• Trials Beginning on Drug to ‘Correct or Improve’ Fragile X

• Commentary: Justin Fallon’s group at Brown University recently reported observation of the FMR1 protein in particles present in neurons early in development (Christie et al. The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits. J Neurosci (2009) vol. 29 (5) pp. 1514-24). Of particular interest was the finding that these particles are located in the axonal, or pre-synaptic processes of neurons, those parts of the cell that carry signals to downstream neurons. In the past several years, the majority of groups have focused on the role of the FMR1 protein in dendrites, the parts of neurons that receive signals from upstream neurons, where there is now abundant evidence for a defect in the absence of FMR1. The findings of the Fallon group reinforce the likelihood that FMR1 protein has a role at both axons and dendrites, and will stimulate efforts to define additional functions for FMR1. This work was funded in part by a grant from the FRAXA Research Foundation.
  Article: http://sfari.org/news/fragile-x-granules-provide-clues-to-autism

• Biologists Discover Link Between CGG Repeats In DNA And Neurological Disorders

• New Drug Shows Promise For Treatment of Adults With Fragile X Syndrome
• A Pilot Open-Label single-Dose Trial of Fenobam in Adults with Fragile X Syndrome

• New Method of Scoring IQ Tests Benefits Children with Intellectual Disabilities

• Researchers Call For Fragile X Testing Throughout The Lifespan

• Study Finds People with Fragile X, Carriers Likely to Have Additional Conditions
• American Journal of Medical Genetics Research Article

• An article about Dr. Carlo Paribello’s work and featuring a photo of his two sons. Dr. Paribello is a member of the Fragile X Clinical & Research Consortium

• Fragile X Research: A Status Report – July 2008 Read More...

• Lack Of Fragile X And Related Gene Fractures Sleep

NFXF Note: Investigator Stephen Warren is a member of the National Fragile X Foundation’s Scientific and Clinical Advisory Committee and a scheduled speaker at its July 2008 11th International Fragile X Conference. ScienceDaily (Mar. 9, 2008) — Scientists using a new drug screening method in Drosophila (fruit flies), have identified several drugs and small molecules that reverse the features of fragile X syndrome -- a frequent form of mental retardation and one of the leading known causes of autism. The discovery sets the stage for developing new treatments for fragile X syndrome. Read More...

ScienceDaily (Feb. 1, 2008) — Scientists at The Scripps Research Institute have discovered a new gene involved in fragile X syndrome, a condition that often shares many symptoms of autism. The discovery may lead to new tests or treatments for several neurological disorders. Read More...

Washington, February 19: A double-blind, placebo-controlled multi-center study has confirmed that a form of the amino acid carnitine called L-acetyl carnitine (LAC) is a safe alternative to stimulants that are used for the treatment of attention deficit and/or hyperactivity disorder (ADHD) in children who are also suffering from Fragile X Syndrome, the most common hereditary form of mental retardation. Read More...

It’s probably no news to many of you that new medications may be on the near horizon. Read More...

New findings have major therapeutic implications for fragile X syndrome and autism

Embryonic stem cell study uncovers mechanism for Fragile X gene mutation (NFXF-funded) Read More...
Published in "Cell StemCell"

Reports:
United Press International: Advance reported in FXTAS syndrome
Genetic Engineering & Biotechnology News: Researchers Discover Disease Pathway for FXTAS

Reports:
http://timesofindia.indiatimes.com/HealthScience/Indians_crack_mental_illness/articleshow/2148715.cms
http://www.eurekalert.org/pub_releases/2007-06/miot-mrr062507.php

Commentary: Previous work by Tonegawa's MIT lab and collaborators from India had shown that mice expressing a mutated PAK gene (p21-activated kinase) exhibited features of cortical neuron spine morphology and deficits in cortical long term potentiation opposite to that seen in fragile X KO (Knock Out) mice. By selective breeding, they obtained mice with both mutations present. They now show improvement of the brain structure and behavioral changes as compared to when either mutation is present alone. Further, they found that the fragile X protein (FMRP) directly interacts with the PAK protein. They suggest that suppression of PAK gene expression could be a target for future treatment in fragile X syndrome.

