Experimental cancer drug reverses intellectual disability in mice.

Laboratory mouse

When the drug was given to mice it could reverse the damage of a genetic mutation which prevents the formation of new neurons.

An experimental cancer drug may help reverse the effects of an intellectual disability known as fragile X syndrome, which is commonly found in people with autism, researchers said.

The study in the journal Science Translational Medicine was done on lab mice, so any potential application for humans remains far off, cautioned the authors.

But the findings point to a pathway for further research on an inherited disability that has no cure and affects about one in 4,000 males and one in 8,000 females.

Those with fragile X syndrome display a range of cognitive problems and learning disabilities, may have unusually long faces and large ears, and about 30 per cent are also on the autism spectrum.

“We are a long way from declaring a cure for fragile X, but these results are promising,” said lead author Xinyu Zhao, a professor of neuroscience at the University of Wisconsin-Madison.

The drug, known as Nutlin-3, is currently in phase one trials for the eye cancer retinoblastoma, and has not been approved for widespread use.

Researchers found when they gave the drug to mice, it could reverse damage from a genetic mutation that causes fragile X syndrome.

This mutation means mice fail to make a protein known as FMRP, which prevents the formation of new neurons, so they cannot remember things, like a toy or object they might have recently been checking out.

When mice with this defect were given Nutlin-3 for two weeks, they “regained the ability to remember what they had seen — and smelled — in their first visit to a test chamber”, said the study.

A small dose of the drug — about 10 per cent of the amount being tested currently in human trials — appeared to block the last stage of the chain reaction set off by a mutation in the FMRP gene.

“There are many hurdles,” said Professor Zhao. “Among the many questions that need to be answered is how often the treatment would be needed. Still, we’ve drawn back the curtain on fragile X a bit, and that makes me optimistic.”

New insights that link Fragile X Syndrome (FXS) and Autism Spectrum Disorders (ASD)

Crucial role for FMRP (Fragile X Mental Retardation Protein) in embryonic development of the brain cortex

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID), as well as the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by the absence or incorrect production of the protein FMRP (Fragile X Mental Retardation Protein). Scientists at VIB and KU Leuven (Belgium), in collaboration with Tor Vergata University (Italy) and VU University of Amsterdam (The Netherlands) have pinpointed a novel role that FMRP plays during the embryonic development of the brain cortex. The study reveals that the absence of FMRP leads to a delay in the proper formation of the cortex and shows that FMRP is responsible for transformation of neurons into a “locomotion mode” to reach their final position in the cortex. This delay in the neurodevelopmental program has an effect on the early postnatal life and the fine-tuning of brain connectivity.

“Our research underlines the critical role of FMRP in brain development, more specifically in the correct positioning of brain cells during the early stages of development of the cortex. These findings contribute to our current understanding of Fragile X and might provide insights into the cellular mechanisms affected in patients with Fragile X that have autism spectrum disorders and epilepsy: two neurological disorders marked by affected cortical development and brain connectivity” says Claudia Bagni (VIB/KU Leuven/University Tor Vergata) who led the work.

The discovery in brief: FMRP, an important player in the development of our brain.
The study of the Fragile X syndrome (FXS) has been the research object of Claudia Bagni and her team for more than 15 years. Using a mouse model for FXS, her collaborators Giorgio La Fata, Annette Gärtner and Nuria Domínguez-Iturza could prove that FMRP regulates the maturation (multipolar to bipolar) and positioning of the brain cells in the cortex during embryonic development. Furthermore the team unraveled the molecular mechanism through which FMRP regulates this processes and were able, upon the reintegration of FMRP in the embryo, to normalize the early postnatal brain wiring deficits.

The brain cortex is the domain of the brain where information from the rest of the body is received, processed and interpreted. The elaborated information is then converted into thoughts and concrete driving signals for the body. Thus, mistakes or delays in the correct development of the brain cortex are thought to lead to an impaired ability to interpret and process information required for our daily life. Because affected brain connectivity is a hallmark of ASD, this study might explain why some patients with FXS have autism-related symptoms.

