Testing for 4 Gene Variations May Predict Risk of PML Brain Infection

Genetic variations in certain genes may increase the risk of developing progressive multifocal leukoencephalopathy (PML), a serious brain infection associated with certain treatments for multiple sclerosis (MS) and other conditions, a new study shows.

The findings suggest that testing for four specific genetic variant could help to predict the risk of this infection and select adequate treatment options for patients most at risk of PML.

“Simple, low-cost genetic screening in patients considering drugs with known or suspected PML risk will prevent future cases,” the researchers wrote.

The study, “Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies,” was published in Frontiers in Neurology. The work was funded in part by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke.

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Progressive multifocal leukoencephalopathy, or PML, is a rare brain infection that is often severe and can be life-threatening. It is caused by the John Cunningham virus, known as JCV.

Most people have been infected with JCV at some point, but most of the time, the virus doesn’t cause disease. It only causes PML in people with weakened immune systems.

Thus, individuals with conditions that affect the immune system — like HIV infection or blood cancers — are most at risk, along with those receiving treatments that make immune cells less effective at clearing out infections.

Several approved treatments for MS that work by suppressing immune activity list PML as a rare but potentially serious side effect. Among them are Tecfidera (dimethyl fumarate), Gilenya (fingolimod), and Ocrevus (ocrelizumab). Tysabri (natalizumab) also is on that list, though the medication is only available in the U.S. through a restricted distribution program due to the risk of PML.

While PML can develop in immunosuppressed people who are infected with JCV, not everyone with a weakened immune system who is infected with the virus will develop a brain infection. The reasons why some people develop the severe infection, but not others, has long been a puzzle.

In a previous study, researchers at Emerald Lake Safety and Population Bio compared genetic data from more than 180 people with PML within the general population. The team identified 19 rare genetic variants that were more common among the PML patients, suggesting they may predispose them toward the brain infection.

To further investigate these PML-linked variants, researchers in this study compared genetic data from 110 people with PML due to medications to data from 718 medication-exposed controls. These were MS patients who were on a therapy known to increase the risk of PML for at least two years and were positive for JCV, but had never developed the infection. Among the 110 PML patients, most (94, or 85%) had MS; the rest had other conditions like blood cancers.

In both the PML group and the medication-exposed controls, the most common therapy given was Tysabri (natalizumab), accounting for over 75% of patients in both groups.

From the 19 previously identified genetic variations, this analysis identified four that were significantly more common among PML patients. These variants were located in the genes C8B, FCN2, LY9, and STXBP2, all of which are known to play roles in immune function.

The researchers noted that all four of these variants are quite rare, present in less than 0.5% of the general population. They also noted that, based on the particular genetic sequences, these variants likely interfere with the function of the immune-related genes — a plausible mechanism that might explain why these mutations are associated with higher PML risk.

Notably, an analysis comparing genetic data from more than 30,000 MS patients and a similar number of people without the disease showed that none of these four variants are disproportionately more common in MS than in the general population.

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In addition, the researchers determined that a four-gene panel testing for these variations could predict the risk of PML with a very high specificity (98.6%) but low sensitivity (10.9%) — in other words, the genetic test was statistically very good at identifying patients who did not develop PML, though it’s ability to identify patients who would develop the infection was more limited.

“These results suggest that the 4-variant PML risk genetic test could be used for advising on PML risk in general and for preventing [medication-related] PML cases. … Testing for these four variants could prevent a substantial number of patients from developing PML without deterring most patients from their treatment plan,” the researchers concluded.

“Due to the seriousness of a PML diagnosis — particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops — it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they added.

Simple, low-cost genetic screening in patients considering drugs with known or suspected PML risk will prevent future cases

The researchers noted that the statistical association of the four-variant panel with PML compares favorably with other genetic tests that have become widespread in medical use — for example, the link between these four variants and PML was statistically slightly stronger than the link between breast cancer and mutations in the BRCA genes.

“It’s critical to be able to identify genetic mutations that greatly increase a person’s risk of this devastating infection,” Lawrence Steinman, MD, a professor at Stanford University whose lab helped discover Tysabri, said in a joint press release from Emerald Lake and Population Bio.

“Preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies,” said Steinman, who was not involved in the present study.