Glycogen storage disease type 1A (GSD-1A), also known as Von Gierke disease, is a rare genetic disorder that belongs to a group of conditions known as glycogen storage diseases. GSD1A specifically results from a deficiency of the enzyme glucose-6-phosphatase, which plays a crucial role in glucose metabolism. The prevalence of GSD-1A is 1 case per 100,000 individuals, and it is more common in the Ashkenazi Jewish population.
Glycogen storage disease type 1A 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 1A include:
- Impaired Glucose Production: The deficiency of glucose-6-phosphatase impairs the conversion of glucose-6-phosphate to glucose in the liver. This leads to an inability to release glucose into the bloodstream during periods of fasting.
- Hypoglycemia: Individuals with GSD1A experience hypoglycemia (low blood sugar), especially during fasting or between meals. This can lead to weakness, fatigue, irritability, and, in severe cases, seizures.
- Enlarged Liver: Due to excessive glycogen accumulation in the liver, individuals with GSD1A often have an enlarged liver (hepatomegaly). The excess glycogen cannot be converted back to glucose, leading to storage within the liver cells.
- Elevated Blood Lactic Acid: In the absence of glucose production, the body resorts to alternative energy pathways, leading to increased lactic acid production. Elevated blood lactic acid levels can contribute to metabolic acidosis.
- Hyperlipidemia: An increased production of triglycerides and cholesterol leads to hyperlipidemia (elevated levels of fats in the blood).
- Hyperuricemia: The increased breakdown of purines from stored glycogen results in elevated uric acid levels in the blood, leading to hyperuricemia.
Management of Glycogen Storage Disease Type 1A involves a carefully controlled diet that includes frequent meals and nocturnal feeding to prevent prolonged fasting. The goal is to maintain blood glucose levels and to avoid hypoglycemia. Uncooked cornstarch is often used as a slow-release glucose source during fasting periods. Medications may also be prescribed to help manage specific aspects of the condition.
Regular monitoring, including blood glucose levels, liver function, and metabolic parameters, is essential for individuals with GSD1A. Genetic counseling is necessary for affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children.
While GSD1A 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 and metabolic abnormalities.
More Information
GSD-1A is caused by pathogenic variants in the G6PC1 gene encoding for the alpha subunit of glucose-6-phosphatase.
Glucose-6-phosphatase is located in the membrane of the endoplasmic reticulum and, together with the glucose-6-phosphate transporter, known as SLC37A4, forms a molecular complex responsible for glucose production by catalyzing the final step of glycogenolysis and gluconeogenesis. Therefore, glucose-6-phosphatase is a critical enzyme in regulating blood glucose levels, and its disruption results in the pathogenic accumulation of glycogen and fat in the liver.
Pathogenic variants in SLC37A4 are responsible for glycogenosis type 1B (GSD-1B), which is also analyzed in Diagnostiki Athinon. Approximately 80% of people with GSD I have type IA, and 20% have type IB.
Up to 100 pathogenic variants in G6PC1 are currently known. Although the disease follows an autosomal recessive mode of inheritance, it has been shown that there are variants that can produce the disease in compound heterozygosis. The most frequent variants in Ashkenazi Jews are c.247C>T and c.1039C>T, while the predominant G6PC1 mutation in East Asian populations is c.648G>T. The c.248G>A variant is common in patients from China, accounting for 38% of alleles.
The c.247C>T mutation in turn has been observed in patients with different ethnic origins both in homozygosis and compound heterozygosis. This variant produces an amino acid change that alters the secondary structure of the enzyme and significantly reduces its activity. c.247C>T accounts for 32% of mutant alleles of European origin and 93-100% in Ashkenazi Jews.
The c.1039C>T variant produces an early stop codon, resulting in a non-functional truncated protein. This mutation accounts for 22% of mutant alleles in the Caucasian population.
Glycogen storage disease type 1A genetic testing analyzes the 15 most frequent pathogenic mutations of the G6PC1 gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
