Fabry disease is a rare genetic condition caused by mutations in the GLA gene, which contains the necessary information to make the alpha-galactosidase A enzyme. More than 700 mutations have been identified that could be responsible for low or absent alpha-galactosidase A.

As a result of this enzyme deficiency, an intermediate molecule called globotriaosylceramide (Gb3 or Gl-3) builds up inside cells, leading to organ damage.

Inheritance of Fabry disease

Fabry disease is an X-linked condition, meaning that the disease-causing gene passes down to the next generation through the X chromosome. Chromosomes are structures that hold the DNA in a densely packed form in the nucleus of the cells. Every person has two of each chromosome except for the sex chromosomes X and Y.

Women have two X chromosomes, whereas men have one X and one Y chromosome. Girls inherit one X chromosome from each parent; boys inherit the X chromosome from the mother and the Y chromosome from the father. There is a 50 percent chance of each child inheriting the X chromosome carrying the faulty GLA gene from a mother with Fabry disease. Fathers with Fabry disease pass the condition only to their daughters.

Classic Fabry disease

Classic Fabry disease is the most common form and mainly affects men. The first symptoms of this form of the disease usually emerge in childhood or adolescence.

In classic Fabry disease, mutations in the GLA gene cause a form of alpha-galactosidase A that is completely dysfunctional or has very low activity. This results in an excessive build-up of Gb3 and severe tissue damage.

Fabry disease in women

Women have two X chromosomes, but having a mutation in the GLA gene on one of the X chromosomes is sufficient to cause disease symptoms. That is because during early development one of the two X chromosomes in females is inactivated to compensate for the double amount of genes they carry compared to men. This process is random and leaves some cells in the body with the GLA-mutated X chromosome, and other cells with the one carrying the fully functional gene. The type, intensity, and timing of the symptoms vary greatly depending on the number of cells with the GLA mutation in each organ; some women may live their entire life without any signs of disease.

Later-onset (atypical) Fabry disease

Some GLA mutations cause a decreased amount of functional alpha-galactosidase A, resulting in a slower Gb3 build-up in the cells. That is why later-onset Fabry disease is a milder condition and the damage may be confined to a single organ, such as the kidneys or the heart. Patients with this form of Fabry start experiencing symptoms much later in life, or they may never show any symptoms.

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