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Glycogen Storage Disease Type 3, Genetic Testing

Glycogen storage disease type 3 (GSD3), Cori disease or Forbes disease, is a rare genetic disorder affecting glycogen metabolism. It is caused by mutations in the AGL gene, leading to a deficiency of the glycogen debranching enzyme (GDE), which is essential for breaking down glycogen. The disease is caused by mutations in the AGL gene, resulting in a deficit of GDE. The GDE enzyme acts together with the enzyme glycogen phosphorylase during the breakdown of glycogen (a substance our body uses to store glucose). The deficiency can affect the liver and muscles (subtype 3a) or only the liver (subtype 3b). Its prevalence is estimated at approximately 1 case per 100.000 births (may be higher among North Africans).

Glycogen storage disease type 3 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 3 include:

  • Accumulation of Abnormal Glycogen: Due to the deficiency of glycogen debranching enzyme, abnormal glycogen accumulates with long outer branches in various tissues, particularly the liver and muscles.
  • Hepatomegaly (Enlarged Liver): Individuals with GSD3 often present with an enlarged liver (hepatomegaly). The excess glycogen cannot be broken down properly, leading to storage within liver cells.
  • Hypoglycemia (Low Blood Sugar): Similar to other glycogen storage diseases, GSD3 can cause hypoglycemia, especially during fasting or between meals. This can result in symptoms such as weakness, fatigue, and, in severe cases, seizures.
  • Muscle Weakness: GSD3 can lead to muscle weakness and myopathy. Some individuals may experience difficulty with muscle coordination and mobility.
  • Growth Retardation: Children with GSD3 may experience growth retardation and delayed puberty.
  • Cardiomyopathy: In some cases, GSD3 can be associated with developing cardiomyopathy, which affects the heart muscle.
  • Excessive Glycogen in Muscles: In addition to liver involvement, GSD3 can accumulate glycogen in muscle tissues, contributing to muscle-related symptoms.

Diagnosis of Glycogen Storage Disease Type 3 involves clinical evaluation, blood tests, and genetic testing to identify mutations in the AGL gene. Imaging studies, such as ultrasounds or MRIs, may be used to assess liver size and muscle involvement.

Management of GSD3 includes dietary measures to maintain blood glucose levels, including frequent meals, uncooked cornstarch supplementation, and sometimes continuous nocturnal feeds. Regular monitoring of liver function, blood glucose levels, and muscle function is essential.

While GSD3 is a lifelong condition, appropriate management can help individuals lead relatively everyday lives. Early diagnosis and intervention are crucial for optimizing outcomes and preventing complications associated with hypoglycemia, liver enlargement, and muscle-related symptoms. Genetic counseling is essential for affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children.

More Information

GSD3 is caused by mutations in the AGL gene coding for the glycogen debranching enzyme (GDE). The disease is caused by two copies of the same variant (homozygosis) and one copy of two different pathogenic variants in AGL (compound heterozygosis). The severity of symptoms depends on the effect of the variants on the GDE enzyme.

The pathogenic variant c.2039G>A has been described in both homozygotes and compound heterozygotes. The mutation introduces an early stop codon, resulting in a non-functional truncated protein. Its frequency is estimated to be approximately 10% of mutant alleles.

Two variants, c.2590C>T and c.3682C>T, account for approximately 28% of the pathogenic variants identified in individuals of European origin. In both, the nucleotide change produces an early stop codon. As a consequence, a non-functional truncated protein is generated. Cases of patients carrying mutations in homozygosis, heterozygosis, and compound heterozygosis have been observed, although many asymptomatic individuals indicate incomplete penetrance.

Glycogen storage disease type 3 genetic testing analyzes the AGL gene's 12 most frequent pathogenic mutations.

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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