The GBA gene is a segment of DNA that holds the instructions for building a specialized protein. The proper functioning of this gene is part of the complex system that ensures cellular health.
The Normal Function of the GBA Gene
The GBA gene’s primary responsibility is to provide the instructions for producing an enzyme called glucocerebrosidase, often abbreviated as GCase. This enzyme operates within specific compartments inside cells known as lysosomes. Lysosomes function as the cell’s recycling and waste disposal centers, breaking down various substances into simpler components that can be reused.
Within these recycling hubs, GCase has a specific job: to break down a fatty substance called glucocerebroside. This substance is a normal component of cell membranes. This routine breakdown is a fundamental housekeeping task that prevents the fatty substance from accumulating and interfering with normal cell operations.
GBA Gene Mutations and Gaucher Disease
When the GBA gene has mutations, it can no longer produce a fully functional GCase enzyme. These genetic errors can result in an enzyme that is misshapen, unstable, or produced in insufficient quantities, reducing its ability to break down glucocerebroside.
Consequently, this fatty substance builds up inside the lysosomes of certain cells, particularly in macrophages. This accumulation causes the cells to become swollen and dysfunctional, leading to the condition known as Gaucher disease.
Gaucher disease is the most common lysosomal storage disorder and is categorized into three main types based on the absence or presence of neurological symptoms. Type 1 is the most prevalent form and is characterized by an enlarged liver and spleen, anemia, low platelet counts, and bone problems, including pain and fractures. Type 1 does not involve the primary nervous system.
In contrast, Types 2 and 3 are defined by their impact on the central nervous system. Type 2 is a severe, rapidly progressing form that appears in infancy and involves extensive brain damage. Type 3 has a later onset than Type 2 and a slower progression of neurological symptoms, which can include difficulties with eye movement, coordination, and seizures.
The Link to Parkinson’s Disease and Other Synucleinopathies
The impact of GBA mutations extends beyond Gaucher disease, establishing a connection to certain neurodegenerative disorders. Carrying just one mutated copy of the GBA gene is the greatest known genetic risk factor for developing Parkinson’s disease. It is also linked to a higher risk for related conditions, such as Dementia with Lewy Bodies (DLB), which share common features with Parkinson’s.
A GBA mutation is a risk factor, not a direct cause. Many people with a single GBA mutation will never develop Parkinson’s disease. However, its presence increases the likelihood of the disease appearing, often at an earlier age than in individuals without the mutation.
The link is explained by a “two-way street” of negative influence between GCase and a protein called alpha-synuclein. In Parkinson’s disease, alpha-synuclein clumps together in the brain, forming toxic aggregates called Lewy bodies.
The lysosomal dysfunction caused by a faulty GCase enzyme hinders the cell’s ability to clear out excess alpha-synuclein, promoting its accumulation. Conversely, the buildup of alpha-synuclein further impairs the normal function of the GCase enzyme, creating a feedback loop that accelerates damage to neurons.
Inheritance Patterns and Genetic Testing
The inheritance pattern for Gaucher disease is autosomal recessive, meaning an individual must inherit two mutated copies of the GBA gene—one from each parent—to develop the condition. A person who inherits one normal copy and one mutated copy is known as a carrier. Carriers do not have Gaucher disease but can pass the mutated gene to their children.
Genetic testing for GBA mutations is available and is for individuals with a family history of Gaucher disease or those with symptoms suggestive of the condition. Testing is also relevant for people in certain ethnic populations, such as Ashkenazi Jews, where GBA mutations are more common. Understanding one’s carrier status can be valuable for family planning.
For those who pursue testing, genetic counseling is beneficial. Counselors help individuals and families understand the results, the associated health risks, and the implications for relatives. This guidance allows for informed decisions.
Therapeutic Approaches and Current Research
For individuals with Gaucher disease, effective treatments address the underlying enzyme deficiency. The most established is enzyme replacement therapy (ERT), which involves regular intravenous infusions of a manufactured GCase enzyme. This therapy helps to break down the accumulated glucocerebroside, reducing spleen and liver size and improving bone and blood-related symptoms.
Another approach is substrate reduction therapy (SRT), an oral medication that works by decreasing the body’s production of glucocerebroside, thereby preventing its buildup.
While these therapies are effective for the systemic symptoms of Gaucher disease, they do not cross the blood-brain barrier. They cannot treat the neurological aspects of Types 2 and 3, or the associated risk of Parkinson’s disease. This limitation has spurred research into treatments that can reach the central nervous system.
Scientists are investigating small molecule chaperones that could help stabilize the mutated GCase enzyme, as well as gene therapy approaches aimed at correcting the faulty GBA gene itself. These strategies hold promise not only for Gaucher patients with neurological symptoms but also for Parkinson’s patients whose disease is linked to GBA mutations.