Alpha galactosidase A (GLA), also known as alpha-Gal A, is a lysosomal hydrolase protein. It operates within the lysosome, the cell’s recycling center. Its function is to break down complex molecules into smaller components that the cell can reuse or excrete. This catabolic process maintains cellular health and prevents the toxic buildup of waste products.
The Enzyme’s Specific Biological Function
The primary biochemical task of alpha galactosidase A is the catabolism of certain glycolipids and glycoproteins. Its main target molecule is globotriaosylceramide (Gb3). The GLA enzyme facilitates a precise chemical reaction: cleaving the terminal alpha-galactosyl residue from the Gb3 molecule, initiating its degradation and recycling within the lysosome.
Without a properly functioning GLA enzyme, this essential step in the metabolic pathway cannot occur efficiently. Failure to perform this cleavage leads directly to the accumulation of undigested Gb3 and its deacylated form, lyso-Gb3, within the lysosomes. This progressive lipid accumulation is the pathological consequence of deficient GLA activity.
The Disease State Resulting from Deficiency
A functional deficiency or total absence of alpha galactosidase A activity causes a progressive condition known as Fabry disease. This condition is classified as an X-linked lysosomal storage disorder. The relentless buildup of Gb3 and lyso-Gb3 in the lysosomes leads to cellular and tissue dysfunction across multiple organ systems.
The kidneys are highly susceptible to damage, often leading to proteinuria, progressive kidney failure, and the eventual need for dialysis or transplantation. Cardiac complications are common, manifesting as cardiomyopathy (thickening of the heart muscle) and arrhythmias due to lipid deposits. Neurological issues include painful episodes, known as Fabry crises, which present as a burning or tingling sensation in the hands and feet.
Other symptoms include angiokeratomas (small, dark red or purple spots on the skin) and decreased ability to sweat, leading to heat intolerance. Since the gene is X-linked, males typically experience a more severe, classical form of the disease. Females can have a highly variable presentation, ranging from largely asymptomatic to developing severe symptoms.
Diagnosis typically begins with a simple enzyme assay, a blood test that measures the level of GLA activity in the plasma or leukocytes. For males, a low or absent enzyme activity level is usually sufficient for a diagnosis of the classical form. However, for females, enzyme activity can sometimes be near-normal, which requires subsequent confirmation through genetic testing to identify the specific mutation in the GLA gene. Early diagnosis is important to begin interventions before irreversible organ damage occurs.
Therapeutic Strategies for Enzyme Replacement
The primary approach to managing the enzyme deficiency in Fabry disease is Enzyme Replacement Therapy (ERT). This treatment involves administering a manufactured, functional version of the alpha galactosidase A enzyme directly into the patient’s bloodstream through intravenous infusion. The goal of ERT is to replenish the missing enzyme, allowing it to be transported to the lysosomes where it can break down the stored Gb3.
The replacement enzyme helps to reduce the accumulation of Gb3 in various tissues and can slow the progression of organ damage, particularly in the kidneys and heart. ERT is typically administered every two weeks. While effective, the treatment requires frequent infusions and can sometimes provoke an immune response.
An alternative option for some patients is pharmacological chaperone therapy (PCT), which uses a small molecule drug to stabilize the patient’s existing, but defective, GLA enzyme. This oral medication binds to the active site of the misfolded enzyme, helping it to fold correctly and avoid premature degradation by the cell’s quality control system. The stabilized enzyme can then successfully traffic to the lysosome, where it regains function and begins to degrade the accumulated Gb3. This therapy is only suitable for patients whose GLA gene mutation results in a misfolded but potentially functional enzyme.
Another emerging strategy is Substrate Reduction Therapy (SRT). SRT works by inhibiting an enzyme involved in the synthesis of Gb3, reducing the overall amount of the fatty substance produced by the body. By limiting the production of Gb3, SRT aims to decrease the substrate load on the deficient GLA enzyme, thereby slowing the rate of accumulation. This approach targets the root of the buildup and offers a complementary or alternative treatment path to ERT and PCT.