Technical paper: Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice

Report: Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome

Commentary: Fragile X Syndrome (FXS) is caused by the inherited loss of FMRP, an mRNA binding protein that is hypothesized to regulate the local synthesis of specific proteins at brain synapses. The inability to locally synthesize protein machinery at synapses in FXS is believed to contribute to the impairments in cognitive function in FXS. A major goal has been to identify which proteins are defective in their local production at synapses in FXS. In this study, Gary Bassell and colleagues at Emory University have discovered new FMRP targets, PSD-95, GluR1/2 and CaMKIIa whose synaptic protein synthesis is defective in a mouse model of Fragile X. Each of these targets are known to have critical roles in synaptic plasticity, learning and memory. This study advances our understanding on how brain synapses in FXS are altered and opens up potential new targets for clinical intervention.

Report: FMR4 and Its Possible Relationship to Fragile X

Researchers from Scripps Florida think that a recent discovery will lead to a new understanding of fragile X syndrome

Commentary: The National Fragile X Foundation has received a number of questions regarding recent news reports. While this research has not yet been subject to peer review, this is a good opportunity to place news reports of this type in the broader context of Fragile X research.

Many years of research by a large number of investigators has demonstrated conclusively that the Fragile X gene (FMR1), when mutated, causes fragile X syndrome as well as several additional disorders, such as FXTAS and POF. Exactly how the gene works and how its various associated disorders can be treated is the subject of a great deal of research. However, it is clear that more work on the FMR1 gene itself, and work on the development of drugs that modulate the consequences of abnormal FMR1 gene expression on the glutaminergic and GABAergic neural circuits, is likely to lead to useful therapies for fragile X syndrome and associated disorders. WhatFMR4 does is not known. However, the more we learn about what is going on in and around the FMR1 gene the better.

The Foundation looks forward to reporting further on this interesting research once it has been published in a peer-reviewed journal.

Report: http://www.genengnews.com/news/bnitem.aspx?name=15507799

Editor's Note: The following commentary is based on feedback provided by the National Fragile X Foundation's Scientific and Clinical Advisory Committee. Commentary: The link between FXS and Down Syndrome is weak. The two disorders both have similar faulty wiring but this does not say they develop the faulty wiring though the same mechanism. Rather that there are elements of a final common pathway for both disorders. The genetic defect in DS is a lot more complex because it affects all the genes regulating wiring on the entire chromosome 21. The interesting thing about these [types of] studies is that they significantly extend information we have on pre-synaptic deficits in FXS. (Much of the prior work has been focused on post-synaptic effects.)

This is a relationship on a most broad level in that both have aspects of synaptic dysfunction. It is important to recognize that unlike fragile X syndrome, which is due to a single gene and the absence of a single protein, Down syndrome is much more complex due to the extra copy of chromosome 21. No one gene on chromosome 21 is responsible for the cognitive problems in Down syndrome (which are typically more severe). Many genes on chromosome 21 are therefore over expressed and some of these actually modulate expression of genes elsewhere, up and down. So while there may be similarity at one level, the mechanisms may be quite different.

From the Scientific & Clinical Advisory Committee of the National Fragile X Foundation

Update on Biomedical Treatment Studies in Fragile X Syndrome:
MPEP, Ampakine and Mifepristone

Edited by Allan L. Reiss, M.D., Chair, Scientific and Clinical Advisory Committee of the National Fragile X Foundation

MPEP

We are now entering a time in which syndrome-specific treatments for persons with fragile X syndrome are being conceived, developed and, in some cases, tested in animals or humans. For example, a study recently reported at the 2003 Society for Neuroscience meeting in New Orleans by Drs. Yan, Rothschild and Bauchwitz at Columbia University indicated that the anti-seizure agent, "MPEP" (2-methyl-6-phenylethynyl-pyridine), was effective in blocking a type of sound induced seizure in the mouse (knockout) model for fragile X syndrome. This finding, while only tested to date in a small number of animals, supports suggestions from other scientists that the glutamate neurotransmitter system may contribute to some neurological problems associated with fragile X. However, whether MPEP effects are specific to fragile X and whether there may eventually be any direct benefits from MPEP-like drugs in the future for individuals with fragile X are unknown at this time.

