Fabry disease is an inherited condition (runs in families) that is caused by a mutation or defect in a gene called the GLA gene (also called the Fabry gene) located on the X chromosome.

A person with Fabry’s disease is unable to make enough of an enzyme called alpha-galactosidase A (or alpha-GAL) that is responsible for breaking down and clearing a fatty substance called globotriaosylceramide or GL-3. As a result, Gl-3 accumulates in various tissues in the body such as the kidneys, heart, and skin, and can cause symptoms such as mini-strokes, marble-like patterning in the eyes, hearing loss, heart disease, digestive problems, skin changes, an inability to sweat, or temperature sensitivity. Left untreated, Fabry disease can reduce life expectancy by 15 years in women and 20 years in men.

What are the symptoms of Fabry disease?

Symptoms of Fabry disease are caused by the build-up of GL-3 which starts to build up before birth and continues throughout a person’s life. Symptoms can vary depending on how old the person is, how severe their disease is, the activity of their enzymes, or their type of genetic variation. Symptoms may include:

• Chest pain
• Corneal whirling (marble-like patterns in the eyes)
• Digestive problems, such as diarrhea, abdominal pain, early satiety (feeling full after only a little food), and nausea
• Kidney disease
• Hearing loss
• Heart disease
• Inability to sweat
• Ministrokes or transient ischemic attacks (TIAs)
• Pain in the hands or the feet
• Reddish or purple spots on the skin
• Temperature sensitivity
• Tinnitus.

Some symptoms may worsen with time without the person noticing. Left untreated, Fabry disease can reduce life expectancy by 15 years in women and 20 years in men.

How is Fabry disease diagnosed?

Genetic testing for the GLA gene is the most reliable and informative method for diagnosing Fabry disease in both males and females. This uses cells from a sample of blood or saliva to look for disease-causing mutations in the GLA gene. Males and females only have to inherit one mutated GLA gene copy to develop the disease.

In male patients, enzyme tests, which measure the activity of alpha-GAL in the blood, may be used to diagnose Fabry disease in males. Levels of less than 1% of normal are typical of classic, more severe, Fabry disease. Levels above 1% but lower than the normal range suggest a late-onset, milder form. The activity of Alpha-GAL is often within the normal range in female patients limiting the usefulness of these tests, and genetic tests should be used to diagnose females and confirm the diagnosis in males.

Some states also offer newborn screening for Fabry disease. This involves collecting a blood spot from a heel prick and analyzing the levels of Gal A activity.

Enzyme and genetic testing also can be done before birth to see if an unborn baby has a disease-causing GLA mutation. This may be done at about 10 weeks of pregnancy, using a placenta sample or by analyzing the liquid surrounding the fetus at about 15 weeks (just past three months) of gestation.

A test for Lyso-Gb3, another fatty substance that accumulates in the blood or the urine as a result of Gal A deficiency, may be used to diagnose Fabry disease, particularly in female patients.

After a diagnosis of Fabry disease has been established, other tests such as echocardiograms, electrocardiograms, brain and heart MRI scans, and blood tests may be used to determine what organs are affected. 

Fabry disease is frequently misdiagnosed because symptoms of the condition can be very nonspecific (such as gastrointestinal complaints such as abdominal pain or diarrhea) especially those that present early in life, and many healthcare providers are unfamiliar with the disease. The full range of symptoms of Fabry disease may not present until adulthood.

How many people have Fabry disease and how is it passed on?

Fabry disease affects people of all ages and ethnicities and traditionally has been thought to be very rare, affecting up to 1 in 40,000 to 50,000 males, with an unknown prevalence in women because they tend to be carriers with no or nonsignificant symptoms.

However, the true incidence of Fabry disease is likely to be much higher, because newborn screening studies in some countries identified the condition in 1 in 3400–4000 newborns. The National Fabry Disease Foundation estimates 50,000 people in the U.S. carry the Fabry gene, many of whom remain undiagnosed or misdiagnosed with other conditions. 

On average, five family members are diagnosed with Fabry disease for every patient identified. Testing family members can help diagnose cases of Fabry disease early before serious problems arise, as well as identify girls and women who carry a mutated GLA copy but have no symptoms (called carriers). These women can pass it to their children, especially boys since males only have one X chromosome (inherited from the mother) and thereby will develop the more severe disease when inheriting a mutated gene. In females who inherit two X chromosomes, one from the mother and one from the father, the presence of a healthy gene copy can compensate for the mutated copy to a certain extent.

Men with Fabry disease will transmit the GLA mutation to all their daughters, who typically will develop the disease, but not to a son, because boys receive a Y sex chromosome from their fathers, instead of an X chromosome. Most female patients who carry only one mutated GLA gene copy will have a 50% chance of passing the mutated gene to each of their children, both daughters, and sons.

How is Fabry disease treated?

There is no cure for Fabry disease but treatments can help replace the missing alpha-GAL enzyme,  restore alpha-GAL activity, prevent organ damage, and ease symptoms. Treatments include:

• Enzyme replacement therapies such as Fabrazyme
• Chaperone therapies such as Galafold.
• Other treatments such as dialysis or kidney transplants.

References

• Fabrazyme (agalsidase beta) [Product information]. Updated 03/2021. Sanofi Genzyme https://www.drugs.com/pro/fabrazyme.html
• Fabrazyme. Fabrazyme.com 2021.
• Zar-Kessler C, Karaa A, Sims KB, Clarke V, Kuo B. Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis. Therap Adv Gastroenterol. 2016;9(4):626-634. doi:10.1177/1756283X16642936
• Diagnosis of Fabry Disease. Fabry Disease News. 2021 https://fabrydiseasenews.com/diagnosis-of-fabry-disease/

Drugs used to treat Fabry Disease