Glycogen Storage Diseases

Introduction

• Glycogen is the principal storage form of glucose in humans.
• It is a highly branched polysaccharide composed of glucose molecules linked mainly by α-1,4 glycosidic bonds, with branches formed through α-1,6 glycosidic bonds.

The major sites of glycogen storage are:

• Liver
• Skeletal muscle

Liver glycogen

• The primary function of liver glycogen is to help maintain blood glucose concentration, particularly during fasting.

Muscle glycogen

• Muscle glycogen serves mainly as a local energy source for muscle contraction.
• Skeletal muscle cannot normally release free glucose into the circulation because it lacks significant glucose-6-phosphatase activity.
• Normal glycogen metabolism requires several enzymes.
• Genetic defects affecting these enzymes can interfere with glycogen synthesis, degradation, structure, or utilization.
• These inherited disorders are collectively called glycogen storage diseases (GSDs).

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What Is Glycogen Metabolism?

Glycogen metabolism includes two major processes:

1. Glycogenesis

• Glycogenesis is the synthesis of glycogen from glucose.
• Glucose → Glucose-6-phosphate → Glucose-1-phosphate → UDP-glucose → Glycogen
• It occurs mainly after a meal when blood glucose is abundant.

2. Glycogenolysis

• Glycogenolysis is the breakdown of glycogen to provide glucose or energy.
• Glycogen → Glucose-1-phosphate → Glucose-6-phosphate
• In the liver, glucose-6-phosphate can be converted into free glucose and released into the blood.
• In skeletal muscle, glucose-6-phosphate enters glycolysis to generate energy.

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What Are Glycogen Storage Diseases?

Glycogen storage diseases are inherited metabolic disorders caused by defects in enzymes or proteins involved in glycogen synthesis, breakdown, or regulation.

These defects may result in:

• Excessive glycogen accumulation
• Abnormal glycogen structure
• Reduced glycogen breakdown
• Impaired glucose release
• Exercise intolerance
• Hypoglycemia
• Muscle weakness
• Cardiomyopathy
• Hepatomegaly

Most GSDs are inherited in an autosomal recessive manner, although some have different inheritance patterns.

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Classification of Glycogen Storage Diseases

GSDs are commonly classified according to the affected enzyme and the major organ involved.

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Glycogen Storage Disease Type 0

• GSD Type 0 is a rare inherited disorder of glycogen synthesis.
• It is caused by glycogen synthase deficiency.
• Unlike most GSDs, it causes reduced glycogen storage, not glycogen accumulation.

Genetic Defect

• Liver glycogen synthase deficiency: GYS2 gene
• Muscle glycogen synthase deficiency: GYS1 gene

Pathophysiology

Glycogen synthase deficiency

↓

↓ Glycogen synthesis

↓

↓ Hepatic glycogen stores

↓

After meals

• Postprandial hyperglycemia
• Postprandial hyperlactatemia

During fasting

• Hypoglycemia
• Ketosis
• Major Clinical Features

Fasting ketotic hypoglycemia

• Postprandial hyperglycemia
• Possible growth retardation
• Usually no significant hepatomegaly

Laboratory Findings

• ↓ Blood glucose during fasting
• ↑ Ketone bodies
• ↑ Postprandial glucose
• ↑ Lactate after meals may occur
• Reduced glycogen stores

Diagnosis

• Blood glucose and ketone measurement
• Lactate measurement
• Specialized enzyme testing when indicated
• Genetic testing for confirmation

Treatment

• Avoid prolonged fasting
• Frequent meals and snacks
• Adequate carbohydrate intake
• Bedtime carbohydrate snack when indicated
• Close monitoring during illness

High-Yield Point

• GSD Type 0 = Glycogen synthase deficiency → ↓ glycogen storage → postprandial hyperglycemia + fasting ketotic hypoglycemia.

Easy Mnemonic

• “Type 0 = Zero glycogen storage.”

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Von Gierke Disease

• Von Gierke disease is Glycogen Storage Disease Type I (GSD I).
• It is an inherited disorder of glycogen metabolism.
• It is characterized by impaired conversion of glucose-6-phosphate to free glucose.
• It mainly affects the liver and kidneys.
• It causes severe fasting hypoglycemia and excessive accumulation of glycogen in tissues.

Enzyme Defect

GSD I has two major forms:

Type Ia

• Deficiency of glucose-6-phosphatase (G6Pase).
• Caused by pathogenic variants in the G6PC gene.

Type Ib

• Deficiency of the glucose-6-phosphate transporter.
• Caused by pathogenic variants in the SLC37A4 gene.
• Type Ib may additionally cause neutropenia and recurrent infections.

Normal Reaction

Normally:

Glucose-6-phosphate → Glucose

• This reaction occurs mainly in the liver, kidney, and intestine.
• It is essential for maintaining blood glucose during fasting.

Pathophysiology

Glucose-6-phosphatase system deficiency

↓

↓ Conversion of glucose-6-phosphate to glucose

↓

Glucose-6-phosphate accumulates

↓

It is diverted into:

• Glycogen synthesis → glycogen accumulation
• Glycolysis → ↑ lactate
• Lipogenesis → ↑ triglycerides
• Purine metabolism → ↑ uric acid

Therefore:

GSD I → Hypoglycemia + Lactic acidosis + Hyperlipidemia + Hyperuricemia

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Major Clinical Features

A. Severe Fasting Hypoglycemia

• The most important feature.
• Occurs because the liver cannot adequately release glucose during fasting.
• May cause:
  • Irritability
  • Sweating
  • Tremors
  • Seizures in severe cases

B. Hepatomegaly

• Excessive glycogen and lipid accumulation causes marked enlargement of the liver.