FMRP is a key regulator of cell shape and polarity.
The team could demonstrate that in a healthy brain FMRP assures the correct production of the protein N-Cadherin. In the absence of FMRP the levels of N-cadherin are reduced with the consequence that neuronal cells are delayed in their maturation, a developmental program called multipolar to bipolar transition, which is prerequisite for correct positioning in the cortex during development. In collaboration with Carlos Dotti (VIB/KULeuven) and Meredith Rhiannon (VU University of Amsterdam), the team showed that the re-introduction of FMRP or N-cadherin before birth normalized the maturation and positioning of the brain cells and the wiring deficits observed at early postnatal stages.

Into sophisticated MRI for diagnosis of intellectual disabilities.
Finally, in collaboration with the team of Uwe Himmelreich (MOSAIC, KU Leuven) the VIB/KUL/TV scientists combined the cellular and molecular approaches with high-resolution DTI-MRI (Diffusion-Tensor Imaging – Magnetic Resonance Imaging). Currently, DTI-MRI is one of the most powerful tools to anatomically investigate brain connectivity, as it can be used to study the orientation and integrity of white matter tracts. Taking advantage of an extremely powerful MRI system for small animals, which enables to scan the brains of FXS mice, the scientists obtained structural information of the juvenile FXS mouse brain that revealed abnormalities in the connectivity of the cortex.

UNC child neurologist finds potential route to better treatments for Fragile X, autism.

When you experience something, neurons in the brain send chemical signals called neurotransmitters across synapses to receptors on other neurons. How well that process unfolds determines how you comprehend the experience and what behaviors might follow. In people with Fragile X syndrome, a third of whom are eventually diagnosed with Autism Spectrum Disorder, that process is severely hindered, leading to intellectual impairments and abnormal behaviors.

In a study published in the online journal PLoS One, a team of UNC School of Medicine researchers led by pharmacologist C.J. Malanga, MD, PhD, describes a major reason why current medications only moderately alleviate Fragile X symptoms. Using mouse models, Malanga discovered that three specific drugs affect three different kinds of neurotransmitter receptors that all seem to play roles in Fragile X. As a result, current Fragile X drugs have limited benefit because most of them only affect one receptor.

“There likely won’t be one magic bullet that really helps people with Fragile X,” said Malanga, an associate professor in the Department of Neurology. “It’s going to take therapies acting through different receptors to improve their behavioral symptoms and intellectual outcomes.”

Nearly one million people in the United States have Fragile X Syndrome, which is the result of a single mutated gene called FMR1. In people without Fragile X, the gene produces a protein that helps maintain the proper strength of synaptic communication between neurons. In people with Fragile X, FMR1 doesn’t produce the protein, the synaptic connection weakens, and there’s a decrease in synaptic input, leading to mild to severe learning disabilities and behavioral issues, such as hyperactivity, anxiety, and sensitivity to sensory stimulation, especially touch and noise.

More than two decades ago, researchers discovered that – in people with mental and behavior problems – a receptor called mGluR5 could not properly regulate the effect of the neurotransmitter, glutamate. Since then, pharmaceutical companies have been trying to develop drugs that target glutamate receptors. “It’s been a challenging goal,” Malanga said. “No one so far has made it work very well, and kids with Fragile X have been illustrative of this.”

But there are other receptors that regulate other neurotransmitters in similar ways to mGluR5. And there are drugs already available for human use that act on those receptors. So Malanga’s team checked how those drugs might affect mice in which the Fragile X gene has been knocked out.

By electrically stimulating specific brain circuits, Malanga’s team first learned how the mice perceived reward. The mice learned very quickly that if they press a lever, they get rewarded via a mild electrical stimulation. Then his team provided a drug molecule that acts on the same reward circuitry to see how the drugs affect the response patterns and other behaviors in the mice.

His team studied one drug that blocked dopamine receptors, another drug that blocked mGluR5 receptors, and another drug that blocked mAChR1, or M1, receptors. Three different types of neurotransmitters – dopamine, glutamate, and acetylcholine – act on those receptors. And there were big differences in how sensitive the mice were to each drug.

