Glycogen storage disease type 2 (GSD2), or Pompe disease, is a rare inherited disorder characterized by the buildup of a complex sugar called glycogen in the body's cells. Pompe disease is caused by mutations in the GAA gene, which provides instructions for making the enzyme acid alpha-glucosidase (GAA). The deficiency or dysfunction of this enzyme leads to glycogen accumulation primarily in the lysosomes, cellular structures responsible for breaking down various substances. The frequency of Pompe disease is approximately 1 case per 40.000 live births, although the incidence may be higher.
Glycogen storage disease type 2 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 2 (Pompe Disease) include:
- Muscle Weakness: Pompe disease primarily affects muscle cells, leading to progressive muscle weakness. This weakness often starts in the legs and later affects other muscles, including those involved in breathing.
- Cardiomyopathy: Glycogen accumulation can also impact the heart muscle, leading to cardiomyopathy. Cardiac involvement is a common feature of Pompe disease and can contribute to respiratory difficulties.
- Respiratory Complications: Weakness of the respiratory muscles can result in respiratory difficulties, including difficulty breathing and decreased lung function. This is a significant concern, particularly in the later stages of the disease.
- Enlarged Heart (Hypertrophic Cardiomyopathy): The heart may enlarge due to glycogen accumulation, leading to hypertrophic cardiomyopathy.
- Infantile-Onset and Late-Onset Forms: Pompe disease can manifest in two primary forms—infantile-onset and late-onset. The infantile-onset form is more severe, typically presenting within the first few months of life and leading to rapid progression of symptoms. The late-onset form can present later in childhood, adolescence, or adulthood, and the progression of symptoms is generally slower.
Diagnosis of Pompe disease involves clinical evaluation, blood tests to measure GAA enzyme activity, and genetic testing to identify mutations in the GAA gene. Imaging studies like echocardiography and muscle biopsies may also contribute to the diagnostic process.
Enzyme replacement therapy (ERT) is an approved treatment for Pompe disease. It involves administering a synthetic form of the missing enzyme (recombinant human acid alpha-glucosidase). ERT aims to reduce the accumulation of glycogen and improve symptoms.
Management of Pompe disease may also involve supportive measures, including respiratory support and physical therapy. Early diagnosis and intervention are critical for optimizing outcomes, particularly in the infantile-onset form.
Genetic counseling is essential for affected individuals and their families to understand the inheritance pattern, assess the risk of having affected children, and explore available treatment options.
More Information
Glycogen storage disease type 2 is caused by homozygous pathogenic variants in the GAA gene that produce a deficiency in the enzyme acid alpha-glucosidase and, in some cases, may be caused by two variants in compound heterozygosis.
More than 500 pathogenic variants in GAA have been described, some of which are predominant in specific populations. The c.-32-13T>G variant reduces acid alpha-glucosidase levels and causes the late-onset form of the disease. The incidence of this variant is higher in Caucasians and has been identified in up to 90% of adult-onset Pompe patients. Another variant, which is quite frequent in late-onset Pompe patients, is c.525del, which in some cases has been observed combined in compound heterozygosity with c.-32-13T>G. For example, the c.525del variant has been found in the Netherlands, Italy, and Colombia.
The c.1935C>A mutation causes a change in a highly conserved amino acid, resulting in a significant reduction in enzyme activity levels. This variant is more frequent in China, Taiwan, and Thailand, although it has also been found in other populations.
The pathogenic variant c.2238G>C has been found in patients with juvenile-onset Pompe and late Pompe. The variant reduces enzyme activity to 10-29%.
Another population-specific variant is c.2560C>T, found predominantly in African American patients.
Glycogen storage disease type 2 genetic testing analyzes the 13 most frequent pathogenic mutations of the GAA 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).
