Ciruolo Michela – Colla Saveria – Diotallevi Margherita
An autosomal recessive inherited type of glycogen storage disease caused by deficiency of myophosphorylase. It results in myalgias, muscle cramping and stiffness, and exercise intolerance.
The Diseases Database
The glycogenosis are rare diseases caused by a deficit of one of the enzymes involved in glycogen metabolism.
In particoular, McArdle syndrome is caused by a defect in a gene (on chromosome 11) that makes
an enzyme called muscular glycogen phosphorylase (PYGM).
Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the
α(1 --> 4) glycosidic linkages of glycogen, releasing glucose-1-phosphate as the reaction product. PYGM is a
homodimeric enzyme subject to allosteric control, and exhibits transitions between "relaxed" (active)
(inhibited) conformations. The active form is called glycogen phosphorylase “a” and its activation is regulated by a specific intracellular cascade that has place in the muscle:
Adrenalin --> Gsa (stimulating G protein) --> ATP --> cAMP --> PKA --> phospohorilase kinase b -->
phosphorilase kinase a --> glycogen --> glucose 1-P --> glycolysis --> muscular contraction
Glycogen phosphorylase activation
Pyridoxal phosphate (PLP), a derivative of vitamin B6 serves as prosthetic group for Glycogen Phosphorylase. Vitamin B6
So, as a result of McArdle disease, the body cannot break down glycogen, which accumulates in the skeletal
This fact inhibits the normal muscolar function: the conversion from glycogen to glucose and the consequent
releasment of ATP, foundamental for muscolar contraction.
McArdle disease was the first metabolic myopathy to be recognized, and it was discovered in 1951 by an english
paediatrician, Brian McArdle (1911-2002).
This disorder affects about 1/100.000 people and its onset is usually noticed in childhood, but often not
diagnosed until the third or fourth decade of life.
We can find people affected by McArdle syndrome all over the World.
The defect on the gene sited on the chromosome 11 can be caused by different kind of mutations, and recent
studies seem to show that the kind and the frequence of these mutations is different in different countries.
Patients suffering from GSDV have muscles that can’t properly metabolize energy. In fact, they may experience
muscolar fatigue, muscle cramps, muscle pain and weakness, and failure during strenuous activities.
exercise, half of individuals presents an important increase of creatine-kinases and rhabdomyolysis, where muscle
cells breakdown, sending their contents into the bloodstream. This disorder is called myoglobinuria, and it is
responsable of burgundy-color urine.
Some patients, may show a phenomenon called “second wind”; it is characterized by the patient’s better
tolerance for aerobic exercise, such as walking and cycling, after approximately 10 minutes. This is attributed
to the combination of increased blood flow and the ability of the body to find alternative sources of energy,
like fatty acids and proteins. In the long term, patients may exhibit renal failure due to the myoglobinuria,
and with age, patients may exhibit progressively increasing weakness and substantial muscle loss.
symptoms don’t appear out of exercise, even if some individuals may present a constant muscolar weakness.
In many cases,
the disease appears in its classic form, but in some situations, patients may present a tender form of the
McArdle disease can be diagnosed in several ways:
• Electromyography (EMG ): a test that checks the health of the muscles and the nerves that control them
• Genetic testing: the genes are sequenced in order to determine the presence of gene mutations.
This type of testing involves bidirectional sequencing of the coding regions of all 20 PYGM exons plus about 50 Bp
of non-coding DNA on each side. These tests require a simple blood draw
• Research of lactic acid and ammonia in blood: this is an ischemic forearm exercise test.
A sphygmomanometer cuff is placed on the patient’s forearm and, puffing up, it occludes the veins, causing
ischemia. In normal conditions, ischemic muscles may produce lactic acid (as a result of glucose metabolism),
but in people affected by McArdle disease, lactate levels are very low. On the contrary, can be noticed
exaggerated rise of ammonia levels. These findings would indicate a severe muscle glycolytic block. Ammonia
arises from the impaired buffering of ADP, which leads to an increase in AMP concentration resulting in an
increase in AMP deamination
• Magnetic resonance imaging ( MRI ): a non invasive way to take pictures of the body
• Muscle biopsy: an invasive method to prove the accumulation of glycogen in muscle and the presence
• Dosage of myoglobin in urine
• Research of creatine kinase in muscle (CK): an increase of CK indicates a glucose deficiency, because
this enzyme is used as the only energy source
GSDV is an autosomal recessive disease, with childhood-onset or adult-onset.
The gene for myophosphorylase, PYGM, is located on chromosome 11q13.
According to the most recent publications, 95 different mutations have been reported. The forms of the
mutations may vary between ethnic groups. For example, the Arg49Stop mutation is most common in North
America and Europe, the R49X mutation is most common in Dutch patients, and the Y84X mutation is most
common among central Europeans.
The exact method of protein disruption has been elucidated in certain mutations. For example, R138W
is known to disrupt to pyridoxal phosphate binding site.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance
of being a carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known
to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes are generally asymptomatic.
It is known the existence of very rare infantil forms, which are rapidly fatal, with hypotonia, muscolar
weakness and progressive respiratory failure.
A specific treatment doesn’t exist, but it’s possible to keep under control the symptoms, avoiding intense
phisycal exercises and resting at the beginning of muscle pain.
A regular and aerobic exercise is important to improve physical performances. In this way, the patient
can use effectively the fatty acids oxidation, in order to obtain energy.
This treatment has to be accompanied by a right diet, which consists of an ingestion of glucose, in particular
through sugar, shortly before a brief physical exercise.
However, recent studies have shown the benefits of some molecules in the treatment of McArdle disease:
• Vitamin B6: it can enhance the residual activity of PYGM and improve insufficient anaerobic glycolysis
of skeletal muscle.
Confirmation of the efficacy of vitamin B(6) supplementation for McArdle disease by follow-up muscle biopsy, 2012
• Creatine: it has to be administered at lower doses, because at higher doses it can cause negative
effects, such as muscular cramping. Creatine
Creatine as a therapeutic strategy for myopaties, 2011