Glycogen storage disease type V
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# Overview
Glycogen storage disease type V also known as McArdle's disease is caused by the deficiency of myophosphorylase. In 1951, Brian McArdle first described glycogen storage disease type V. It is an autosomal recessive disorder caused by mutation of the gene PYGM which is located on chromosome 11q13. Myophosphorylase is the isozyme of phosphorylase specific to muscles. Its deficiency leads to blockage of carbohydrate metabolic pathways causing accumulation of excess glycogen in the muscles. Muscles are unable to produce energy from glycogen and may lead to rhabdomyolysis. Glycogen storage disease type V commonly affects individuals in the 2nd-3rd decade of their life. There is insufficient evidence to recommend routine screening for glycogen storage disease type V but carrier screening of at-risk relatives may be done. Different individuals present uniquely depending on the severity of enzyme deficiency. Some adults can develop progressive proximal muscle weakness or fixed motor weakness. A "Second-wind phenomenon" can be seen in patients suffering from glycogen storage disease type V. Burgundy-colored urine can be seen after an intense session of exercise due to rhabdomyolysis. On physical examination, persistent weakness and muscle wasting may be seen as the patient ages. Laboratory findings may show elevated levels of creatine kinase levels in almost 90% of patients suffering from glycogen storage disease type V. Forearm exercise test and electromyography are used to diagnose GSD type V. Treatment includes dietary modification and mild to moderate aerobic exercises like walking or bicycling.

# Historical Perspective
- Glycogen storage disease type V was first described by Brian McArdle, a Scottish physician, in 1951.
- In 1993, the first PYGM pathogenic mutations were described.

# Classification
There is no established system for the classification of glycogen storage disease type V.

# Pathophysiology

## Pathogenesis
- Glycogen storage disease type V is caused by the deficiency of liver myophosphorylase.
- Normal function of phophorylase is:
Maintains the glucose homeostasis.
Leads to the degradation of glycogen into glucose-1-phosphate.
Alpha-1,4-glucoside residues are removed from the outer branches of the glycogen molecule.
Degradation is done until glycogen is broken down to branches of approximately 4 glucosyl units.
- Maintains the glucose homeostasis.
- Leads to the degradation of glycogen into glucose-1-phosphate.
- Alpha-1,4-glucoside residues are removed from the outer branches of the glycogen molecule.
- Degradation is done until glycogen is broken down to branches of approximately 4 glucosyl units.
- 3 Isozymes of phosphorylase are found in the muscles, liver, and brain.
- Myophosphorylase is the isozyme specific to muscles.
- Carbohydrate metabolic pathways are blocked which lead to accumulation of excess glycogen in muscles.
- Muscles are unable to produce energy from glycogen due to deficiency of this enzyme.
- There is an increase in the cellular mechanical stress due to:
Accumulation of glycogen.
Downregulation of sodium-potassium pumps.
Elevation of sarcoplasmic calcium.
- Accumulation of glycogen.
- Downregulation of sodium-potassium pumps.
- Elevation of sarcoplasmic calcium.
- This processes may lead to rhabdomyolysis.
- Muscle damage is done due to oxidative stress and purine nucleotide metabolism.
- Hypoglycemia is not seen as liver phosphorylase is not involved.

## Metabolic Pathway

# Causes
- Glycogen storage disease type V is an autosomal recessive disorder.
- Glycogen storage disease type V is caused by the deficiency of the myophosphorylase enzyme. PYGM gene mutation responsible for the myophosphorylase enzyme deficiency is located on chromosome 11q13.
- Disease severity can be  correlated with the genotype at the angiotensin-converting enzyme (ACE) locus.

# Differentiating Glycogen storage disease type V from Other Diseases

# Epidemiology and Demographics
- The prevalence of glycogen storage disease type V is approximately 0.6 in 100,000 individuals in spanish community.
- The prevalence of glycogen storage disease type V is approximately 1 in 100,000 individuals in Texas, USA.
- Glycogen storage disease type V commonly affects individuals in the 2nd-3rd decade of life.

# Risk Factors
- The most potent risk factor in the development of glycogen storage disease type V is a sibling with glycogen storage disease type V.

# Screening
- There is insufficient evidence to recommend routine screening for glycogen storage disease type V.
- Carrier screening of at-risk relatives may be done.

# Natural History, Complications, and Prognosis

## Complications
- Glycogen storage disease type V may have potential anesthetic and perioperative risks.
Malignant hyperthermia
Acute rhabdomyolysis
Myoglobinuria
Acute kidney injury
- Malignant hyperthermia
- Acute rhabdomyolysis
- Myoglobinuria
- Acute kidney injury
- Statin should be used with caution as they can lead to myopathy in individuals suffering from glycogen storage disease type V.

