Fragile X Syndrome Linked to Impaired Brain White Matter Development, Researchers Say

Fragile X Syndrome Linked to Impaired Brain White Matter Development, Researchers Say

Babies with fragile X syndrome have less-developed brain white matter compared to those without the syndrome, according to researchers. 

Their study, “Development of White Matter Circuitry in Infants With Fragile X Syndrome,” was published in JAMA Psychiatry.

Fragile X syndrome is caused by mutations in the FMR1 gene, which provides instructions for building the protein FMRP. The genetic mutations lead to intellectual disabilities and behavioral changes starting in infancy.

Previous studies have shown that functional loss of the FMRP protein leads to an abnormal structure of nerve cells in the brain (neurons), which may lead to their impaired activity and communication.

Although these cellular changes have been linked to the abnormal development of the brain, there is little evidence to demonstrate the role of FMR1 and the impact of its mutations.

University of North Carolina at Chapel Hill researchers and colleagues analyzed the brain of 27 infants diagnosed with fragile X and 73 infants without the disease, who were followed in two academic medical centers from 2008 to 2016.

Using magnetic resonance imaging (MRI) scans, the team analyzed 19 major white matter fiber tracks in the brain. These are nerve cell communication networks composed of bundles of myelinated axons — the long parts of nerve cells that extend across the brain or throughout the nervous system.

Twelve of the 19 analyzed pathways were found to be less developed in fragile X infants compared to the control group. These altered white matter networks affected several regions of the brain and were not associated with age, suggesting the pathways were established at the earliest stages of the disease, in infants 6 months old or younger.

“These results substantiate what other researchers have shown in rodents — the essential role of fragile X gene expression on early development of white matter in babies,” Jason Wolff, PhD, a former postdoc fellow at UNC, now assistant professor at the University of Minnesota and co-first author of the study, said in a UNC news story by Mark Derewicz.

“Our work highlights that white matter circuitry is a potentially promising and measurable target for early intervention. However, achieving the goal of infant intervention for fragile X would likely require expanded newborn screening efforts,” Wolff added.

Experimental treatments in clinical trials have failed to achieve efficacy in treating fragile X. These findings may offer options not only by helping to identify potential therapeutic targets, but by providing enhanced treatment-responsive outcome measures or biomarkers.

“It’s our hope that earlier diagnosis and intervention will help children with fragile X and their families,” said the study’s co-author, Meghan Swanson, PhD. “We also hope that this knowledge might inform drug development research.”

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