The body performs thousands of metabolic processes, which are necessary for the production of vital compounds and the recycling or removal of others. One such compound — globotriaosylceramide is formed of three sugars and a fatty substance, ceramide — is found in most cells of the body. Normally globotriaosylceramide is metabolized into lactosylceramide by the enzyme a-galactosidase A.
In patients with Fabry disease, this enzyme either does not function properly or is absent, and globotriaosylceramide cannot be broken down in cells, leading to its progressive accumulation. Fabry disease is a storage disorder because of the abnormal accumulation of globotriaosylceramide. In patients with Fabry disease, globotriaosylceramide accumulates preferentially in the walls of blood vessels. As the abnormal storage of this fatty compound increases with time, the channels of these vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally fed by these vessels. This process occurs in all blood vessels throughout the body, but particularly affects small vessels in the skin, kidneys, heart, and nervous system.
Inheriting Fabry Disease
Fabry disease is an inherited disorder. The defective gene is on the X chromosome, which is one of the two chromosomes that determine an individual's sex. Males have one X chromosome inherited from their mothers and one Y chromosome inherited from their fathers. Since males have only one X-chromosome, if it contains a nonworking Fabry disease gene, affected males exhibit the clinical symptoms of Fabry disease.
A female with Fabry has one X chromosome with a defective Fabry gene and one X chromosome with a working Fabry gene. In all females, one of the two X chromosomes in somatic cells is randomly inactivated to compensate for the differences between male (XY) and female (XX). This inactivation occurs early in development, and the X chromosome that is inactivated in a given embryonic cell will remain inactive in all descendants of that cell. X chromosome inactivation has major consequences for females who have a nonworking Fabry gene. Depending on which and how many cells of a particular tissue have the X chromosome active containing the mutant gene, a female with a Fabry mutation may have clinical symptoms of Fabry disease which range from mild to as severe as affected males.
The inheritance pattern of Fabry disease is termed X-linked inheritance. As illustrated in Figure 1 below, a female with a Fabry mutation has a 50 percent chance of transmitting the defective Fabry gene to her sons who will develop Fabry disease. In addition, she has a 50 percent chance of transmitting the defective Fabry gene to her daughters who will also receive a second copy of the Fabry gene from their father. It must be emphasized that these risk figures apply to each pregnancy individually, that is, for each male child there is a 50 percent chance to have the disease, and for each female child there is a 50 percent risk to inherit the nonworking Fabry gene. In these females, symptoms presentation will vary depending on the X inactivation process in the early embryo.