C. Renal Enlargement

• Glycogen accumulation may also affect the kidneys.

D. Growth Retardation

• Poor growth and delayed puberty may occur.

E. Doll-like Facial Appearance

• Children may develop characteristic rounded or “doll-like” facial features.

F. Bleeding Tendency

• Platelet dysfunction and metabolic abnormalities can contribute to bleeding in some patients.

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Important Biochemical Abnormalities

1. Hypoglycemia

• Severe fasting hypoglycemia

2. Lactic Acidosis

• ↑ Blood lactate
• Due to increased availability of glucose-6-phosphate for glycolysis.

3. Hyperlipidemia

• ↑ Triglycerides
• ↑ Cholesterol

4. Hyperuricemia

• ↑ Uric acid
• May lead to gout or uric acid nephropathy.

5. Ketosis

• Ketosis may occur during fasting, although the metabolic pattern differs from simple starvation.

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Laboratory Diagnosis

Important investigations include:

• Blood glucose: ↓
• Lactate: ↑
• Triglycerides: ↑
• Cholesterol: ↑
• Uric acid: ↑
• Liver enzymes: may be elevated
• Renal function: assessment when indicated
• Complete blood count: particularly important in suspected Type Ib because of neutropenia

Confirmatory Tests

• Genetic testing is an important confirmatory investigation.
• Enzyme or functional testing may be used in specialized settings.

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Treatment

The main goal is to prevent fasting and maintain normal blood glucose.

Dietary Management

• Frequent meals
• Complex carbohydrates
• Uncooked cornstarch may be used to provide a slow, sustained glucose source.
• Avoid prolonged fasting.

Management of Complications

• Hyperlipidemia management
• Hyperuricemia management
• Renal monitoring
• Monitoring for hepatic complications

Type Ib

• Patients with neutropenia may require specific treatment and monitoring for infections.

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Major Complications

Long-term complications may include:

• Growth retardation
• Delayed puberty
• Gout
• Renal disease
• Osteoporosis
• Hepatic adenomas
• Hepatocellular carcinoma risk
• Pulmonary hypertension in some patients
• Renal dysfunction

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High-Yield Examination Points

• GSD Type I = Von Gierke disease
• Type Ia → Glucose-6-phosphatase deficiency
• Type Ib → Glucose-6-phosphate transporter deficiency
• G6PC → Type Ia
• SLC37A4 → Type Ib
• Main organs: liver and kidney
• Most important feature: severe fasting hypoglycemia
• Hepatomegaly is prominent.
• Lactic acidosis is characteristic.
• Hyperuricemia is characteristic.
• Hyperlipidemia is common.
• Type Ib may cause neutropenia and recurrent infections.

---

Easy Mnemonic

“Von Gierke = Low Glucose, High Lactate, Lipids and Uric acid”

GSD I

→ ↓ Glucose

→ ↑ Lactate

→ ↑ Lipids

→ ↑ Uric acid

→ Hepatomegaly

 

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Pompe Disease

• Pompe disease is Glycogen Storage Disease Type II (GSD II).
• It is a rare inherited disorder caused by deficiency of lysosomal acid α-glucosidase (acid maltase).
• It results in accumulation of glycogen inside lysosomes, particularly in muscle cells.
• The disease mainly affects skeletal muscle, cardiac muscle, and respiratory muscles.

Enzyme Defect

• Deficient enzyme: Lysosomal acid α-glucosidase
• Also called: Acid maltase
• Gene: GAA
• Inheritance: Autosomal recessive

---

Normal Function

Normally, lysosomal acid α-glucosidase breaks down glycogen within lysosomes.

Lysosomal glycogen

↓

Acid α-glucosidase

↓

Glucose

In Pompe disease:

↓ Acid α-glucosidase

↓

↓ Lysosomal glycogen breakdown

↓

↑ Glycogen accumulation inside lysosomes

↓

Muscle cell damage

---

Major Organs Affected

Pompe disease primarily affects:

• Skeletal muscles
• Cardiac muscle
• Respiratory muscles

The pattern and severity of organ involvement depend on the age of onset and residual enzyme activity.

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Clinical Forms

A. Infantile-Onset Pompe Disease

• Usually presents during infancy.
• Severe skeletal muscle weakness
• Hypotonia (“floppy infant”)
• Poor feeding
• Difficulty swallowing
• Delayed motor development
• Hypertrophic cardiomyopathy
• Respiratory muscle weakness
• Respiratory failure may occur

Important feature

Severe infantile Pompe disease is characterized by muscle weakness with prominent cardiac involvement.

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B. Late-Onset Pompe Disease

• May present during childhood, adolescence, or adulthood.
• Progressive skeletal muscle weakness
• Difficulty climbing stairs
• Difficulty running or walking
• Fatigue
• Respiratory muscle weakness
• Reduced exercise capacity

Important feature

• Cardiac involvement is generally less prominent than in classic infantile-onset disease.

