemic version is preferred because the ischaemic test risks contracture and compartment syndrome (Orphanet J Rare Dis 2015). Genetic testing now leads: two pathogenic PYGM variants confirm the diagnosis and muscle biopsy is no longer routine (BMC Genomics 2017; JIMD Reports 2023).

There is no cure. Care means supervised aerobic training and avoiding unaccustomed strenuous, isometric or plyometric effort. In children, 25 g of maltodextrin before exercise reduced rated exertion (JIMD Reports 2023).

Tarui disease (type VII)

Tarui disease is deficiency of muscle phosphofructokinase-1 (PFKM), a glycolytic enzyme. Glycogen accumulates in muscle, and red cell enzyme activity is about 50% reduced, which explains the haemolysis (BBA Clinical 2016).

Patients have exercise intolerance, cramps, nausea and vomiting after strenuous exercise, myoglobinuria with kidney risk, and haemolytic anaemia that can occur alone (MedlinePlus). The forearm test gives a suboptimal lactate rise.

Telling McArdle from Tarui

Sources: Orphanet J Rare Dis 2015, JIMD Reports 2023, BBA Clinical 2016. Memory aid: McArdle is "Muscle, second wind"; Tarui is "muscle plus red cells".

Using the Glycogen Storage Diseases Table to Answer Clinical Stems

When a stem gives you a clue, work from the organ first. Fasting hypoglycaemia with hepatomegaly points to a liver type. Then use lactate and uric acid to split them: raised in type I, usually normal in III and VI (World J Gastroenterol 2023).

If the stem describes a cardiac picture in an infant, think of Pompe. If it describes cramps in a young adult with dark urine after exercise, decide between McArdle and Tarui by the second wind and the haemolysis. Fructose and galactose restriction is specific to type I, and enzyme replacement is established only for Pompe disease.

A useful drill is to draw the glycogen pathway from memory, mark the enzyme blocked in each type, and add the organ and one clue beside it. Compare your sketch with the table above. For more practice with enzymes and carbohydrate metabolism, work through carbohydrate metabolism practice questions, and revisit glycolysis for NEET PG because Tarui disease sits in that pathway.

Conclusion

Glycogen storage diseases reduce to one question: which enzyme in the build-and-break cycle is missing, and which organ depends on it? Liver types give fasting hypoglycaemia and hepatomegaly, muscle types give exercise intolerance, and Pompe disease stands apart as a lysosomal disorder with cardiac involvement and a specific enzyme replacement treatment. Rebuild the master table from memory until the clue, enzyme and organ come to you together.