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:

Glycogen storage disease type V
ICD-10	E74.0
ICD-9	271.0
OMIM	232600
DiseasesDB	5307
eMedicine	med/911
MeSH	D006012

Overview

Glycogen storage disease type V is a metabolic disorder, more specifically a glycogen storage disease, caused by a deficiency of myophosphorylase.

GSD type V is also known as McArdle's disease or muscle phosphorylase deficiency. The disease was first reported in 1951 by Dr. Brian McArdle of Guy's Hospital, London.

People with this disease experience difficulty when their muscles are called upon to perform relatively brief yet intense activity. The inability to break down glycogen into glucose results in an energy shortage within the muscle, resulting in muscle pain and cramping, and sometimes causing serious injury to the muscles. The typical features of McArdle disease include exercise intolerance with myalgia, early fatigue, and stiffness of exercising muscles, which are sometimes relieved by rest. Following a short period of rest, most patients experience a second wind and can resume exercise with less difficulty.The prevailing levels of fatty acids as potential energy sources for muscle may account for the second wind phenomenon. In addition, rhabdomyolysis—the breakdown of muscle tissue—can cause myoglobinuria, a red-to-brown-colored urine. The myoglobinuria can cause kidney damage. The disease is hereditary and is inherited as an autosomal recessive trait. Anaerobic exercise must be avoided but regular gentle aerobic exercise is beneficial.

Historical Perspective

• McArdle's disease 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 Mcardle's disease.

Pathophysiology

• Glycogen storage disease type VI is caused by the deficiency of liver Myophosphorylase.
• Normal function of phophorylase is :-
  • Phosphorylase maintains the glucose homeostasis.
  • It 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 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.
• Muscles are unable to produce energy from glycogen due to deficiency of this enzyme.
• There occurs increase in the Cellular mechanical stress due to :-
  • Accumulation of glycogen stores.
  • Downregulation of sodium-potassium pumps.
  • Elevation of sarcoplasmic calcium.
• All this can 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.

Genetics

• Myophosphorylase deficiency is an autosomal recessive disorder.
• Mutations occurs in the muscle isoform of phosphorylase - PYGM.
• PYGM is located at chromosome 11q13.
• Affected individual carries one normal allele and one pathogenic allele.
• Each pregnancy
  • 25% chance of the baby developing myophosphorylase deficiency by inheriting two alleles containing a pathogenic mutation.
  • 50% are unaffected carriers - one normal allele and one pathogenic allele.
    • Carriers of myophosphorylase deficiency do not become symptomatic.
  • 25% are normal - inheriting two normal copies of the gene.
• Disease severity can be correlated with the genotype at the angiotensin-converting enzyme (ACE) locus.

Causes

• The most common cause of glycogen storage disease type V is the deficiency of muscle myophosphorylase, a muscle isoform of the enzyme glycogen phosphorylase.

• It occurs due to a mutation in the gene PYGM located at chromosome 11q13.

Differentiating Glycogen storage disease type V from Other Diseases

Number	Enzyme deficiency	Eponym	Incidence	Hypo- glycemia?	Hepato- megaly?	Hyperlip- idemia?	Muscle symptoms	Development/ prognosis	Other symptoms
GSD type I	glucose-6-phosphatase	von Gierke's disease	1 in 50,000- 100,000 births	Yes	Yes	Yes	None	Growth failure	Lactic acidosis, hyperuricemia
GSD type II	acid maltase	Pompe's disease	1 in 60,000- 140,000 births	No	Yes	No	Muscle weakness	*Death by age ~2 years (infantile variant)	heart failure
GSD type III	glycogen debrancher	Cori's disease or Forbes' disease	1 in 100,000 births	Yes	Yes	Yes	Myopathy
GSD type IV	glycogen branching enzyme	Andersen disease		No	Yes, also cirrhosis	No	None	Failure to thrive, death at age ~5 years
GSD type V	muscle glycogen phosphorylase	McArdle disease	1 in 100,000	No	No	No	Exercise-induced cramps, Rhabdomyolysis		Renal failure by myoglobinuria
GSD type VI	liver glycogen phosphorylase	Hers' disease	1 in 65,000- 85,000 births	Yes	Yes	No	None
GSD type VII	muscle phosphofructokinase	Tarui's disease		No	No	No	Exercise-induced muscle cramps and weakness	growth retardation	Haemolytic anaemia
GSD type IX	phosphorylase kinase, PHKA2	-		Yes	No	Yes	None	Delayed motor development, Growth retardation
GSD type XI	glucose transporter, GLUT2	Fanconi-Bickel syndrome		Yes	Yes	No	None
GSD type XII	Aldolase A	Red cell aldolase deficiency		?	?	?	Exercise intolerance, cramps
GSD type XIII	β-enolase	-		?	?	?	Exercise intolerance, cramps	Increasing intensity of myalgias over decades	Serum CK: Episodic elevations; Reduced with rest
GSD type 0	glycogen synthase	-		Yes	No	No	Occasional muscle cramping

Epidemiology and Demographics

• The prevalence of McArdle's disease is approximately 1 in 167,000 individuals in spanish community.

•  The prevalence of McArdle's disease is approximately 1 in 100,000 individuals in Texas, USA.
• McArdle's disease 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 VI is a family member with glycogen storage disease type V.

Screening

• There is insufficient evidence to recommend routine screening for mcardle's disease.

• Carrier screening of at-risk relatives may be done.

Natural History, Complications, and Prognosis

Complications

• Mcardle's disease can 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 mcardle's disease,

Prognosis

• Mcardle's disease is a chronic disorder.

Diagnosis

Diagnostic Criteria

There are no established criteria for the diagnosis of glycogen storage disease type V.

History and Symptoms

• Different individuals present uniquely depending on the severity on enzyme activity.
• Some adults can develop:-
  • Progressive proximal 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.

Other Diagnostic Studies

• McArdles disease is genetically heterogeneous.
• Most common mutation that is seen in McArdle's disease is substitution of thymine for cytosine at codon 49.
• In 90% patients, their leukocyte can be used to make diagnosis.
• By doing this muscle biopsy can be avoided.

External links

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

References

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