Researchers have furthered their knowledge of fragile X syndrome – the most common known cause of inherited intellectual disability – thanks to a patient with a mutation in a specific gene exhibiting some of the disorder’s symptoms.

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The new insight given by the study could have an impact on the development of treatments for fragile X syndrome.

Usually, fragile X syndrome is caused by the disabling of the fragile X mental retardation (FMR1) gene responsible for creating a protein – fragile X mental retardation protein (FMRP). FMRP is used to regulate electrical signals in the brain.

However, the patient examined in the study had only a single error in this gene and exhibited just two of the primary symptoms of the disorder. As a result, the researchers were able to analyze a hitherto unknown role for the gene.

“This individual case has allowed us to separate two independent functions of the fragile X protein in the brain,” says co-senior author Prof. Vitaly A. Klyachko, associate professor of cell biology and physiology at Washington University School of Medicine in St. Louis, MO.

“By finding the mutation, even in just one patient, and linking it to a partial set of traits, we have identified a distinct function that this gene is responsible for and that is likely impaired in all people with fragile X.”

According to the Centers for Disease Control and Prevention (CDC), it is estimated that around one in 5,000 males are born with fragile X syndrome. The condition can lead to severe intellectual disability, including an inability to communicate. Fragile X syndrome is most likely to affect males as the FMR1 gene is on the X chromosome.

People with fragile X syndrome can also experience anxiety and seizures, along with physical symptoms such as enlarged heads or flat feet. In addition, a third of people with the disorder exhibit symptoms of autism spectrum disorders.

For the study, published in Proceedings of the National Academy of Sciences, researchers from Washington University and Emory University School of Medicine in Atlanta, GA, examined genetic sequencing data for over 900 males with intellectual disabilities but not fragile X syndrome.

Their aim was to find mutations in the FMR1 gene that impaired FMRP but did not fully eliminate it. Only one patient was found from the sample that had abnormal FMRP, caused by a small mutation in the FMR1 gene’s DNA code.

The individual had intellectual disability and experienced seizures but had no physical features that were associated with fragile X syndrome, nor symptoms of autism.

After replicating the mutation in the mouse brain cells, the researchers found that FMRP appeared to work normally, indicating that the patient’s brain cells received signals normally, working just as they would in healthy people without the disorder.

“This patient presents a case of partial fragile X syndrome associated with mutated, rather than absent, FMRP,” says Prof. Klyachko. “As far as I know, this is the only known case of this. It’s a unique opportunity to parse out the functions of FMRP. What does this mutation impair to cause only two symptoms of fragile X?”

The team then replicated the mutation in fruit flies to try and answer this question. They found that the mutation led to an increase in the number of transmitters in the brain cells – problematic as it could result in too many signals being sent within the brain.

Previously, research into fragile X syndrome has focused on problems occurring with how and when signals are received in the brain, particularly looking at receivers that are overly sensitive and allow in too much information.

The researchers’ findings suggest that drugs recently tested as treatment for fragile X syndrome may be ineffective due to targeting receivers in the brain and not addressing higher levels of signal transmission.

Prof. Klyachko’s team were able to verify the effect observed in the fruit flies in mammals and connect it to human disease. The increased number of transmitters caused by the patient’s mutation also occurred with a total loss of FMRP.

The researchers acknowledge that there may be other problems caused by both the mutation and fragile X syndrome, but for now this study has identified one dysfunction that was previously unknown.

“The mechanisms that researchers have long thought were the entirety of the problem with fragile X are obviously still very much in play,” Prof. Klyachko observes. “But this unique case has allowed us to see that something else is going on.”

Last year, Medical News Today reported on a study in which researchers identified a drug target for the behavioral symptoms of fragile X syndrome.