Due to the progressive nature of Fabry disease, it is important for clinicians to make a diagnosis as early as is possible. Such diagnoses are usually made through genetic or enzyme testing. Newborn screening can detect the disease, but it is only available in a few U.S. states.
Fabry is a genetic disorder caused by mutations in GLA, a gene located on the X chromosome — one of the sex chromosomes – that provides the instructions for making the alpha-galactosidase A (Gal A) enzyme.
The absence or markedly deficient activity of this enzyme in patients results in the progressive buildup of a fatty substance called globotriaosylceramide (Gb3 or GL-3) inside cells. That buildup, in turn, leads to a wide range of serious symptoms.
Typically, the less the Gal A activity, the earlier and more severe the symptoms. However, it’s not necessarily that straightforward in female patients. For that reason, several types of tests are used to reach a diagnosis of Fabry disease, with genetic testing as the most reliable and informative method for both sexes.
Given that the disease is progressive, an earlier Fabry diagnosis is particularly important in terms of treatment. The sooner treatment — such as enzyme replacement therapy or chaperone therapy — starts, the more likely it is to prevent further damage, lessen symptoms, and promote better outcomes. If a person shows common symptoms of Fabry disease and/or has a history of the disease in the family, further tests should be conducted.
Enzyme tests, which measure the activity of the Gal A enzyme in the blood, are the first-line assay for diagnosing Fabry disease in male patients. An activity level of less than 1% of normal is highly indicative of classic Fabry disease, the more severe form of the condition. Levels above that threshold, but still lower than the normal range suggest a late-onset, milder form.
These tests use blood drawn from the arm, and can be done at a doctor’s office or in a lab setting.
Notably, Gal A’s activity is often within the normal range in female patients, limiting its usefulness to these individuals. Therefore, a genetic test is required for females, and also is recommended to confirm the diagnosis in male patients.
The most definitive assessment, a genetic test, looks for disease-causing mutations in the GLA gene. Both males and females only have to inherit one mutated GLA gene copy to develop the disease. Cells from a sample of blood or saliva are usually used in such testing.
This type of test should be considered for any individual with a confirmed or suspected clinical diagnosis of Fabry, or a family history of the disease. 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). Such data may help inform family planning decisions.
While female carriers may not develop the disease, they can pass it to their children, especially boys, since males only have one X chromosome (inherited from the mother) and thereby will develop more severe disease when inheriting a mutated gene. In females — who have two X chromosomes, one from the mother and one from the father — the typical 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.
Prenatal testing and newborn screening
Enzyme and genetic testing also can be done before birth to see if an unborn baby has a disease-causing GLA mutation. At about 10 weeks of pregnancy, a placenta sample may be used for these tests, while the liquid surrounding the fetus may be collected and analyzed at about 15 weeks (just past three months) of gestation.
Newborn screening for Fabry disease typically involves collecting a blood spot from a heel prick and analyzing the levels of Gal A activity. So far, newborn screening programs to detect the disease have been implemented in Taiwan and some U.S. states, including Illinois, Missouri, and Tennessee.
A test for lyso-Gb3, another fatty substance that accumulates in the blood or in the urine as a result of Gal A deficiency, also can help to achieve a Fabry diagnosis, particularly in female patients, and indicate the severity of the disease.
After a diagnosis is established, Fabry patients will undergo a number of other tests to diagnose problems in the most commonly affected organs, including the heart, kidney, and nervous system. Tests include echocardiograms, electrocardigrams, brain and heart MRI scans, and blood tests to detect protein or blood in the urine.
Last updated: June 1, 2021
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