---

Pathophysiology

GAA gene defect

↓

↓ Acid α-glucosidase

↓

↓ Lysosomal glycogen degradation

↓

↑ Glycogen accumulation in lysosomes

↓

Lysosomal enlargement and cellular damage

↓

Progressive muscle dysfunction

↓

• Skeletal muscle weakness
• Cardiomyopathy
• Respiratory muscle weakness

---

Major Clinical Features

Muscle

• Progressive muscle weakness
• Hypotonia
• Reduced muscle strength
• Difficulty walking
• Exercise intolerance

Heart

• Hypertrophic cardiomyopathy, particularly in infantile disease
• Cardiomegaly

Respiratory system

• Respiratory muscle weakness
• Reduced respiratory capacity
• Sleep-disordered breathing
• Respiratory failure in severe disease

Feeding

• Poor sucking
• Difficulty swallowing
• Feeding difficulties, especially in infants

---

Laboratory Diagnosis

Important investigations include:

1. Enzyme Activity

• Measurement of acid α-glucosidase activity is central to diagnosis.
• Testing can be performed using blood-based methods and confirmed with appropriate biochemical or genetic studies.

2. Creatine Kinase

• CK may be elevated because of muscle injury.

3. Genetic Testing

• Identification of pathogenic variants in the GAA gene can confirm the diagnosis.

4. Cardiac Evaluation

In infantile disease:

• Echocardiography
• ECG
• Assessment for hypertrophic cardiomyopathy

5. Respiratory Assessment

• Pulmonary function testing
• Assessment of respiratory muscle strength

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Treatment

Enzyme Replacement Therapy

• Enzyme replacement therapy (ERT) is an important disease-specific treatment.
• Recombinant acid α-glucosidase is administered to replace the deficient enzyme.
• Early treatment is particularly important in infantile-onset disease.

Supportive Treatment

Depending on the patient’s needs:

• Respiratory support
• Physiotherapy
• Nutritional support
• Feeding assistance
• Cardiac monitoring
• Multidisciplinary rehabilitation

---

Complications

Possible complications include:

• Progressive muscle weakness
• Respiratory failure
• Cardiomyopathy
• Difficulty swallowing
• Feeding problems
• Reduced mobility
• Contractures
• Sleep-related breathing disorders

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High-Yield Examination Points

• GSD Type II = Pompe disease
• Enzyme: Acid α-glucosidase
• Also called: Acid maltase
• Gene: GAA
• Inheritance: Autosomal recessive
• Location of glycogen accumulation: Lysosomes
• Major tissues affected:
  • Skeletal muscle
  • Cardiac muscle
  • Respiratory muscles
• Infantile form: Hypotonia + hypertrophic cardiomyopathy
• Late-onset form: Progressive skeletal and respiratory muscle weakness
• CK: May be elevated
• Diagnosis: Enzyme activity + genetic testing
• Treatment: Enzyme replacement therapy

---

Easy Mnemonic

“Pompe = Pump + Muscle”

Pompe disease

→ Acid maltase deficiency

→ Lysosomal glycogen accumulation

→ Muscle weakness

→ Cardiomyopathy

→ Respiratory muscle involvement

---

Cori Disease

• Cori disease is Glycogen Storage Disease Type III (GSD III).
• It is an inherited disorder of glycogen breakdown.
• It is caused by deficiency of the glycogen debranching enzyme.
• It results in accumulation of abnormally structured glycogen in tissues.
• The main organs affected are the liver and skeletal muscle.

Enzyme Defect

• Deficient enzyme: Glycogen debranching enzyme
• Gene: AGL
• Inheritance: Autosomal recessive

The debranching enzyme has two important activities:

1. 4-α-glucanotransferase activity
2. Amylo-1,6-glucosidase activity

These activities are required for complete breakdown of glycogen.

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Normal Function

During glycogenolysis:

Glycogen

↓

Glycogen phosphorylase

↓

Glucose-1-phosphate

↓

Debranching enzyme removes branch points

↓

Complete glycogen breakdown

In Cori disease:

↓ Debranching enzyme

↓

Incomplete glycogen breakdown

↓

Abnormal glycogen accumulation

---

Pathophysiology

AGL gene mutation

↓

↓ Debranching enzyme activity

↓

Incomplete glycogen degradation

↓

Accumulation of abnormal glycogen

↓

Mainly affects:

• Liver
• Skeletal muscle
• Heart in some patients

↓

Clinical manifestations

• Hepatomegaly
• Fasting hypoglycemia
• Muscle weakness
• Cardiomyopathy in some patients

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Clinical Features

A. Hepatomegaly

• One of the common clinical features.
• Abnormal glycogen accumulates in the liver.
• The liver may become enlarged.

B. Fasting Hypoglycemia

• Usually less severe than in Von Gierke disease.
• Occurs because glycogen cannot be completely broken down during fasting.
• Ketosis may occur.

C. Muscle Weakness

• Skeletal muscle involvement may cause:
  • Muscle weakness
  • Exercise intolerance
  • Reduced muscle strength
• Muscle involvement is generally more prominent in some subtypes than others.

D. Cardiomyopathy

• Some patients develop hypertrophic cardiomyopathy.
• Cardiac involvement is particularly important in certain forms of GSD III.

