Glycogen storage disease type V

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sargun Singh Walia M.B.B.S.[2]

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

• 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.
• 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.
• 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.

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

Glycogen storage disease			Enzyme deficiency	Genetics			History and symptoms		Physical examination		Laboratory findings	Imaging	Other features
				Gene mutation	Inheritance	Chromosome	Hypoglycemia	Muscle weakness	Hypotonia	Hepatomegaly	Elevated CK	Cardiomegaly
Glycogen storage disease type I	Von Gierke's disease	GSD type Ia	Glucose-6-phosphatase	G6PC gene mutation	Autosomal recessive	17q21	+	+	+	+	-	-	Lactic acidosis Hyperlipidemia Hyperuricemia
		GSD type Ib	Microsomal glucose-6-phosphate transporter	SLC37A4 gene mutation	Autosomal recessive	11q23
Glycogen storage disease type II	Pompe disease	Infantile onset	Alpha acid-glucosidase	GAA gene	Autosomal recessive	17q25	-	+	+	+	+	+	Elevated LDH Elevated liver aminotransferases Elevated urinary glc4
		Late onset			Autosomal recessive		-	+	+	+	+	+/-
Glycogen storage disease type III	Cori disease	GSD type IIIa	Debranching enzyme (deficiency in muscle and liver)	AGL gene mutation	Autosomal recessive	1p21	+	+	-	+	+	+	Ketosis Hyperlipidemia Elevated liver aminotransferases
		GSD type IIIb	Debranching enzyme (deficiency in liver only)		Autosomal recessive
Glycogen storage disease type IV	Andersen's disease		Branching enzyme	GBE1 gene mutation	Autosomal recessive	3p12	+	+	-	+	+	+	-
Glycogen storage disease type V	McArdle disease		Muscle glycogen phosphorylase	PYGM gene mutation	Autosomal recessive	11q13	-	+	-	-	+	-	Myoglobuminuria, may result in renal failure
Glycogen storage disease type VI	Hers' disease	Autosomal	Liver glycogen phosphorylase	PYGL gene mutation	Autosomal recessive	14q22	+/-	+	+/-	+	-	-	Hyperlipidemia Elevated liver aminotransferases
		X-linked			X-linked recessive
Glycogen storage disease type VII	Tauri's disease		Muscle phosphofruktokinase	PFKM gene mutation	Autosomal recessive	12q13	+	+	-	-	+	+	Reticulocytosis Hyperuricemia Myoglobinuria Hemolytic anemia
Glycogen storage disease type IX		GSD type IXa	Phosphorylase b kinase (deficiency in liver only)	PHKA2 gene mutation	X-linked recessive	Xp22	+	-	-	+	-	-	Hyperlipidemia Elevated liver aminotransferases Hyperuricemia Fasting ketosis
		GSD type IXb	Phosphorylase b kinase (deficiency in liver and muscle)	PHKB gene mutation	Autosomal recessive	16q12	+	-	-	+	-	-	Hyperlipidemia Elevated liver aminotransferases
Glycogen storage disease type X			Phosphoglycerate mutase	PGAM2 gene mutation	Autosomal recessive	7p13	-	-	-	-	+	-	Myoglobinuria Gout (tophy) Severe coronary arteriosclerosis
Glycogen storage disease type XI	Lactate dehydrogenase A deficiency		LDH A deficiency	LDHA gene mutation	Autosomal recessive	11p15	-	-	-	-	+	-	Muscle stiffness Lactic acidosis Myoglobinuria Easy fatigue
Glycogen storage disease type XII	Aldolase A deficiency		Aldolase A	ALDOA gene mutation	Autosomal recessive	16p11	-	+	-	+	-	-	Hemolytic anemia Splenomegaly
Glycogen storage disease type XIII			Beta-enolase	ENO3 gene mutation	Autosomal recessive	17p13	-	+	-	-	+	-	-
Glycogen storage disease type XIV			Phosphoglucomutase type 2	PGM1 gene mutation	Autosomal recessive	1p31	+/-	+	-	-	+	-	Elevated liver aminotransferases
Glycogen storage disease type 0	Lewis' disease		Hepatic glycogen synthase	GYS1 gene mutation (muscle) GYS2 gene mutation (liver)	Autosomal recessive	12p12	+	-	-	-	-	-	Fasting hypoglycemia and ketosis Postprandial hyperglycemia and lactic acidosis

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
• 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
• 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.
•  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
• Burgundy-colored urine can be seen after an intense session of exercise.
  • 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.
•  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.
• Biochemical assay
  • 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.

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.
• 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.

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.

External links

• The Association for Glycogen Storage Disease
• The Association for Glycogen Storage Disease (UK)

References

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