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Glycogen Storage Disease Type 5, Genetic Testing

Glycogen storage disease type 5 (GSD5), or McArdle disease, is a rare genetic disorder affecting glycogen metabolism. It is caused by mutations in the PYGM gene, leading to a deficiency of the enzyme myophosphorylase. Myophosphorylase is essential for breaking down glycogen into glucose within muscle cells. The prevalence of McArdle's disease is estimated at 1 -2 cases per 200.000 people.

Glycogen storage disease type 5 genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Critical features of Glycogen Storage Disease Type 5 include:

  • Exercise Intolerance: Individuals with McArdle disease typically experience exercise intolerance, especially during strenuous or prolonged physical activity. Symptoms may include muscle pain, cramps, and fatigue.
  • Second Wind Phenomenon: One characteristic feature of McArdle disease is the "second wind" phenomenon. After a brief period of rest during exercise, individuals may experience an improvement in muscle function and a reduction in symptoms, allowing them to continue with physical activity.
  • Myoglobinuria: In some cases, intense exercise can lead to the release of myoglobin into the bloodstream, a condition known as myoglobinuria. Myoglobinuria may cause urine to appear dark or reddish-brown.
  • Nocturnal Cramps: Individuals with GSD5 may experience nocturnal cramps, particularly after a day of physical activity.
  • Rhabdomyolysis: In severe cases, repetitive muscle breakdown during physical activity can lead to rhabdomyolysis, which is characterized by releasing muscle proteins into the bloodstream and potentially causing kidney damage.

Diagnosis of Glycogen Storage Disease Type 5 involves clinical evaluation, exercise testing, and genetic testing to identify mutations in the PYGM gene. Exercise testing, such as the forearm ischemic exercise test, can be instrumental in diagnosing McArdle's disease.

Management of GSD5 includes avoiding intense or prolonged physical activity, especially activities that may trigger symptoms. Adequate warm-up and stretching before exercise may help prevent symptoms. Individuals are also advised to consume a diet with sufficient carbohydrates to provide an alternative energy source during exercise.

While GSD5 is a lifelong condition, individuals with McArdle disease can lead relatively everyday lives with proper management. Avoiding strenuous physical activity and understanding one's limitations is essential to the management strategy. Genetic counseling may be offered to affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children.

More Information

The disease is caused by homozygous or compound heterozygous mutations in the PYGM gene, leading to muscle phosphorylase deficiency or myophosphorylase. The enzyme plays a crucial role in skeletal muscle, catalyzing the first reaction in the glycogen degradation pathway. In McArdle's patients, myophosphorylase activity is significantly reduced or virtually absent, resulting in glycogen accumulation leading to muscle damage that is intensified during exercise and intolerance.

More than 150 pathogenic variants have been described in PYGM. The most frequent variant in Caucasians is c.148C>T (p.Arg50Ter), which has been observed in both homozygosis and compound heterozygosis. This variant introduces a stop codon that produces a truncated and non-functional protein. It is a frequent variant in the United Kingdom and North America, accounting for 81% and 63% of alleles, respectively. The c.148C>T variant is also present in Europe, especially in Germany, France, and Spain (where it accounts for 50-55% of alleles) and less frequently in Italy.

The second most frequent mutation in the PYGM gene is c.613G>A (p.Gly205Ser). It represents 10% of alleles in US patients and 9% in Spanish patients.

Glycogen storage disease type 5 genetic testing analyzes the 10 most frequent pathogenic mutations of the PYGM gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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