E. Growth Retardation

• Poor growth and delayed development may occur, especially in childhood.

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Major Subtypes

GSD III can be broadly divided into:

Type IIIa

• Most common form.
• Affects:
  • Liver
  • Skeletal muscle
  • Heart

Type IIIb

• Mainly affects the liver.
• Skeletal muscle involvement is absent or minimal.

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Laboratory Findings

Important biochemical findings include:

Blood glucose

• Fasting hypoglycemia
• Usually less severe than GSD I.

Ketones

• Ketosis may occur during fasting.

Liver enzymes

• ALT and AST may be elevated.

Creatine kinase

• CK may be increased, particularly when muscle is involved.

Lipid profile

• Hyperlipidemia may occur.

Lactate

• Lactic acidosis is generally less prominent than in GSD I.

---

Diagnosis

Diagnosis is based on clinical findings, biochemical investigations, and genetic testing.

Important investigations

• Blood glucose
• Ketone bodies
• Liver function tests
• Creatine kinase
• Lipid profile
• AGL gene testing

Confirmatory diagnosis

Molecular genetic testing can identify pathogenic variants in the AGL gene.

Enzyme activity testing may also be performed in specialized laboratories.

---

Treatment

Treatment is mainly aimed at maintaining adequate glucose availability and managing complications.

A. Dietary Management

• Avoid prolonged fasting.
• Frequent meals may be recommended.
• Adequate carbohydrate intake is important.
• Uncooked cornstarch may be used in selected patients to provide a sustained glucose source.

B. High-Protein Diet

• A relatively higher protein intake may be beneficial in some patients.
• It can provide substrates for gluconeogenesis and support muscle health.

Dietary management should be individualized by an appropriate metabolic or nutrition team.

C. Management of Muscle Disease

• Physiotherapy
• Appropriate physical activity
• Monitoring of muscle function

D. Cardiac Management

Patients with cardiac involvement require:

• Regular cardiac evaluation
• Echocardiography
• Appropriate management of cardiomyopathy

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Complications

Possible complications include:

• Hepatomegaly
• Fasting hypoglycemia
• Growth retardation
• Muscle weakness
• Cardiomyopathy
• Liver fibrosis or cirrhosis in some patients
• Hepatic adenomas in some patients

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Cori Disease vs Von Gierke Disease

Feature	Cori Disease – GSD III	Von Gierke Disease – GSD I
Enzyme defect	Debranching enzyme	Glucose-6-phosphatase system
Glycogen	Abnormal, partially degraded	Excess accumulation
Hypoglycemia	Usually moderate	Severe
Hepatomegaly	Present	Prominent
Muscle involvement	Common in IIIa	Not a primary feature
Cardiomyopathy	May occur	Not typical
Lactic acidosis	Less prominent	Prominent
Hyperuricemia	Not characteristic	Characteristic
Hyperlipidemia	May occur	Prominent

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High-Yield Examination Points

• GSD Type III = Cori disease
• Also called Forbes disease.
• Enzyme: Glycogen debranching enzyme
• Gene: AGL
• Inheritance: Autosomal recessive
• Main organs:
  • Liver
  • Skeletal muscle
  • Heart in some patients
• Hepatomegaly is common.
• Fasting hypoglycemia occurs but is generally less severe than GSD I.
• Ketosis may occur.
• Muscle weakness and cardiomyopathy may occur.
• Lactic acidosis is less prominent than in GSD I.
• GSD IIIa: liver + muscle ± heart.
• GSD IIIb: predominantly liver.

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Easy Mnemonic

“Cori = Cannot Remove Branches”

Cori disease

→ Debranching enzyme deficiency

→ Incomplete glycogen breakdown

→ Abnormal glycogen accumulation

→ Liver + Muscle involvement

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Andersen Disease

• Andersen disease is Glycogen Storage Disease Type IV (GSD IV).
• It is a rare inherited disorder of glycogen synthesis.
• It is caused by deficiency of the glycogen branching enzyme.
• The defect results in formation of abnormally structured glycogen.
• The liver is commonly affected, but skeletal muscle and the nervous system may also be involved.

Enzyme Defect

• Deficient enzyme: Glycogen branching enzyme
• Gene: GBE1
• Inheritance: Autosomal recessive

Normal function

The branching enzyme creates α-1,6 glycosidic bonds during glycogen synthesis.

It converts:

Long glycogen chains

↓

Branched glycogen

↓

Normal, soluble glycogen structure

In Andersen disease:

↓ Branching enzyme

↓

Poorly branched glycogen

↓

Abnormal glycogen accumulation

---

Pathophysiology

GBE1 gene mutation

↓

↓ Glycogen branching enzyme activity

↓

Reduced formation of α-1,6 branches

↓

Abnormally structured glycogen

↓

Glycogen accumulation in tissues

↓

Progressive tissue damage

The abnormal glycogen resembles polyglucosan and is less soluble than normal glycogen.

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Major Clinical Features

A. Hepatomegaly

• Enlargement of the liver is common.
• Abnormal glycogen accumulates in hepatocytes.

B. Progressive Liver Disease

• Liver dysfunction may develop.
• Progressive hepatic fibrosis can occur.
• Severe cases may develop cirrhosis.

C. Growth Retardation

• Poor growth and failure to thrive may occur.