Ampakine and Mifepristone

Treatment trials in humans with fragile X syndrome also have begun. Drs. Elizabeth Berry- Kravis of Rush University Medical Center and Randi Hagerman of the UC Davis MIND Institute are using the drug CX516, an Ampakine, to activate glutamate neurotransmitter receptors in the brains of individuals with fragile X. In the other trial, Dr. Allan Reiss of Stanford University is using the drug, Mifepristone, to block the effects of the stress hormone, cortisol, in the brains of persons with fragile X syndrome. The effects of these treatments on behavior and learning are being assessed in both trials. Results from these studies are not yet available.

Summary and Commentary

Biomedical studies such as these are the beginning of a new era of research on fragile X syndrome and offer the potential to increase our understanding of brain dysfunction in affected individuals. At the same time, these studies represent only the first steps in a long, deliberate process of testing and refining future research that will eventually culminate in safe and effective treatments for fragile X syndrome. It is likely that this process will take years before specific treatments can be approved for use in persons affected by fragile X syndrome. As a result, we also must continue to prioritize the development of better educational, therapeutic, behavioral, and environmental interventions for fragile X, that can be used alone, or in combination with future biomedical treatments.

It is an exciting time in the field and we should be cautiously hopeful that the years ahead will bring us increasingly more effective treatments for our family members, students, patients and friends with fragile X syndrome.

EDITORS NOTE: The funding sources for the above studies are as follows: Ampakine: Elizabeth Berry-Kravis, MD, PhD and MPEP: Drs. Yan, Rothschild and Bauchwitz, funded by FRAXA Research Foundation
Mifepristone: Allan Reiss, MD funded by Private Donors Ampakine: Randi Hagerman, MD, funded by The M.I.N.D Institute at UC Davis

How do families find out about fragile X syndrome? Each family has a unique story. Usually learning about fragile X syndrome is a journey involving lots of detective work. In our longitudinal study of young children with FXS, we became aware of many of these stories, and decided to do a larger study to learn more about family experiences and the results of having or not having information about their child’s diagnosis. Our article summarizing survey data from 274 families appeared in the February, 2003 issue of Pediatrics, the official journal of the American Academy of Pediatrics. We felt that this was an important audience to learn about the frustrations and challenges in discovering fragile X syndrome, since the pediatrician is usually the first professional to whom parents turn when they have questions or concerns about their children. Hopefully this study will help raise awareness of the importance of early identification and of following up on parental concerns to get an accurate diagnosis. Don Bailey, Ph.D.

ABSTRACT: Discovering Fragile X Syndrome: Family Experiences and Perceptions Donald B. Bailey, Jr, PhD; Debra Skinner, PhD; and Karen L. Sparkman, EdS We used surveys from 274 families who had at least I child with fragile X syndrome (FXS) to determine their experiences in discovering FXS, factors associated with the timeliness of discovery, and the perceived consequences of obtaining this information. For families of male children who were born in the last decade, someone first became concerned about the child’s development at an average age of 13 months. Professional confirmation of a developmental delay did not occur until an average age of 21 months, and a FXS diagnosis occurred at an average age of nearly 32 months. Families reported several barriers to discovering FXS and frustration with the process. Many families had additional children with FXS without knowing reproductive risk. A range of perceived benefits and challenges associated with the discovery were reported. We conclude that selected pediatric practices could promote earlier identification but in only a limited way and predict that disorders such as FXS will continue to challenge current criteria for determining viable candidate disorders for newborn screening. Pediatrics 2003;111:407—416; fragile X syndrome, pediatric screening, early identification.

Editor’s Note: The entire article/research paper can be viewed at http://www.pediatrics.org/cgi/content/full/111/2/407 by paying a one-time fee of $10.00.
Required by the American Academy of Pediatrics