[5] In the classic phenotype, the onset of this disease is usually noticed in childhood,[6][7][8] but often not diagnosed until the third or fourth decade of life, frequently due to misdiagnosis and dismissal of symptoms.

[6][8] There is an ultra-rare adult-onset, limb–girdle phenotype that presents very late in life (70+ years of age) due to a recessive homozygous PYGM mutation (p. Lys42Profs*48) resulting in severe upper and lower limb atrophy, with the possibility of ptosis (drooping eyelids) and camptocormia (stooped posture).

[9] In 1980, a woman also had a limb–girdle phenotype with onset at age 60, histochemical staining showed myophosphorylase deficiency; however the genetic mutation was unknown.

[10] There is an ultra-rare, fatal infantile-onset phenotype that results in profound muscle weakness ("floppy baby") and respiratory failure within weeks of birth (perinatal asphyxia).

Post-mortem biopsy showed a deficiency of myophosphorylase and abnormal glycogen accumulation in skeletal muscle tissue.

Heart rate during exercise is a key indicator as, unlike the symptoms of muscle fatigue and cramping, it is a medical sign (meaning that it is observable and measurable by a third party rather than felt subjectively by the patient).

In regularly active individuals with McArdle disease, they may not feel the usual symptoms of muscle fatigue and cramping until they increase their speed to very brisk walking, jogging, or cycling; however, they will still show an inappropriately rapid heart rate response to exercise, with a declining heart rate once second wind has been achieved.

[25][24] Younger people may display unusual symptoms, such as difficulty chewing, swallowing, or utilizing normal oral motor functions.

[18][32] They may exhibit a "second wind" phenomenon, which is characterized by the individual's better tolerance for aerobic exercise such as walking and cycling after approximately 10 minutes.

Along with the myokinase reaction, AMP is also produced by the purine nucleotide cycle, which also runs when the ATP reservoir in muscle cells is low, and is a part of protein metabolism.

GSD-V patients may experience myogenic hyperuricemia (exercise-induced accelerated breakdown of purine nucleotides in skeletal muscle).

These require urgent assessment for rhabdomyolysis as in about 30% of cases this leads to acute kidney injury, which left untreated can be life-threatening.

[citation needed] Myophosphorylase is the form of the glycogen phosphorylase found in muscle that catalyses the following reaction:[41][42][43] ((1→4)-alpha-D-glucosyl) (n) + phosphate = ((1→4)-alpha-D-glucosyl) (n-1) + alpha-D-glucose 1-phosphate During exercise, a deficiency of this enzyme ultimately leads to rapid depletion of phosphocreatine, a decrease in available ATP, and an exaggerated rise of ADP and AMP.

The enzyme removes 1,4 glycosyl residues from the outer branches of glycogen and adds inorganic phosphate to form glucose-1-phosphate.

Ordinarily, the removal of 1,4 glycosyl residues by myophosphorylase leads to the formation of glucose-1-phosphate during glycogen breakdown and the polar, phosphorylated glucose cannot leave the cell membrane and so is marked for intracellular catabolism.

In McArdle's disease, deficiency of myophosphorylase leads to the accumulation of intramuscular glycogen and a lack of glucose-1-phosphate for cellular fuel.

Findings consistent with McArdle's disease would include a failure of lactate to rise in venous blood and exaggerated ammonia levels.

Serum lactate may fail to rise in part because of increased uptake via the monocarboxylate transporter (MCT1), which is upregulated in skeletal muscle in McArdle disease.

This can help distinguish McArdle's syndrome from carnitine palmitoyltransferase II deficiency (CPT-II), a lipid-based metabolic disorder that prevents fatty acids from being transported into mitochondria for use as an energy source.

If rhabdomyolysis is suspected, serum myoglobin, creatine kinase, lactate dehydrogenase, electrolytes, and renal function will be checked.

The 12 Minute Walk Test (12MWT) can be used to determine "second wind," which requires a treadmill (no incline), heart rate monitor, stopwatch, pain scale, and that the patient has rested for 30 minutes before the test to ensure that "second wind" has stopped (that is, that increased ATP production primarily from free fatty acids has returned to resting levels).

[20][52] Electromyography (EMG) may show normal or myopathic results (short duration, polyphasic, small amplitude MUAPs).

[58] This is because the ingestion of a high-carbohydrate meal or drink causes transient hyperglycaemia, with the exercising muscle cells utilizing the high glucose in the blood for the glycolytic pathway.

[19] The frequent ingestion of sucrose (e.g. sugary drinks), to avoid premature muscle fatigue and cramping, is also problematic in that it can lead to obesity as insulin will also stimulate triglyceride synthesis (develop body fat),[59] and obesity-related ill health (e.g. type II diabetes and heart disease).

The deficiency was the first metabolic myopathy to be recognized when the physician Brian McArdle described the first case in a 30-year-old man who always experienced pain and weakness after exercise.

McArdle noticed this patient's cramps were electrically silent and his venous lactate levels failed to increase upon ischemic exercise.

[65] McArdle accurately concluded that the patient had a disorder of glycogen breakdown that specifically affected skeletal muscle.