The Possible Medical Treatments of Fragile X

One of my personality traits [or defense mechanisms] is that when confronted with a situation that I can not control or that affects me or someone I love in a negative way I tend to study up and research the issue. I’m sure everyone here did the same thing when they learned that one of their loved ones/children was diagnosed with Fragile X.

So let me point out first I am in no way suggesting anything of the things I am about to tell you about but figured that knowledge sharing is the best thing we can all do. Please know that I am new to the board, new to being a father with a son with Fragile X and that I just need to post this right now.

[I am pretty sure all of you already know all of this so if you do I apologize in advance…]

So here we go friends…

What we know – we know that Fragile X syndrome is a genetic disorder where on the X chromosome the FRM1 produces little to no FRMP. There is also a repeat in the CGG above what is normal [5 – 55 depending on what resources you are reading]. In permutation there are repeats from 56 – 200 and in full mutation there are over 200 repeats [my son has 600]. The effects of FX are almost as broad as the autism spectrum of disorders [in my opinion]. Right now they believe that the protein not being produced or under produced by the FRM1 helps in regulating communications between brain cell receptors. They believe that many of the symptoms can be attributed by overactive signaling by group 1 metabotropic glutamate receptors [or GP1 mGluRs]. fruit flies were bred to imitate human fragile X full mutation and drugs that inhibit GP1 mGluRs and given drugs that targeted this mammalian mGluRs and the defective behavior cleared up.

With the mGlurs theory findings and what we know about GP1 mGluRs activation in the brain suggested that many of the symptoms of Fragile X could be simply accounted for by an overactive mGluR signal. mGluR is necessary for normal cerebellar function and by using these drugs [one of which is Lithium chloride] you can calm down the over stimulus and bring brain functions closer to normal.


Also that the full mutation of the FRM1 and lack or underproduction of FRMP which plays an important role in AMPA receptor protein which calms the excitability of brain cell at synapses and maintaining the proper level of excitability or “strength” of these connections.

There was a study funded by FRAXA Research Foundation and carried out by Cortex Pharmaceuticals, Inc on a drug called CX516 Ampalex that has been proven to enhance glutamate transmission in the brain through activation of AMPA receptors.


Though the study didn’t have the results we would want to see it did suggest that there were “Problems with potency of CX516 in other studies have suggested dosing may have been inadequate for therapeutic effect. In fact, when only subjects treated with an antipsychotic upon entering the CX516 study were analyzed, there appeared to be improvement in global cognitive and behavioral functioning in the CX516-treated group relative to the placebo group. Given the known ability of antipsychotics to potentiate the effect of CX516 in animal models, this would suggest that the CX516 was likely insufficiently potent”

Which leaves the door open to more clinical studies.


There was a new recent article [Sept this year] that brings renewed hope to a medication that can help people with fragile X. It goes back to the mGluR5 on the surface of the neurons. When mice were treated with a mGluR5 antagonist called MPEP that they were able to reverse the effects of the mutation. This MPEP is not a suitable drug to use in humans but it puts out a path for researches to follow down in the development of a new drug that could help. They will be starting new clinical studies in the fall on people with Fragile X and these new drugs.

“This is a very hopeful message,” Hagerman said. “This means that there will be very specific treatments that will have an impact in the very near future.”


Now here is the other thing that I found which I would have never thought to be possible until I started my research. All of the problems from Fragile X come from one little gene being in the off state. There is a company that has discovered how to turn on and off genes using something called Zinc Fingers which occur naturally in a nucleus.


I hope that maybe one day one of these paths will bear fruit for our community. Right now it is all about therapy, OT, PT, speech and calming techniques.

Thanks for letting me babble.


MIT locates key enzyme for reversing retardation in mice
‘Elegant genetic manipulation’ inhibits Fragile X symptoms

Deborah Halber, News Office Correspondent
June 25, 2007

Researchers at the Picower Institute for Learning and Memory at MIT have, for the first time, reversed symptoms of mental retardation and autism in mice.