## Prognosis
- Glycogen storage disease type V is a chronic disorder.

# Diagnosis

## Diagnostic Study of Choice

### Forearm exercise test
- Forearm exercise test is of 2 types:
Non-ischemic - preferred type.
Minimally ischemic
- Non-ischemic - preferred type.
- Minimally ischemic
- Normal chemical reactions and products of muscle activity are analysed.
- One-second handgrips are performed every other second for one minute (approximately 30 contractions)
- Blood samples are taken to check for lactate, ammonia, and creatine kinase before starting the test and at 1, 2, 4, 6, 10, 20, and 30 minutes after the end of the exercise.
- A flat venous lactate curve with normal increase in ammonia is diagnostic of myophosphorylase deficiency.
- Earlier blood pressure cuff was used instead of handgrips, but it was stopped because it lead to more muscle pain and acute compartment syndrome.

### Electromyography
- Electromyography of resting muscle are normal.
- No electrical activity during contracture is diagnostic of myophosphorylase deficiency.

## History and Symptoms
- Different individuals present uniquely depending on the severity on enzyme deficiency.
- Some adults can develop:
Progressive proximal muscle weakness.
Fixed motor weakness.
- Progressive proximal muscle weakness.
- Fixed motor weakness.
- Second-wind phenomenon:
When a patient nearing fatigue slows down the intensity of exercise to a certain level, it can be increased again without recurrence of symptoms.
This phenomenon may be due to recruitment of: 
Increased number of motor units
Increased cardiac output
Use of free fatty acids for muscle metabolism
- When a patient nearing fatigue slows down the intensity of exercise to a certain level, it can be increased again without recurrence of symptoms.
- This phenomenon may be due to recruitment of: 
Increased number of motor units
Increased cardiac output
Use of free fatty acids for muscle metabolism
- Increased number of motor units
- Increased cardiac output
- Use of free fatty acids for muscle metabolism
- Burgundy-colored urine can be seen after an intense session of exercise.
This is believed to be due to rhabdomyolysis.
- This is believed to be due to rhabdomyolysis.

## Physical Examination
- Normal muscle strength and reflexes may be seen.
- Persistent weakness and muscle wasting may be seen as the patient ages.

## Laboratory Findings
- Creatine kinase levels are checked in all cases with suspicion of glycogen storage disease.
90% patients suffering from glycogen storage disease type V have elevated levels.
- 90% patients suffering from glycogen storage disease type V have elevated levels.
- Fasting glucose testing is done to rule out hypoglycemia.
- Myoglobinuria
Urine analysis is done to check for it.
It is seen in 50% cases after exercise.
- Urine analysis is done to check for it.
- It is seen in 50% cases after exercise.
- Biochemical assay
Phosphorylase reaction is absent.
- Phosphorylase reaction is absent.

## Other Diagnostic Studies

### Muscle Biopsy
- Muscle biopsy reveals:
Fiber size variability
Positive subsarcolemmal blebs with periodic acid-Schiff stain
Intermyofibril vacuoles
Selective atrophy of type 1 muscle fibers may be seen.
- Fiber size variability
- Positive subsarcolemmal blebs with periodic acid-Schiff stain
- Intermyofibril vacuoles
- Selective atrophy of type 1 muscle fibers may be seen.

# Treatment

## Medical Therapy
- Dietary modification
Higher-carbohydrate diet
High-protein intake
Simple carbohydrates (eg, sucrose) consumption before exercise can help to improve exercise tolerance.
Dietary supplementation with creatine can help to some extent.
- Higher-carbohydrate diet
- High-protein intake
- Simple carbohydrates (eg, sucrose) consumption before exercise can help to improve exercise tolerance.
- Dietary supplementation with creatine can help to some extent.
- Exercise
Mild-to-moderate aerobic exercise like walking, bicycling, or stationary cycling, is beneficial.
Helps to improve cardiovascular fitness and increases muscle oxidative capacity.
Strenuous aerobic exercise should be avoided.
- Mild-to-moderate aerobic exercise like walking, bicycling, or stationary cycling, is beneficial.
- Helps to improve cardiovascular fitness and increases muscle oxidative capacity.
- Strenuous aerobic exercise should be avoided.

## Surgery
- Surgical intervention is not recommended for the management of glycogen storage disease type V.

## Primary Prevention
- Effective measures for primary prevention of glycogen storage disease type 5 include genetic counseling, prenatal diagnosis, and screening.