Fragile X

Mutations Causing Syndromic Autism Define an Axis of Synaptic Pathophysiology

Source: 
Nature
Date Published: 
November 23, 2011
Year Published: 
2011

New research reveals that two genetic forms of autism, fragile X syndrome and tuberous sclerosis, are actually caused by opposite malfunctions – while fragile X is caused by overproduction of proteins at the synapse, tuberous sclerosis is caused by underproduction. Interestingly, while the causes of fragile X and tuberous sclerosis are distinctly different, both disorders often result in intellectual disability and autism spectrum disorder. Researchers made the discovery while studying mGluR5 (Metabotropic glutamate receptor 5), a receptor on the surface of neurons that is key in aiding communication at the synapse – the junction between neurons. During normal signaling, the mGluR5 receptor binds to the neurotransmitter glutamate after it is released across the synapse, resulting in the production of new synaptic proteins. Fragile X protein (FMRP) halts protein synthesis to ensure that the appropriate amount is produced -- in fragile X syndrome, changes to the gene that controls FMRP allow synaptic proteins to continue production unchecked, resulting in too much protein. Researchers have previously shown that introducing a substance to block mGluR5 reverses some of the symptoms of fragile X, and human drug trials are currently underway. Armed with an understanding of the underlying causes of fragile X, researchers in this study examined mice with tuberous sclerosis mutations and discovered something surprising. In this case, the disorder was caused by the opposite malfunction – too little protein synthesis at the synapse, which could be treated with a drug stimulating mGluR5. Further, when the researchers bred the two mice together, many of their autistic features went away. The findings of the study indicate that proper brain function can only occur within a narrow range of mGluR5 protein synthesis – changes in either direction lead to syndromes with similar behavioral symptoms. This also suggests that drug treatments for autism spectrum disorder will need to be individually tailored, as conditions that appear similar may have quite different underlying causes.

--IACC 2011 Summary of Advances in ASD Research

How Brain's Structure And Genes Affect Autism And Fragile X Syndrome

Source: 
Medical News Today
Date Published: 
November 17, 2011
Abstract: 

Research just released shows that scientists are finding new tools to help understand neurodevelopmental disorders like autism and fragile X syndrome.

Study In Fruit Flies Has Implications For Autism, Other Cognitive Impairment Syndromes

Source: 
Medical News Today
Date Published: 
November 1, 2011
Abstract: 

Loss of FMR1 function is the most common genetic cause of autism. Understanding how this gene works is vital to finding new treatments to help Fragile X patients and others...

Institute For Basic Research in New York seeking adults with Fragile X for New Clinical Trial

Source: 
October 17, 2011
Abstract: 

The Institute for Basic Research in Staten Island is seeking adult participants for a new Fragile X treatment trial. This is a large scale trial of AFQ056 from Novartis for people aged 18-45 who have Fragile X. AFQ056 is an mGluR5 antagonist. The current study is just for adults but the next step is to extend the trial to ages 12-17. After completing the 20 week trial, participants will be offered the option of taking this medication free of charge until it comes to market.

The Institute for Basic Research in Staten Island is seeking adult participants for a new Fragile X treatment trial. 

This is a large scale trial of AFQ056 from Novartis for people aged 18-45 who have Fragile X.  AFQ056 is an mGluR5 antagonist.  The current study is just for adults but the next step is to extend the trial to ages 12-17.  After completing the 20 week trial, participants will be offered the option of taking this medication free of charge until it comes to market.

The principal investigator on this study is Dr. Angelo Porto, Dept. of Psychology, Institute for Basic Research(IBR). porto_a@medscape.com or 718-494-8028

Additional information about AFQ056 and the study can be found at fraxa.org/getInvolved_studies.aspx

Protein Interactome Reveals Converging Molecular Pathways

Source: 
Science Translational Medicine
Date Published: 
June 8, 2011
Year Published: 
2011

A recent study sheds light on how a variety of different mutations in genes that seemingly have little in common can each result in the symptoms of autism. To answer this question, researchers developed a molecular map of protein networks or "interactome" to identify how proteins associated with ASD interact with hundreds of other proteins. Researchers used genes known to be associated with syndromic autism as a starting point for building the interactome. Syndromic autism occurs as part of a broader genetic disorder such as fragile X, Angelman syndrome, and Rett syndrome -- understanding protein interactions with syndromic autism may give insight into idiopathic autism, or autism with no known cause. Using 26 genes associated with syndromic autism, researchers hypothesized that the seemingly dissimilar genes might interact with shared partners in common molecular pathways, leading to the symptoms of autism. Indeed, researchers identified a complex network of 539 proteins that interacted with the autism-related proteins, successfully demonstrating that all of the proteins linked to autism are connected by interactions with common partners. The interactome confirmed previously suspected gene relationships and several new pairings, such as the connection between SHANK3 and TSC1, which share 21 common protein partners. Researchers then performed a microarray analysis on 288 individuals with idiopathic autism in a search for genes within the interactome. They identified three novel copy number variations -- chromosomal deletions and duplications -- on genes found in the network, demonstrating that the interactome may help to identify new genes related to ASD and understand complicated genetic variation.

--IACC 2011 Summary of Advances in ASD Research

Study Shows Promise For New Drug To Treat Fragile X

Source: 
Science Daily
Date Published: 
January 8, 2011
Abstract: 

The first drug to treat the underlying disorder instead of the symptoms of Fragile X, the most common cause of inherited intellectual disability, shows some promise.

Better Way Developed to See Molecules at Work in Living Brain

Source: 
Science Daily
Date Published: 
October 12, 2010
Abstract: 

By creating a better way to see molecules at work in living brain cells, researchers affiliated with MIT's Picower Institute for Learning and Memory and the MIT Department of Chemistry are helping elucidate molecular mechanisms of synapse formation. These studies could also help further understanding of how synapses go awry in developmental diseases such as autism and Fragile X syndrome.

Seaside Therapeutics Reports Positive Data from Phase 2 Study of STX209 in Autism Spectrum Disorders

Source: 
Seaside Therapeutics
Date Published: 
September 9, 2010
Abstract: 

Seaside Therapeutics reported findings on STX209 at the 42nd Autism Society National Conference. STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist being studied for the treatment of ASD and fragile X syndrome (FXS).

As previously reported, STX209 demonstrated statistically significant improvements across a number of global and specific neurobehavioral outcomes in the open-label Phase 2a study, including significant improvements in social impairment—a core symptom of ASD.