D. Muscle Involvement

Some patients may develop:

• Muscle weakness
• Exercise intolerance
• Muscle wasting

E. Neuromuscular Involvement

Certain later-onset forms may involve:

• Peripheral nerves
• Skeletal muscle
• Central nervous system

The clinical presentation can therefore vary considerably.

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Clinical Forms

Andersen disease has a broad clinical spectrum.

Classic hepatic form

Usually presents in childhood with:

• Hepatomegaly
• Growth retardation
• Progressive liver dysfunction
• Fibrosis
• Cirrhosis

Neuromuscular forms

Later-onset forms may predominantly involve:

• Skeletal muscle
• Peripheral nerves
• Nervous system

These forms may present with muscle weakness or other neuromuscular manifestations.

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Laboratory Findings

Laboratory abnormalities depend on the severity and organs involved.

Common findings may include:

• ↑ AST
• ↑ ALT
• Abnormal liver function tests
• Evidence of progressive hepatic dysfunction
• Elevated CK when muscle is involved

Hypoglycemia may occur but is generally less prominent than in GSD type I.

---

Diagnosis

Diagnosis involves clinical, biochemical, enzymatic, and molecular evaluation.

Important investigations

• Liver function tests
• Creatine kinase when muscle involvement is suspected
• Glycogen structure/enzyme studies in specialized laboratories
• Genetic testing for GBE1 variants

Confirmatory diagnosis

Identification of pathogenic variants in the GBE1 gene supports confirmation of GSD IV.

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Treatment

• There is currently no simple enzyme replacement therapy equivalent to that used for Pompe disease.
• Treatment is mainly supportive and directed toward complications.

Management may include:

• Nutritional support
• Monitoring of liver function
• Management of liver complications
• Monitoring for muscle and neurological involvement
• Regular cardiac assessment when indicated

Liver transplantation

• Liver transplantation may be considered in selected patients with severe progressive hepatic disease.
• It can address the liver manifestations but does not necessarily correct disease affecting other tissues.

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Complications

Possible complications include:

• Progressive hepatic fibrosis
• Cirrhosis
• Liver failure
• Growth retardation
• Portal hypertension
• Muscle weakness
• Neurological complications
• Cardiomyopathy in some phenotypes

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Andersen Disease vs Cori Disease

Feature	Andersen Disease – GSD IV	Cori Disease – GSD III
Enzyme defect	Branching enzyme	Debranching enzyme
Gene	GBE1	AGL
Main problem	Abnormal glycogen synthesis	Incomplete glycogen breakdown
Glycogen	Poorly branched	Abnormally short/limit-dextrin-like
Liver involvement	Prominent	Prominent
Fibrosis/cirrhosis	Common in severe classic form	May occur
Muscle involvement	Variable	Common in IIIa
Hypoglycemia	Variable	Common
Cardiomyopathy	May occur	May occur

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High-Yield Examination Points

• GSD Type IV = Andersen disease
• Enzyme: Glycogen branching enzyme
• Gene: GBE1
• Inheritance: Autosomal recessive
• Defect causes poorly branched, abnormal glycogen.
• Liver is commonly affected.
• Progressive hepatic fibrosis and cirrhosis are important features.
• Muscle and neurological involvement may occur.
• Hypoglycemia is generally less prominent than in GSD I.
• Diagnosis is supported by genetic testing.
• Severe hepatic disease may require liver transplantation.

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Easy Mnemonic

“Andersen = Abnormal Branches”

Andersen disease

→ Branching enzyme deficiency

→ GBE1 mutation

→ Poorly branched glycogen

→ Liver disease

→ Fibrosis → Cirrhosis

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McArdle Disease

• McArdle disease is Glycogen Storage Disease Type V (GSD V).
• It is an inherited disorder of muscle glycogen breakdown.
• It is caused by deficiency of muscle glycogen phosphorylase (myophosphorylase).
• The disease primarily affects skeletal muscle.
• Patients have difficulty using muscle glycogen during strenuous exercise.

---

Enzyme Defect

• Deficient enzyme: Muscle glycogen phosphorylase
• Also called: Myophosphorylase
• Gene: PYGM
• Inheritance: Autosomal recessive

Normal reaction

Normally:

Glycogen

↓

Muscle glycogen phosphorylase

↓

Glucose-1-phosphate

↓

Glycolysis

↓

ATP production

In McArdle disease:

↓ Myophosphorylase

↓

↓ Glycogen breakdown

↓

↓ Glucose-1-phosphate availability

↓

↓ ATP production during intense exercise

↓

Muscle pain + fatigue + cramps

---

Pathophysiology

• Skeletal muscle depends partly on stored glycogen for rapid energy production during exercise.
• In McArdle disease, muscle glycogen cannot be adequately mobilized.
• This is particularly important during short, intense exercise.
• Reduced availability of glycogen-derived glucose limits ATP generation.
• Muscle fibers may become damaged, resulting in rhabdomyolysis.

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Major Clinical Features

A. Exercise Intolerance

• The most characteristic symptom.
• Symptoms occur particularly during:
  • Sprinting
  • Weight lifting
  • Climbing stairs rapidly
  • Sudden intense exercise

B. Muscle Cramps and Pain

• Patients may develop:
  • Severe muscle cramps
  • Muscle pain
  • Stiffness
  • Early fatigue
• Symptoms usually occur shortly after starting strenuous exercise.

