Alpha-galactosidase A is an enzyme, a protein that speeds up chemical reactions within cells. Its primary purpose is to act as a cellular “housekeeper,” breaking down a specific substance to maintain health. This enzyme is produced based on instructions from the GLA gene, and its proper function is necessary for recycling cellular components.
The Role of Alpha-Galactosidase A in the Body
The main function of alpha-galactosidase A takes place within a cellular compartment called the lysosome. Lysosomes serve as the cell’s recycling centers, where molecules are broken down and their components are repurposed. Within this environment, alpha-galactosidase A catalyzes the breakdown of a fatty substance known as globotriaosylceramide (Gb3).
This enzyme works by breaking the terminal bond of the sugar chain on Gb3. This process is a normal part of recycling cellular materials, particularly from old red blood cells. By continuously breaking down Gb3, alpha-galactosidase A prevents this fatty substance from accumulating, ensuring that cells can function without disruption.
The enzyme’s action is required to keep levels of this substrate low within the lysosomes of all cells. This balance is important for the long-term health and stability of various systems. These include the blood vessels, heart, kidneys, and the nervous system.
Consequences of Enzyme Deficiency
A deficiency of functional alpha-galactosidase A results in a rare genetic condition known as Fabry disease. This disorder occurs because the enzyme is absent, produced in insufficient quantities, or is structurally faulty. The specific mutation in the GLA gene determines the severity of the malfunction, as some mutations cause a more severe form of the disease in childhood.
Without a working enzyme, globotriaosylceramide (Gb3) accumulates inside the lysosomes. This buildup causes the lysosomes to swell, disrupting cellular activities and eventually leading to cell damage. This process happens slowly over many years, affecting cells throughout the body, particularly those lining blood vessels and in major organs. The accumulation obstructs blood flow, which can reduce oxygen and nutrients in surrounding tissues.
The progressive accumulation of Gb3 leads to the signs and symptoms of Fabry disease. Individuals may experience severe pain in their hands and feet, especially during fever or exercise. Another common sign is the appearance of small, dark red spots on the skin called angiokeratomas. Over time, Gb3 storage can lead to health complications, including progressive kidney disease, an enlarged heart, and an increased risk for heart attack and stroke.
Diagnosis of a Deficiency
Diagnosing a deficiency in alpha-galactosidase A involves biochemical testing and genetic analysis. The initial step is an enzyme assay on a blood sample, which measures the enzyme’s activity level in white blood cells. In males, a significantly low level of enzyme activity is generally sufficient to confirm a diagnosis of Fabry disease.
For females, however, enzyme assays can be misleading. Because the GLA gene is inherited on the X chromosome, female carriers may show a wide range of enzyme activity, from very low to nearly normal levels. This makes the assay less reliable, so genetic testing is the definitive method for diagnosis in females and for confirming the mutation in males.
Genetic testing analyzes the DNA sequence of the GLA gene to identify the exact mutation responsible for the faulty enzyme. Identifying the specific genetic change provides a conclusive diagnosis and helps predict the disease’s potential severity. This testing is also valuable for family planning and for identifying other family members who may be carriers but do not yet show symptoms.
Therapeutic Approaches
The primary treatment for alpha-galactosidase A deficiency is enzyme replacement therapy (ERT). This therapy addresses the root cause of the disease by replacing the missing enzyme with regular intravenous infusions of a manufactured version. This bioengineered enzyme is designed to function like the natural one, traveling through the bloodstream to the body’s cells.
Once inside the cells, the replacement enzyme is taken up by the lysosomes, where it breaks down the accumulated globotriaosylceramide (Gb3). With continued use, ERT can reduce the amount of Gb3 stored in the cells of the heart, kidneys, and liver. This process helps to slow the disease’s progression, alleviate some symptoms like pain, and reduce the risk of organ damage over the long term.
Chaperone therapy offers an alternative for some patients. This approach uses small molecules that act as “chaperones” instead of replacing the enzyme. These molecules are for patients who produce a misfolded enzyme that could still be functional. The chaperone drug binds to the patient’s misfolded enzyme, helping it fold correctly and stabilizing it for transport to the lysosome.