The work will be reported in the online early edition of the Proceedings of the National Academy of Sciences the week of June 25-29.

The mice were genetically manipulated to model Fragile X Syndrome (FXS), the leading inherited cause of mental retardation and the most common genetic cause of autism. The condition, tied to a mutated X chromosome gene called fragile X mental retardation 1 (FMR1) gene, causes mild learning disabilities to severe autism.

According to the Centers for Disease Control, FXS affects one in 4,000 males and one in 6,000 females of all races and ethnic groups. The prevalence of autism ranges from one in 500 to one in 166 children. There is no effective treatment for FXS and other types of autism.

“Our study suggests that inhibiting a certain enzyme in the brain could be an effective therapy for countering the debilitating symptoms of FXS in children, and possibly in autistic kids as well,” said co-author Mansuo L. Hayashi, a former Picower Institute postdoctoral fellow currently at Merck Research Laboratories in Boston.

The study identifies a key enzyme-a chemical reaction-inducing protein-as a possible target for an FXS drug. The enzyme, called p21-activated kinase, or PAK, affects the number, size and shape of connections between neurons in the brain.

Halting PAK’s enzymatic activity reversed the structural abnormality of neuronal connections found in the FXS mice, said co-author Susumu Tonegawa, 1987 Nobel laureate and Picower Professor of Biology and Neuroscience. “Strikingly, PAK inhibition also restored electrical communication between neurons in the brains of the FXS mice, correcting their behavioral abnormalities in the process,” he said.

There are known chemical compounds that inhibit the enzymatic activity of PAK. These compounds or versions of them may be useful in the future development of drugs for treating FXS, he said.

“These are intriguing findings because the expression of the gene that inhibits PAK occurs in the third week after birth, which means that the neuronal abnormalities in the fragile X mouse are reversed after they appear,” said Eric Klann, a professor at New York University’s Center for Neural Science. “This is very exciting because it suggests that PAK inhibitors could be used for therapeutic purposes to reverse already established mental impairments in fragile X children.”
Restoring neuronal connections

Tonegawa, Hayashi, MIT graduate student Bridget M. Dolan of the Department of Biology and colleagues study the molecules that govern the formation of neuronal connections in the brain. They explore how abnormalities in these molecules could interfere with an animal’s behavior.

In the brain, small protrusions called dendritic spines on the branch-like dendrites of one neuron receive chemical signals from other neurons and communicate them to the main cell body. The numbers and shapes of dendritic spines are key to normal brain function.

FXS patients have higher numbers of dendritic spines in their brains, but each spine is longer and thinner, and transmits weaker electric signals, than those in non-affected individuals. When the enzymatic activity of PAK was inhibited in the FXS mice, abnormalities in their spine number and structure-as well as the weaker electrical communication between their neurons-were reversed.
Reversing behavioral symptoms

The FXS mice exhibited symptoms similar to those in FXS patients. These included hyperactivity; purposeless, repetitive movements reminiscent of autistic people; attention deficits and difficulty with learning and memory tasks.

“These behavioral abnormalities are ameliorated, partially or fully, by inhibiting the enzymatic activity of PAK,” Tonegawa said. “Notably, due to an elegant genetic manipulation method employed by the Picower Institute researchers, PAK inhibition in the FXS mice did not take place until a few weeks after appearance of disease symptoms. This implies that future treatment may still be effective even after symptoms are already pronounced.”

“While future studies will be necessary to further characterize the precise molecular nature of the interaction between PAK and FMR1, our findings clearly demonstrate that PAK inhibition can counteract several key cellular and behavioral symptoms of FXS,” the authors noted.

In addition to Tonegawa, a Howard Hughes Medical Institute investigator, Hayashi and Dolan, authors include colleagues at the National Institute of Mental Health and Neurosciences; the Tata Institute of Fundamental Research in India; and Seoul National University in Korea.

This work was supported by the FRAXA Foundation, the Simons Foundation, the Wellcome Trust and the National Institutes of Health.