Not all GLA gene mutations cause Fabry disease, case highlights
Report 'underscores importance' of clinical evaluations before treatment
It’s critical to conduct thorough clinical evaluations to determine whether a newly identified mutation in the GLA gene is actually causing Fabry disease — before initiating treatment in patients.
That’s the message highlighted in a report from Italy describing the case of a woman now in her early 40s whose GLA mutation was found, years after starting treatment, to likely not be pathogenic, or disease-causing.
The woman was initially treated for Fabry when the GLA gene mutation was identified, even though she had no signs of the rare condition. There also were no symptoms of Fabry found in the patient’s father, from whom she inherited the genetic change.
“This case underscores the importance of a comprehensive evaluation of new variants of unknown significance to establish their pathogenicity [or ability to cause disease] accurately,” the researchers wrote.
The report, “No evidence of Fabry disease in a patient with the new p.Met70Val GLA gene variant,” was published in the journal Molecular Genetics & Genomic Medicine.
Fabry disease presentation can vary widely in female patients
Fabry disease is caused by mutations in the GLA gene, which disrupt the production of the alpha-galactosidase A (alpha-Gal A) enzyme needed to break down certain fatty molecules in cells. These molecules toxically accumulate in the body’s organs and cause damage.
GLA is found on the X chromosome, one of the body’s sex chromosomes. A person need only inherit one mutated copy of GLA for Fabry to manifest.
Because women have two X chromosomes, having one healthy gene copy can partially compensate for a mutated one. That means that Fabry’s presentation in female patients is far more variable than it is in males, who only have one X chromosome (alongside one Y chromosome). Some women may see severe organ damage similar to their male counterparts, while others could be asymptomatic entirely.
That can make diagnosing Fabry disease in women particularly challenging. Further complicating the matter is that while GLA mutations are the cause of Fabry, not every type of mutation affects the alpha-Gal A protein enough to cause disease. A perfectly healthy person could have a completely benign mutation in the gene.
Given that, according to the researchers, it’s important, if a woman tests positive for a GLA mutation but is asymptomatic, for clinicians to carefully review the case. The healthcare team must consider whether the lack of symptoms occurs because the mutation is not harmful, or because the patient simply has a milder Fabry disease course.
In this case, the patient underwent an MRI in 2014 because she was experiencing persistent dizziness. That scan revealed some signs of nonspecific lesions. The woman had previously experienced a temporary bout of vocal cord paresis, or partial paralysis — a sign of damage to the nerves that enable vocal muscle control.
While blood levels of Fabry-associated fatty molecules were normal, genetic testing revealed a novel mutation in GLA called c.208A>G that had not been previously characterized. Despite the mutation, the woman had not been experiencing any common Fabry symptoms, and she was found to have normal kidney and heart function.
Nevertheless, she was started on Fabry disease enzyme replacement therapy (ERT) at a diagnostic center, because the doctors believed Fabry to be the cause of her neurological issues.
During her third ERT infusion, the woman experienced side effects of abdominal pain, nausea, and fever, which subsided when treatment was stopped.
Woman found to not have Fabry, despite GLA gene mutation
In 2020, at age 41, the woman underwent further evaluation at the scientists’ referral center. She was found to have inherited the GLA mutation from her father, who also did not have obvious signs of Fabry.
The researchers noted that this was a good clue that the GLA gene mutation might not be pathogenic. Should the mutation have proven to be Fabry-causing, the father likely would have shown some sign of that.
This was supported through further kidney and skin biopsy analyses in the woman, where no signs of fatty deposits that would indicate Fabry disease were observed.
Based on these evaluations, it was determined that the GLA mutation was nonpathogenic and that the woman did not have Fabry disease. She was discharged without further Fabry therapies.
This clinical report emphasizes the importance of conducting a comprehensive evaluation, which includes genetic testing and histological examination [e.g. biopsies], to determine the pathogenicity [ability to cause disease] of a variant and guide appropriate treatment decisions.
In their report, the researchers conclude that when any person — man or woman — is found to have a Fabry mutation that’s never been seen before, it is critical to evaluate the gene variation has a true disease-causing role. This is especially important if there are no obvious disease symptoms, the team noted.
“This clinical report emphasizes the importance of conducting a comprehensive evaluation, which includes genetic testing and histological examination [e.g. biopsies], to determine the pathogenicity of a variant and guide appropriate treatment decisions,” the researchers wrote.
Conducting such testing “can provide crucial insights into the potential impact of the variant,” the team added.
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