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Sex differences contribute to vision damage in NF1

Vision problems can be caused by neurofibromatosis. Kids with mutations in the NF1 gene that causes neurofibromatosis often develop tumors on the optic nerve, but not all of them develop vision problems. Interestingly, Washington University researchers previously had learned that girls with tumors on the nerve were five to 10 times more likely to lose vision than boys with tumors of about the same size. Now those same researchers have found, in mice, that estrogen is the reason that females with these tumors are more likely to lose vision. Further study showed that cells called microglia are more common and more active in the tumors females develop. Those cells make substances that are more toxic to nerve cells and, therefore, damage vision. The researchers say strategies to temporarily lower estrogen levels in children with tumors on the optic nerve may make it possible to preserve vision without the need for chemotherapy to shrink such tumors.

TUMORS ON THE OPTIC NERVE ARE A COMMON FEATURE OF A GENETIC CONDITION CALLED NEUROFIBROMATOSIS TYPE 1 (NF1). ABOUT 15 TO 20 PERCENT OF YOUNG BOYS AND GIRLS WHO HAVE NF1 WILL DEVELOP THOSE TUMORS, CALLED OPTIC GLIOMAS. BUT LESS THAN HALF WILL EVER DEVELOP VISION PROBLEMS AS A RESULT. THAT’S IMPORTANT TO KNOW BECAUSE DAVID GUTMANN, DIRECTOR OF THE WASHINGTON UNIVERSITY NF CENTER, SAYS YOU DON’T WANT TO TREAT THE TUMOR WITH CHEMOTHERAPY IF IT’S NOT GOING TO THREATEN VISION.

 

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When we looked at our kids with NF1 who have these optic gliomas,

girls whose tumors were in the nerve were 5 to 10 times more

likely to lose vision than boys with tumors of about the same size.

 

IT TURNS OUT THAT FEMALE SEX HORMONES ARE PARTLY TO BLAME FOR THAT DIFFERENCE. GUTMANN AND HIS TEAM LOOKED AT MOUSE MODELS OF NF1 AND FOUND THAT ONLY FEMALE MICE WERE LOSING VISION FROM THE TUMORS. SO, THEY WORKED TO GET RID OF THE ESTROGEN IN THE FEMALE MICE TO SEE WHAT WOULD HAPPEN.

 

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If you either chemically ablate the ovaries, or remove the

ovaries, in these female mice with optic gliomas, they were

not experiencing the damage to the optic nerve that leads to

vision loss.

 

NEXT, GUTMANN’S TEAM FOUND THAT ESTROGEN WAS ASSOCIATED WITH LARGER NUMBERS OF IMMUNE SYSTEM CELLS CALLED MICROGLIA, AND THOSE MICROGLIA WERE MORE ACTIVE.

 

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And because they were numerous, and because they were changed

in a way that makes them more active, they were making compounds,

chemicals, that were damaging the nerve. And while identifying

those neurotoxins, we were able to establish a cause-and-effect

relationship between estrogen, the microglia and the “death

signals” that eventually cause the nerves to die.

 

GUTMANN SAYS ALTHOUGH THE COMPARISON FROM MOUSE TO HUMAN ISN’T PERFECT, IT IS CLEAR THAT BOYS AND GIRLS, EVEN AT VERY YOUNG AGES, HAVE HIGH ENOUGH LEVELS OF SEX HORMONES IN THEIR BRAINS TO EXPLAIN THESE DIFFERENCES IN MICROGLIA. AND GUTMANN SAYS UNDERSTANDING THE ROLE THAT SEX HORMONES PLAY IN THE DAMAGE TO VISION THAT THESE TUMORS CAN CAUSE ALSO WILL PROVIDE THE RESEARCHERS WITH NEW IDEAS ABOUT HOW TO TREAT OPTIC GLIOMAS IN KIDS WHO HAVE NF1.

 

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We can treat them with conventional therapies, but what I’d like

to see us start moving towards is not focusing on treating the tumor,

but focusing on treating those immune system cells that are damaging

the nerve itself. Because we can “win the battle,” that is, we can

stop the tumor from growing, but over the past 30 years, we haven’t

“won the war.” And the war is really to prevent further vision loss.

 

GUTMANN’S TEAM REPORTS ITS FINDINGS IN THE JOURNAL OF EXPERIMENTAL MEDICINE. I’M JIM DRYDEN…

 

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