Why Do Women Need Genetic Testing for Fabry Disease?

Fabry disease is diagnosed differently in men and women because of how the condition is inherited on the X chromosome ^[1]. While a simple blood test measuring the alpha-galactosidase A (alpha-Gal A) enzyme is usually enough to diagnose a man, this same test is highly unreliable in women ^[2]. Because women have two X chromosomes, their bodies can often produce enough of the enzyme to make blood tests appear normal, even when they have the disease ^[3][4]. Therefore, genetic testing—specifically sequencing the GLA gene—is required to definitively confirm or rule out Fabry disease in females ^[5].

The Role of X Chromosomes and Enzyme Levels

Fabry disease is an X-linked disorder, meaning the genetic mutation that causes it is located on the GLA gene of the X chromosome ^[6].

Men have one X and one Y chromosome. If a man inherits the X chromosome with the mutated GLA gene, his body will produce little to no alpha-Gal A enzyme ^[5][7]. Because this enzyme deficiency is profound and easily detectable, an enzyme assay (blood test) is a highly sensitive and reliable way to diagnose affected men ^[8].

Women, however, have two X chromosomes. During early development, a natural process called X-chromosome inactivation (or lyonization) randomly “turns off” one X chromosome in every cell to prevent a double dose of genetic instructions ^[9]. If a woman has one healthy X chromosome and one with the Fabry mutation, her body becomes a mosaic ^[10]. Some cells will use the healthy gene and produce normal amounts of the enzyme, while other cells will use the mutated gene and produce none ^[11].

Why Normal Enzyme Levels Don’t Rule Out Fabry

Because of this mix of normal and affected cells, the functional X chromosomes can often produce enough alpha-Gal A enzyme to make a standard blood enzyme assay look completely normal ^[9]. In fact, a significant percentage of female patients—with some studies showing up to 70%—have enzyme levels that fall within the normal reference range despite having a confirmed GLA gene mutation ^[2][3][4].

Relying solely on enzyme levels can lead to missed or delayed diagnoses in women, falsely reassuring them that they do not have Fabry disease ^[2].

The Definitive Diagnostic Approach for Women

Because enzyme tests are unreliable for women, current medical guidelines recommend genetic testing (GLA gene sequencing) as the primary and essential tool for diagnosing females ^[12][5]. Genetic testing bypasses the enzyme levels entirely and looks directly at the patient’s DNA to see if the disease-causing mutation is present ^[13].

What to Expect: Genetic testing is typically performed using a simple blood draw or saliva sample. If a family member (such as a brother or father) has already been diagnosed, your doctor can order a “targeted” genetic test that specifically looks for the known mutation in your family. Results generally take a few weeks to come back.

If genetic test results are ambiguous, or to better understand how the mutation is affecting the body, doctors often test for a biomarker called plasma lyso-Gb3 ^[14]. Lyso-Gb3 is a type of fat that builds up in the blood when the alpha-Gal A enzyme isn’t working properly. While this biomarker is much more sensitive than the standard enzyme test for females, it is important to note that lyso-Gb3 levels can still be completely normal in some women, particularly those with late-onset variants of the disease ^[15][16]. Because of this, a normal lyso-Gb3 result does not completely rule out Fabry in women, reinforcing why the genetic test remains the ultimate gold standard ^[12].

Receiving a positive diagnosis can be overwhelming, but confirming the presence of the GLA mutation is the first step toward specialized care. Today, there are specific disease-modifying therapies and management options available that can help protect your organs and improve your quality of life ^[12].