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Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.
Pompe’s disease, also known as glycogen storage disease type II, is a rare lysosomal storage disorder characterized by the accumulation of glycogen in various tissues, particularly in muscle cells.
Glycogen is a way for your body to store energy. Like a “backup battery” that is made from glucose, the sugar our cells use for energy. When we eat carbohydrates, our body breaks them down into glucose, and any extra glucose is stored as glycogen in the liver and muscles. When your body needs quick energy, like during exercise or between meals, it breaks down glycogen back into glucose to fuel your cells.
Glycogen accumulation results from a deficiency of the enzyme alpha-glucosidase (GAA). This enzyme is crucial for glycogen breakdown within cell organelles called lysosomes. Lysosomes are like your cell’s digestive system. Pompe’s disease manifests in a spectrum ranging from severe infantile-onset forms to milder late-onset forms. Understanding the genetic basis of this condition is essential for proper diagnosis, genetic counseling, and the development of targeted therapies.
Pompe’s disease is an inherited metabolic disorder first described by Dr. Johannes Pompe in 1932. It is part of a group of diseases known as glycogen storage disorders, specifically type II. This disease affects individuals of all ethnic backgrounds and has an estimated incidence of 1 in 40,000 births globally. The clinical presentation varies widely, making genetic analysis a critical component of diagnosis and management.
The root cause of Pompe’s disease lies in mutations of the GAA gene located on chromosome 17q25.3. This gene encodes the enzyme lysosomal alpha-glucosidase (GAA), also known as acid maltase. GAA is responsible for breaking down glycogen in the lysosomes into glucose. In the absence or deficiency of functional GAA, glycogen accumulates within lysosomes, leading to cellular dysfunction and damage, particularly in cardiac and skeletal muscle tissues.
The level of residual GAA enzyme activity correlates with the severity of the disease. Patients with less than 1% of normal enzyme activity typically present with the classic infantile-onset form, characterized by hypertrophic cardiomyopathy, muscle weakness, and failure to thrive. Those with higher residual activity may present later in life with milder symptoms predominantly involving skeletal muscles.
To date, over 500 mutations in the GAA gene have been identified. These mutations include missense, nonsense, splicing, small insertions or deletions, and large deletions or rearrangements. Common mutations vary among different populations due to founder effects and genetic drift.
A common splice-site mutation prevalent in European populations associated with late-onset Pompe’s disease (LOPD). This mutation is present in up to 90% of this population. It disrupts mRNA splicing, leading to non-functional enzyme forms. However some normal mRNA is produced, which may explain the delayed symptoms in LOPD.
In a large retrospective study analyzing 30,836 suspected Pompe’s disease cases from 57 countries using dried blood spots, GAA enzyme activity was tested biochemically, and genetically suspicious cases underwent genetic sequencing. A total of 723 Pompe cases were identified, with 283 GAA gene alterations, including 98 previously unpublished variants. The most common mutation was c.-32-13T>G, often found in compound heterozygous late-onset cases. Homozygous mutations were more common in infantile-onset cases, with missense variants enriched in GAA’s catalytic domain.
The c.1935C>A mutation is the most common GAA pathogenic mutation in Southern Han Chinese populations and causes infantile-onset Pompe’s disease (IOPD), presenting with life-threatening symptoms in newborns. In 2022 researchers created a mouse model with this mutation using CRISPR-Cas9 to study the disease. These mice showed muscle weakness, heart enlargement, and glycogen buildup but no early death, mimicking key features of IOPD. This model is valuable for testing new treatments to restore GAA activity and improve symptoms.
Pompe’s disease follows an autosomal recessive inheritance pattern. This means that an affected individual needs to have inherited two defective copies of the GAA gene, one from each parent. Carriers, possessing one normal and one mutated allele, are typically asymptomatic but have a 25% chance of having an affected child if both parents are carriers.
Diagnosis often involves a combination of biochemical assays and molecular genetic testing.
Several countries have incorporated Pompe’s disease into their newborn screening programs, enabling early detection and intervention.
Understanding the genetic mutations in Pompe’s disease has direct implications for treatment strategies.
In ERT a recombinant form of human GAA enzyme is administered intravenously. ERT for Pompe’s disease has been shown to improve cardiac and motor functions, particularly when initiated early.
Recent advancements for Pompe’s disease treatment and monitoring include:
Pompe’s disease exemplifies the critical role of genetics in understanding, diagnosing, and treating metabolic disorders. Ongoing research continues to unveil the complexities of GAA gene mutations and their phenotypic presentations. Advances in genetic therapies hold promise for more effective and personalized treatments, offering hope to those affected by this challenging condition.