C. Rhabdomyolysis

Severe muscle breakdown can occur.

This may cause:

• Markedly elevated CK
• Release of myoglobin
• Myoglobinuria
• Dark or reddish-brown urine
• Acute kidney injury in severe cases

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Second-Wind Phenomenon

The second-wind phenomenon is a classic feature of McArdle disease.

What happens?

• The patient initially develops:
  • Muscle pain
  • Fatigue
  • Exercise intolerance
• After a short period of rest or reduced-intensity activity, exercise may become easier.

Why?

The muscle begins to use alternative energy sources, including:

• Blood glucose
• Fatty acids

Therefore:

Second-wind phenomenon = improvement in exercise tolerance after a brief period of rest or low-intensity activity.

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Clinical Triggers

Symptoms may be triggered by:

• Sudden strenuous exercise
• Sprinting
• Heavy weight lifting
• Intense physical activity
• Prolonged vigorous exercise

Severe episodes can result in rhabdomyolysis.

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Laboratory Findings

A. Creatine Kinase

• CK is often elevated, sometimes markedly.
• It may remain elevated even between symptomatic episodes in some patients.

B. Myoglobin

• Increased during episodes of muscle injury.
• Myoglobin may appear in urine.

C. Urinalysis

• Myoglobinuria may produce dark urine.
• Urine dipstick may be positive for blood despite few or no red blood cells on microscopy.

D. Lactate Response

• An abnormal lactate response during specialized exercise testing may support the diagnosis.

---

Diagnosis

Diagnosis is based on clinical presentation and confirmatory testing.

Important investigations

• Serum CK
• Urine myoglobin during suspected rhabdomyolysis
• Genetic testing for PYGM
• Specialized exercise testing
• Muscle enzyme testing in selected cases

Genetic confirmation

• Identification of pathogenic variants in the PYGM gene supports the diagnosis.

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Treatment and Management

• There is no simple enzyme replacement therapy currently equivalent to that used for Pompe disease.
• Management focuses on preventing exercise-induced muscle injury.

A. Avoid Sudden Intense Exercise

• Patients should avoid abrupt, maximal-intensity exercise.

B. Gradual Exercise

• Gradual warm-up
• Controlled aerobic activity
• Individualized exercise programs

C. Dietary Strategies

• Appropriate carbohydrate intake before planned activity may benefit some patients.
• Dietary strategies should be individualized.

D. Hydration

• Adequate hydration is particularly important during physical activity and after episodes of muscle injury.

E. Management of Rhabdomyolysis

Severe rhabdomyolysis requires prompt medical treatment to prevent:

• Acute kidney injury
• Electrolyte abnormalities
• Other complications

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Complications

Possible complications include:

• Recurrent muscle cramps
• Exercise intolerance
• Severe muscle injury
• Rhabdomyolysis
• Myoglobinuria
• Acute kidney injury
• Reduced physical activity

---

McArdle Disease vs Pompe Disease

Feature	McArdle Disease – GSD V	Pompe Disease – GSD II
Enzyme	Muscle glycogen phosphorylase	Acid α-glucosidase
Gene	PYGM	GAA
Main location	Cytosol	Lysosome
Main tissue	Skeletal muscle	Skeletal + cardiac muscle
Main problem	Exercise-induced muscle symptoms	Progressive muscle weakness
Cardiomyopathy	Not typical	Common in infantile disease
Rhabdomyolysis	Characteristic	Less typical
Second-wind phenomenon	Characteristic	Not typical

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High-Yield Examination Points

• GSD Type V = McArdle disease
• Enzyme: Muscle glycogen phosphorylase
• Also called: Myophosphorylase
• Gene: PYGM
• Inheritance: Autosomal recessive
• Main tissue affected: Skeletal muscle
• Causes impaired muscle glycogenolysis.
• Major symptoms:
  • Exercise intolerance
  • Muscle cramps
  • Muscle pain
  • Fatigue
• Second-wind phenomenon is a classic clue.
• Severe exercise can cause rhabdomyolysis and myoglobinuria.
• CK is often elevated.
• Genetic testing can confirm the diagnosis.

---

Easy Mnemonic

“McArdle = Muscle cannot Access glycogen”

McArdle disease

→ Myophosphorylase deficiency

→ ↓ Muscle glycogen breakdown

→ ↓ Energy during exercise

→ Muscle cramps + Exercise intolerance

→ Second wind

→ Possible Rhabdomyolysis

---

Hers Disease

• Hers disease is Glycogen Storage Disease Type VI (GSD VI).
• It is an inherited disorder of hepatic glycogen breakdown.
• It is caused by deficiency of liver glycogen phosphorylase.
• The disease primarily affects the liver.
• It generally has a milder clinical course than GSD Type I.

---

Enzyme Defect

• Deficient enzyme: Liver glycogen phosphorylase
• Gene: PYGL
• Inheritance: Autosomal recessive

Normal reaction

Normally:

Glycogen

↓

Liver glycogen phosphorylase

↓

Glucose-1-phosphate

↓

Glucose-6-phosphate

↓

Free glucose

↓

Blood

In Hers disease:

↓ Liver glycogen phosphorylase

↓

↓ Glycogen breakdown

↓

↑ Glycogen accumulation in liver

↓

Hepatomegaly + fasting hypoglycemia

---

Pathophysiology

PYGL gene mutation

↓

↓ Liver glycogen phosphorylase

↓

Impaired hepatic glycogenolysis

↓

↑ Glycogen accumulation in liver

↓

Hepatomegaly

Reduced glucose availability during fasting

↓

Mild fasting hypoglycemia

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Major Clinical Features

A. Hepatomegaly

• One of the most common findings.
• Results from accumulation of glycogen in hepatocytes.

