Fabry disease is a genetic disorder caused by mutations in the GLA gene that encodes for an enzyme called alpha-galactosidase A, which is responsible for breaking down a fatty molecule called globotriaosylceramide (Gb3 or GL-3). When the enzyme fails to work as it should, Gb3 accumulates inside cells and, over time, damages them. Such damage leads to disease’s various symptoms.

Symptoms typically appear in childhood, though in milder cases can first become evident later in life. They include both chronic and acute pain, progressive kidney failure, vision and hearing loss, and an increased risk of a heart attack and stroke. A spotted rash may also be present.

A genetic disorder, Fabry disease is passed from parent to child. In very rare cases, however, it can result from a “de novo” mutation appearing for a first time in a child.

How Fabry disease is inherited

Fabry disease is an X-linked disease, meaning that the mutated gene is located on the X chromosome, one of the genes that determine a person’s sex. Because women have two X chromosomes and men have one X and one Y chromosome, the likelihood of disease inheritance depends both on the parents’ sex and the child’s sex.

A baby girl always inherits an X chromosome from her father. This means that a man with Fabry disease will always send a defective gene to his daughter, but never to his son.

Women only pass along an X chromosome to a child — whether a girl or a boy.  A woman with a faulty copy of the GLA gene in one of her two X chromosomes has a 50 percent chance of causing a child to inherit that defective gene. This means that a son has a 50 percent of inheriting  Fabry disease from his mother, depending on whether or not he received the X chromosome with the disease-causing mutation from his mother (a boy always inherits a Y chromosome from his father). A daughter born to a mother who has or is a carrier of Fabry disease also has a 50 percent chance of inheriting a defective GLA gene, but because females of two X chromosomes, she may not develop the disease or show symptoms that are less severe. Her other X chromosome, carrying the healthy gene, can compensate for the faulty one.

Genetic testing, which can determine if a parent carries the disease-causing gene, is recommended for people with family members with Fabry disease.

Genetic testing

A test for the alpha-galactosidase A enzyme will reveal the disease in men — who have no or very low amounts of the enzyme — but can be less accurate for women. Fabry disease can often be detected in men using an enzyme assay test.

In women, who can have near normal, or normal, alpha-galactosidase A enzyme levels, an assay test is not sufficient. A DNA sequence analysis is required, and can confirm the presence of Fabry disease definitively in people with suspected disease, as well as in their family members.

More than 370 mutations have been identified in the GLA gene. Most cause a change in a single amino acid, the building blocks of proteins. There can also be mutations that cause parts of the gene to go missing or that add extra bits of genetic information to the gene. All these mutations lead to the production of an abnormal alpha-galactosidase A enzyme. Genetic testing can identify any such changes in the GLA gene.

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