Scots Scientists Help To Unravel The Mystery Of Fragile X

Scottish scientists have discovered a brain abnormality which causes Fragile X syndrome, a common form of learning difficulty, raising hopes that a therapy could be found. The condition affects one in 4000 children and adults, and can cause slow learning and lead to behavioural problems similar to autism.

It was highlighted last year by the deaths of 12-year-old Ryan Davies and his mother Alison, who both died when she jumped off the Humber Bridge.

The genetic defect which triggers Fragile X was identified more than 30 years ago, but how it causes intellectual disability has remained a mystery. Now scientists at Edinburgh University have identified a chemical pathway in the brain which is likely to be responsible.

Dr Kirsten Dickson found that a protein which forms connections between brain cells is disrupted by the mutated Fragile X gene.

A spokesman for the UK’s leading Fragile X society described the discovery as a major breakthrough, which will open up new avenues for drug companies who are searching for a treatment.

Dr Mark Hirst, senior lecturer in human genetics at the Open University,
said: “I’m very excited by this discovery. It has taken us a long time to get here. This finding backs up the theory that Fragile X is all about connections in the brain. Learning depends on making connections between brain cells.

“There was a theory that Fragile X patients had an inability to form these links between neurons, but there was no known protein which could mediate that. This discovery of this protein helps to complete the picture.”

Despite being the most common inherited form of learning difficulties, there is little public awareness of Fragile X, which has a range of symptoms. Mild cases are not always diagnosed, because children are sociable and friendly, but demand a lot of attention and affection.

In more severe cases, children display antisocial behaviours similar to autistic spectrum disorders. The demands of children places an enormous strain on parents, with children requiring constant attention and supervision.

Dr Hirst said the finding would offer great hope for the future, although he cautioned that it was too early to envisage finding a “cure”.

“This suggests there may be a way in’ for drugs to target this pathway,” he said. “Therapy is a long way off but this certainly opens up new avenues for research. Now that the link has been made, it is time to look at the pathway in more detail.”

Fragile X syndrome is caused by a mutation in a gene on the X chromosome known as FMRP, leading to the loss of the FMRP protein. Scientists have been trying to establish the exact role of FMRP, to determine how its absence could lead to mental impairment.

Working with colleagues at the University of Rome, Dr Dickson discovered that FMRP helps to promote the production of “PSD-95”, a protein which is crucial to the structure and function of neural synapses.

FMRP stabilises the “template” for PSD-95 – a molecule known as mRNA. In the brains of mice lacking FMRP, this mRNA was rapidly degraded, leading to a significant reduction in levels of the PSD-95 protein.

The levels were especially reduced in the hippocampus, a structure crucial for learning, memory and certain kinds of reasoning. Thus, the learning difficulties which Fragile X patients experience may largely be caused by altered circuit wiring and impaired communication of nerve cell networks.

The study has been published in the journal Nature Neuroscience.