fragile x

Peter Saxon

The treatment window for Fragile X syndrome may not close as early as previously thought, according to new research from Drexel University. A study has found that Fragile X may be treatable well into maturity in humans, instead of becoming untreatable during childhood as previous mouse studies have shown. The research, published in Human Molecular Genetics, may offer a broader target for nerve cell therapies.

Fragile X syndrome is the most common autism-related disorder that results in intellectual disabilities, affecting 1 in 4,000 males and half as many females. Currently, therapeutic treatments for the condition are still making their way through clinical trials.

This study examined brain samples from rats and humans, focusing on the region of the brain called the hippocampus, which is primarily in charge of memory. The team found structures known as Fragile X granules in the samples well into maturity. The granules, first discovered in 2009, are thought to contribute to the syndrome when they are decoupled from a gene that codes for the Fragile X mental retardation protein (FMRP) and which is mutated in patients with Fragile X.

Previous studies have used mice to show that the granules disappear when the animals reach maturity. As most prior studies would have been using mice, the evidence that these granules persist in adult humans and rats would have been missed.

“It’s intriguing that this disease-related gene has different expression patterns in humans than in the major preclinical model, mice, that are used to study that gene,” said Michael Akins, Ph.D., leader of the research team and Assistant Professor at Drexel’s College of Arts and Scientists. Akins was also part of the team which initially discovered Fragile X granules.

As Fragile X granules linger in the hippocampus when humans mature, it is possible that the age range for treatment may be broader than initially supposed. Prior to these findings, it was thought that Fragile X could only be treated in childhood while the granules were still present. In this study, the team were able to show that a human sample from a 57 year old person still displayed Fragile X granules and as a result, might still have benefited from treatment.

The study also found that future treatments may need to target nerve cells more broadly than current plans. Neurons relay information within the brain and are made up of two distinct parts: dendrites, which receive information, and axons, which send information. Most research has been focused on FMRP mutations within the dendrites, but previous work by the same team has shown that FMRP is also present in Fragile X granules within the axons. Other labs were able to show that FMRP was very different in the axons and the dendrites but the exact role of FMRP in axon granules was still very unclear.

This study, however, has been able to uncover unexpected similarities between the two forms of FMRP. The findings might mean that certain treatments could affect both forms of FMRP if they are targeted at the similarities they share.

“It’s possible that the symptoms caused by dysregulated Fragile X granules aren’t being addressed by current experimental therapeutic interventions that focus on rescuing FMRP function in the dendrites,” Akins said. “What we found is important because having one medication that targets both dendrites and axons should better treat the symptoms of Fragile X and, with luck, other autism-related disorders.”

Akins and his team are hoping to continue their work to uncover more of the mechanisms behind Fragile X syndrome.

“We’re still trying to understand what the FMRP is doing in the axons – and how its absence from axons contributes to Fragile X – but this is a major step forward,” he said. “We have some new leads.”