B. Fasting Hypoglycemia

• Usually mild to moderate.
• Occurs because stored liver glycogen cannot be efficiently mobilized during fasting.

C. Ketosis

• Ketotic hypoglycemia may occur during fasting.
• Ketone production increases as the body switches to fatty acid oxidation.

D. Growth Retardation

• Some children may have:
  • Short stature
  • Poor weight gain
  • Delayed growth

E. Elevated Liver Enzymes

• Mild to moderate elevation of ALT and AST may occur.

F. Muscle Involvement

• Muscle involvement is generally absent or mild in classic GSD VI.
• Significant muscle disease should raise consideration of other GSDs.

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Laboratory Findings

Important biochemical findings include:

• ↓ Fasting blood glucose
• ↑ Ketone bodies
• ↑ AST and ALT
• Mild hyperlipidemia may occur
• CK is usually normal unless there is another cause of muscle injury

Important distinction

Hers disease usually causes milder hypoglycemia than Von Gierke disease.

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Diagnosis

Diagnosis is based on clinical, biochemical, and molecular findings.

Important investigations

• Blood glucose
• Blood or urine ketones
• Liver function tests
• Lipid profile
• Genetic testing for PYGL

Confirmatory diagnosis

• Identification of pathogenic variants in the PYGL gene confirms the molecular diagnosis.
• Enzyme activity testing may be performed in specialized laboratories when required.

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Treatment

GSD VI is generally managed conservatively.

A. Avoid Prolonged Fasting

• Regular meals help prevent hypoglycemia.
• Young children may require more frequent meals.

B. Adequate Carbohydrate Intake

• Appropriate carbohydrate intake helps maintain blood glucose.
• Complex carbohydrates may provide sustained energy.

C. Uncooked Cornstarch

• May be used in selected patients to provide a prolonged glucose source, particularly during overnight fasting.

D. High-Protein Diet

• Adequate protein intake may help support gluconeogenesis and growth.
• Dietary management should be individualized.

E. Monitor Growth and Liver Function

Regular monitoring should include:

• Height and weight
• Blood glucose
• Liver enzymes
• Lipid profile
• Clinical assessment of hepatomegaly

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Prognosis

• GSD VI generally has a mild clinical course.
• Symptoms may improve with age.
• Many patients experience improvement in hypoglycemia and hepatomegaly as they grow.
• Severe complications are less common than in GSD Type I.

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Complications

Possible complications include:

• Persistent hepatomegaly
• Fasting hypoglycemia
• Growth retardation
• Delayed puberty
• Hyperlipidemia
• Rarely, progressive liver disease

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Hers Disease vs Von Gierke Disease

Feature	Hers Disease – GSD VI	Von Gierke Disease – GSD I
Enzyme	Liver glycogen phosphorylase	Glucose-6-phosphatase system
Gene	PYGL	G6PC / SLC37A4
Main organ	Liver	Liver + kidney
Hypoglycemia	Mild–moderate	Severe
Hepatomegaly	Present	Prominent
Ketosis	Common	Less characteristic
Lactic acidosis	Usually mild/absent	Prominent
Hyperuricemia	Not typical	Common
Hyperlipidemia	Mild	Prominent
Prognosis	Generally good	More serious

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High-Yield Examination Points

• GSD Type VI = Hers disease
• Enzyme: Liver glycogen phosphorylase
• Gene: PYGL
• Inheritance: Autosomal recessive
• Main organ affected: Liver
• Causes impaired hepatic glycogenolysis.
• Hepatomegaly is common.
• Mild fasting ketotic hypoglycemia is characteristic.
• Mild elevation of AST and ALT may occur.
• Usually has a milder course than GSD Type I.
• Symptoms often improve with age.
• Treatment mainly involves avoiding prolonged fasting and maintaining adequate carbohydrate intake.

---

Easy Mnemonic

“Hers = Hepatic Phosphorylase”

Hers disease

→ PYGL mutation

→ ↓ Liver glycogen phosphorylase

→ ↓ Glycogen breakdown

→ ↑ Liver glycogen

→ Hepatomegaly

→ Mild fasting ketotic hypoglycemia

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Tarui Disease

• Tarui disease is Glycogen Storage Disease Type VII (GSD VII).
• It is an inherited disorder affecting glycolysis and muscle energy metabolism.
• It is caused by deficiency of the enzyme phosphofructokinase-1 (PFK-1).
• The disease mainly affects skeletal muscle and red blood cells (RBCs).
• It causes exercise intolerance, muscle cramps, and sometimes hemolytic anemia.

