Fabry disease is a rare genetic condition characterized by the build-up of a fat molecule called globotriaosylceramide (Gb3 or GL-3) inside cells which causes damage and leads to symptoms such as chronic pain, kidney disease, and stroke.
Genetics of Fabry disease
Fabry disease is caused by a mutation in the GLA gene that carries the instructions necessary to make an enzyme called alpha-galactosidase A (α-galA). This enzyme is responsible for the breakdown of GL-3 into smaller molecules that can be used and disposed of by the body.
The mutation in GLA interferes with the production of the α-galA enzyme. Many genetic changes in the GLA gene have been reported, and based on the type of mutation, production of α-galA may be very little or non-existent. As a result, GL-3 is not degraded and accumulates inside cells, leading to the symptoms of Fabry disease.
The GLA gene is located on the X chromosome and is inherited in an X-linked pattern. Women have two X chromosomes, one from each parent and so have two copies of the GLA gene. One healthy copy of the gene can compensate for the mutation in the other, so women are usually not affected by Fabry disease.
Men have only one X chromosome, which is inherited from the mother. Instead of the second X chromosome, they inherit a Y chromosome from their father. Therefore, inheriting a mutated copy of the GLA gene results in the male child developing Fabry disease.
Why is genetic testing required?
Men with a mutation in the GLA gene have α-galA enzyme deficiency and can be diagnosed with a blood test that examines how well the enzyme is working. The GLA gene mutation in women may or may not result in low levels of the enzyme, which cannot always be detected with a blood test. Therefore, a genetic test is required for females, and may also be used to confirm the diagnosis in male patients.
A doctor and healthcare team will first perform a detailed review of the patient’s medical history and symptoms. If Fabry disease is suspected based on this review or blood test results, a genetic test may be prescribed to determine changes in the GLA gene. A buccal (inner cheek) swab or blood sample can be used for genetic testing.
Genetic testing is also recommended for the immediate and extended family members of the affected individual to identify other patients who may be either a carrier of the disease or undiagnosed.
Genetic testing and pregnancy
Couples with a family history of Fabry disease should have a detailed discussion with a genetic counselor who can help them better understand the disease and provide guidance about the options available to them in terms of family planning.
In-vitro fertilization with a pre-implantation genetic testing of the embryo for Fabry disease is an option for mothers who are carriers of the disease.
DNA obtained from a fetus can also be assessed to determine GLA gene mutation. Chorionic villus sampling can be performed early in the pregnancy (at 10 to 12 weeks) in which a sample of the placenta is used for the test. Amniocentesis, done between 13 and 20 weeks of pregnancy, can test the amniotic fluid that surrounds the fetus for any genetic anomalies.
Last updated: Oct. 9, 2019
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