Fabry disease is a rare genetic disease caused by mutations in the GLA gene. This gene provides cells with the instructions necessary to make an enzyme called alpha-galactosidase A, which is responsible for breaking down fat molecules. When the GLA gene is mutated, not enough alpha-galactosidase A enzyme is made. As a result, a waste product called globotriaosylceramide (Gb3 or Gl-3) builds up inside cells, causing tissue and organ damage.
The two main types of Fabry disease are type 1 (classic Fabry disease), and type 2 or late-onset Fabry disease.
Type 1 or classic Fabry disease
Patients with classic Fabry disease have little to no functional alpha-galactosidase A enzyme. This deficiency causes lipid wastes to accumulate in patients’ small blood vessels during childhood and adolescence, which causes excruciating pain in the hands and feet, especially as a result of exercise, fever, or stress (also called acroparesthesias); clusters of red to blue rash-like discolorations on the skin (also called angiokeratomas); decreased sweating; gastrointestinal symptoms such as pain, cramping, and frequent bowel movements; and a characteristic star-burst pattern on the cornea (the clear part over the lens of the eye).
As patients age, the accumulation of lipid waste products in the blood vessels can lead to arrhythmias, left ventricle hypertrophy causing heart disease, progressive kidney failure, transient ischemic attacks, and strokes.
Type 2 or late-onset Fabry disease
Patients with type 2 Fabry disease have some residual alpha-galactosidase A enzyme activity and so there is a slower accumulation of lipid wastes inside their cells. They generally have a normal childhood and adolescence, with heart and kidney disease symptoms appearing sometime between the ages of 30 and 70.
Women with Fabry disease
Fabry disease is an X-linked disorder — meaning that the gene that is mutated is carried on the X chromosome — and is much more common among men than women. Because men have only one X chromosome, if that chromosome contains a mutation in the GLA gene, they will develop classic or late-onset Fabry disease, depending on the type of mutation.
For women, the situation is more complicated. Even if a woman inherits a copy of a mutated GLA gene, she may never develop Fabry disease because she has a second healthy copy of the gene on her other X chromosome, which can compensate for the mutation. However, during development, a biological phenomenon called X-chromosome inactivation can occur: If the chromosome that carries the healthy copy of the GLA gene is inactivated in most cells of a woman’s body, she may develop classic or late-onset Fabry disease.
Last updated: Oct. 8, 2019
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