---

Enzyme Defect

• Deficient enzyme: Phosphofructokinase-1 (PFK-1)
• Muscle isoform: PFKM
• Gene: PFKM
• Inheritance: Autosomal recessive

Normal reaction

PFK-1 catalyzes an important regulatory step in glycolysis:

Fructose-6-phosphate

↓

PFK-1

↓

Fructose-1,6-bisphosphate

↓

Further glycolysis

↓

ATP production

In Tarui disease:

↓ PFK-1 activity

↓

↓ Glycolysis

↓

↓ ATP production

↓

Muscle exercise intolerance

---

Pathophysiology

PFKM gene mutation

↓

↓ Phosphofructokinase-1 activity

↓

Impaired glycolysis

↓

Reduced utilization of glucose and glycogen

↓

Reduced ATP production during exercise

↓

In skeletal muscle

• Exercise intolerance
• Muscle cramps
• Muscle pain
• Rhabdomyolysis

In RBCs

• Reduced glycolytic ATP production
• RBC membrane instability
• Hemolytic anemia

---

Major Clinical Features

A. Exercise Intolerance

• Patients develop difficulty during strenuous physical activity.
• Symptoms may begin during:
  • Running
  • Sprinting
  • Climbing stairs
  • Heavy exercise

B. Muscle Cramps and Pain

• Exercise may cause:
  • Muscle cramps
  • Muscle pain
  • Fatigue
  • Muscle stiffness

C. Rhabdomyolysis

Severe exercise may cause muscle breakdown.

This can lead to:

• ↑ Creatine kinase
• Myoglobin release
• Myoglobinuria
• Dark urine
• Risk of acute kidney injury

5. Hemolytic Anemia

A characteristic feature distinguishing Tarui disease from some other muscle GSDs is hemolytic anemia.

Why?

• RBCs depend entirely on glycolysis for ATP production.
• PFK-1 deficiency reduces glycolytic activity.
• Reduced ATP availability can impair RBC membrane stability.
• This can result in premature RBC destruction.

Findings may include:

• Anemia
• ↑ Reticulocyte count
• ↑ Unconjugated bilirubin
• ↑ LDH
• ↓ Haptoglobin

---

 

Laboratory Findings

Important investigations include:

Muscle-related findings

• ↑ Creatine kinase
• ↑ Myoglobin during muscle injury
• Myoglobinuria after severe exercise

Hemolysis-related findings

• ↓ Hemoglobin
• ↑ Reticulocytes
• ↑ LDH
• ↑ Unconjugated bilirubin
• ↓ Haptoglobin

Specialized testing

• PFK enzyme activity
• Genetic testing

---

Diagnosis

Diagnosis is based on clinical features and confirmatory biochemical or genetic testing.

Important investigations

• Serum CK
• Hemolysis profile
• Urine myoglobin
• Exercise testing where appropriate
• PFKM genetic testing
• PFK enzyme activity assay in specialized laboratories

Confirmatory diagnosis

• Identification of pathogenic variants in the PFKM gene supports confirmation of Tarui disease.

---

Treatment and Management

• There is no widely established enzyme replacement therapy for Tarui disease.
• Management is mainly supportive.

A. Avoid Strenuous Exercise

• Avoid sudden, high-intensity exercise.
• Individualized physical activity is recommended.

B. Gradual Exercise

• Proper warm-up
• Controlled aerobic activity
• Avoidance of sudden intense exertion

C. Nutritional Management

• Adequate nutritional intake is important.
• Dietary management should be individualized.

D. Management of Hemolytic Anemia

• Monitor hemoglobin and hemolysis markers.
• Treat significant anemia and its complications when necessary.

E. Rhabdomyolysis

Severe muscle injury requires prompt medical treatment to reduce the risk of:

• Acute kidney injury
• Electrolyte abnormalities

---

Complications

Possible complications include:

• Exercise intolerance
• Recurrent muscle cramps
• Muscle pain
• Rhabdomyolysis
• Myoglobinuria
• Acute kidney injury
• Hemolytic anemia

---

Tarui Disease vs McArdle Disease

Feature	Tarui Disease – GSD VII	McArdle Disease – GSD V
Enzyme	PFK-1	Muscle glycogen phosphorylase
Gene	PFKM	PYGM
Main defect	Glycolysis	Glycogenolysis
Main tissue	Muscle + RBCs	Skeletal muscle
Exercise intolerance	Yes	Yes
Muscle cramps	Common	Common
Rhabdomyolysis	May occur	Common
Hemolytic anemia	May occur	Not typical
Second-wind phenomenon	Not typical	Characteristic

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High-Yield Examination Points

• GSD Type VII = Tarui disease
• Enzyme: Phosphofructokinase-1 (PFK-1)
• Gene: PFKM
• Inheritance: Autosomal recessive
• Main tissues:
  • Skeletal muscle
  • RBCs
• Causes impaired glycolysis.
• Major clinical features:
  • Exercise intolerance
  • Muscle cramps
  • Muscle pain
  • Rhabdomyolysis
• Hemolytic anemia may occur because RBCs depend on glycolysis for ATP.
• Second-wind phenomenon is not characteristic, unlike McArdle disease.
• CK may be elevated during muscle injury.
• Diagnosis can be confirmed by genetic testing and/or enzyme activity studies.

---

Easy Mnemonic

“Tarui = Trouble in Glycolysis”

Tarui disease

→ PFK-1 deficiency

→ ↓ Glycolysis

→ ↓ ATP

→ Muscle cramps + Exercise intolerance

RBC glycolysis ↓

→ Hemolytic anemia