What Is Fabry Disease?
Fabry disease is a rare genetic disease that runs in families. People affected by the disease cannot breakdown (metabolize) a fat called globotriaosylcermide (GL3). This leads to a buildup of GL3 in the cells of the body, that over time causes damage to multiple tissues and organs. There are two major forms of Fabry disease: classic and non-classic or “later-onset.”
What Causes Fabry Disease and How Is It Inherited?
GL3 is normally broken down by the enzyme alpha-galactosidase A (a-Gal). When this enzyme is deficient GL3 accumulates. The body’s instructions for how to make the enzyme are in a gene called GLA. Variants in this gene result in deficiency of the enzyme. The GLA gene variant that causes Fabry disease is on the X chromosome. This means that Fabry disease affects males and females differently.
People have two sex chromosomes: males have one X and one Y, and females have two X’s. Males who inherit the GLA variant will be affected by Fabry disease because they have only one X chromosome. Women who inherit the GLA variant on one of their two X chromosomes may also develop signs of Fabry disease. This is due to something called random X inactivation or Lyonization. Lyonization occurs during fetal development when one copy of the X chromosome is randomly inactivated in each cell. Therefore, some cells will make a working copy of the GLA gene, and thus make normal a-Gal enzyme. Yet, other cells may have the GLA variant and these cells will not make a-Gal enzyme that works properly.
In the family tree (pedigree) charts below, squares represent males and circles represent females. If the square or circle is solid (filled-in), this means the person has a copy of the GLA variant on an X chromosome (indicated as X*) that causes Fabry disease. The person is considered affected. In the pedigree on the left, the mother is affected. Half of her children (sons and daughters) may be affected. On the right, the father is affected. In this case, all of his daughters will be affected, but none of his sons.
What Are Signs & Symptoms of Fabry Disease?
Symptoms vary widely among patients with Fabry disease. They may include:
- Burning pain or tingling in the hands and feet
- Red or purple rash-like spots on the skin of the lower abdomen or trunk region (angiokeratomas)
- Low tolerance to heat and exercise due to an inability to sweat normally
- Digestion problems including pain, nausea, vomiting and diarrhea
- Hearing loss and ringing in the ears
- Problems with blood flow to the heart and brain
- Kidney and nervous system problems
- Depression and extreme tiredness
- Starburst pattern on the cornea of the eye (corneal whorls)
How Is Fabry Disease Diagnosed?
There are several ways that Fabry disease may be diagnosed. If Fabry disease is suspected in a male, a blood test is used to measure the amount of a-Gal enzyme activity, and then genetic (DNA) testing is done to look for variants in the GLA gene. When Fabry disease is suspected in females, genetic testing is done first. This is because even with Fabry disease, females may have a-Gal enzyme activity in the normal range. In Illinois, Fabry disease is on the newborn screen, which means that all babies born in the state are tested in their first days of life for many disorders and conditions that could benefit from early treatment, including Fabry disease.
How Is Fabry Disease Treated?
Early treatment is important to manage the symptoms and organ damage associated with Fabry disease. There are two FDA-approved treatments for Fabry disease. One is an enzyme replacement therapy (ERT). Patients on ERT receive an infusion of a synthetic form of the a-Gal enzyme (agalsidase beta) through a vein. Infusions are typically done about every 2 weeks, and treatment is lifelong. ERT is not a cure, but it has been shown to stabilize kidney function and slow its decline. The second FDA-approved treatment is migalastat, which is a chaperone therapy. Chaperones help to improve the function of the patient’s own a-Gal enzyme, that otherwise would not work properly. Migalastat is taken orally as a pill. Unfortunately, not all patients with Fabry disease will benefit from migalastat.
What Are the Long-Term Effects of Fabry Disease?
Fabry disease is progressive, and the build-up of GL3 inside the cells of the body can lead to kidney disease and failure, abnormal heart rhythms, heart enlargement and/or strokes.
Disease Treatment and Research at Lurie Children’s
Lurie Children’s treats both children and adults with Fabry disease. The Division of Genetics, Birth Defects & Metabolism has a team of doctors, advanced practice providers, genetic counselors and nurses who are experts in Fabry disease, including Joel Charrow, MD.
In addition, Lurie Children’s is a site for clinical trials to study new treatments for Fabry disease. Questions or inquiries for any of the clinical research trials can be directed to Rachel Katz, Clinical Research Manager, at RKatz@luriechildrens.org.
For more information, please see the following websites: