Research links genetic variants to fatal drug-induced brain infection

Research links genetic variants to fatal drug-induced brain infection


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New research has confirmed a strong link between four genetic mutations and progressive multifocal leukoencephalopathy (PML), a rare but often fatal brain infection that can be triggered by dozens of FDA-approved drugs.

The research, published in Frontiers in Neurology on December 14, will allow physicians to screen out patients at highest risk for PML.

The study found that in people taking PML-inducing drugs, having one of the four genetic variants increased the risk of PML by an average of 8.7 times. One of the variants increased the risk by 33 times.

Eight drugs carry a black box warning for PML, the strongest warning given by the FDA. More than 30 additional drugs carry other PML warnings. In total, cases of PML on more than 75 drugs have been reported to the FDA. The list includes many of the most effective treatments for multiple sclerosis (MS), blood cancers, rheumatoid arthritis, Crohn’s disease and organ transplant rejection.

PML is caused by the JC virus (JCV), a generally harmless virus carried by up to 80% of the population. PML occurs when the virus reactivates and attacks the brain with life-threatening consequences. Researchers have long sought an explanation as to why the virus leads to PML in some people but not others.

In this study, researchers first demonstrated that four genetic variants were significantly more common in patients who developed drug-induced PML than in the general population. They then looked for these variants in the ideal control group: MS patients who carried JCV and took a high-risk drug for years, but who did not develop PML. The results were even stronger compared to these matched controls.

Almost 11% of patients with PML tested positive for at least one of the four variants. To put this finding into perspective, these variants explain a higher percentage of PML cases than the well-known BRCA mutations explain breast cancer cases. Moreover, their predictive power exceeds levels that have led the FDA to require genetic testing for other risky drugs.

Drug-induced PML is increasing as new immunosuppressive therapies are developed. In 2021, there were over 500 cases in the FDA’s adverse event reporting system. These drugs are widely prescribed: in the United States, nearly one million people have MS, another 1.5 million have blood cancers commonly treated with PML-inducing drugs, and 850,000 Americans have received organ transplants.

“It is critical to be able to identify genetic mutations that significantly increase a person’s risk of contracting this devastating infection,” says Dr. Lawrence Steinman, professor of neurology and neurosciences, pediatrics and genetics at the University of Stanford. His lab developed Tysabri, a powerful MS drug that was temporarily taken off the market due to PML and now carries a black box warning. “Preventive screening for these variants should be part of the standard of care. I wish we had more powerful tools like this for other therapies,” he says. Dr. Steinman is not affiliated with this study.

Dr. Joseph Berger, another independent PML expert and Multiple Sclerosis Lead at the University of Pennsylvania Perelman School of Medicine and lead author of the American Academy of Neurology PML Guidelines Committee, says: “Determining Genetic susceptibility to PML is an extremely promising method for reducing disease risk. A simple, inexpensive test can prove revolutionary in this regard.”

More information:
Genetic risk variants of progressive multifocal leukoencephalopathy for pharmacovigilance of immunosuppressive therapies, Frontiers in Neurology (2022). DOI: 10.3389/fneur.2022.1016377, … ur.2022.1016377/full

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Quote: Research links genetic variants to fatal drug-induced brain infection (December 14, 2022) Retrieved December 14, 2022 from medication-induced-fatal.html

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