“Turns out, based on our study and a previous study we did with my UNC colleague Ben Philpot, that Fragile X mice and Angelman Syndrome mice are very different,” Malanga said. “And how the same pharmaceuticals act in these mouse models of Autism Spectrum Disorder is very different.”

Malanga’s finding suggests that not all people with Fragile X share the same biological hurdles. The same is likely true, he said, for people with other autism-related disorders, such as Rett syndrome and Angelman syndrome.

“Fragile X kids likely have very different sensitivities to prescribed drugs than do other kids with different biological causes of autism,” Malanga said.

Arc protein ‘could be key to memory loss’, says study.

Scientists have discovered more about the role of an important brain protein which is instrumental in translating learning into long-term memories.


Writing in Nature Neuroscience, they said further research into the Arc protein’s role could help in finding new ways to fight neurological diseases.

The same protein may also be a factor in autism, the study said.

Recent research found Arc lacking in the brains of Alzheimer’s patients.

Dr Steve Finkbeiner, professor of neurology and physiology at the University of California, who led the research at Gladstone Institutes, said lab work showed that the role of the Arc protein was crucial.

“Scientists knew that Arc was involved in long-term memory, because mice lacking the Arc protein could learn new tasks, but failed to remember them the next day,” he said.

Further experiments revealed that Arc acted as a “master regulator” of the neurons during the process of long-term memory formation.

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Scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory centre, in Alzheimer’s disease patients.”

Dr Finkbeiner

The study explained that during memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories.

The authors found that it was Arc that directed this process, from inside the nucleus.

Dr Finkbeiner said people who lack the protein could have memory problems.

“Scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory centre, in Alzheimer’s disease patients.

“It’s possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer’s.”

The study says that dysfunctions in Arc production and transport could also be a vital player in autism.

The genetic disorder Fragile X syndrome, for example, which is a common cause of both mental disabilities and autism, directly affects the production of Arc in neurons.

The Californian research team said they hoped further research into the Arc protein’s role in human health and disease would provide even deeper insights into these disorders and lay the groundwork for new therapeutic strategies to fight them.

Source: BBC


Fragile X–Associated Tremor/Ataxia SyndromeInfluence of the FMR1 Gene on Motor Fiber Tracts in Males With Normal and Premutation Alleles.

Importance  Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile X–associated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS.

Objective  To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles.

Design and Setting  A case-control study conducted at the University of California, Davis, from April 1, 2008, through August 31, 2009. All data were collected masked to the carrier status of theFMR1 gene.

Participants  Thirty-six male premutation carriers with FXTAS and 26 male premutation carriers without FXTAS were recruited through their family relationships with children affected by fragile X syndrome. The controls were 34 unaffected family members and healthy volunteers from the local community.

Main Outcomes and Measures  The CGG repeat lengths and FMR1 mRNA expression levels in peripheral blood lymphocytes, motor functioning, and white matter structural integrity that were estimated using diffusion tensor imaging. After data collection, we selected 4 motor tracts to reconstruct using diffusion tensor tractography, namely, the middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum.

Results  All fiber tracts exhibited weaker structural connectivity in the FXTAS group (decreased 5%-53% from controls, P ≤ .02). Genetic imaging correlation analysis revealed negative associations of CGG repeat length and FMR1 mRNA with connectivity strength of the superior cerebellar peduncles in both premutation groups (partial r2 = 0.23-0.33, P ≤ .004). In addition, the measurements from the corpus callosum and superior cerebellar peduncles revealed a high correlation with motor functioning in all 3 groups (r between partial least square predicted and actual test scores = 0.41-0.56, P ≤ .04).

Conclusions and Relevance  Distinct pathophysiologic processes may underlie the structural impairment of the motor tracts in FXTAS. Although both the corpus callosum and superior cerebellar peduncles were of great importance to motor functioning, only the superior cerebellar peduncles exhibited an association with the elevated RNA levels in the blood of fragile X premutation carriers.

Source: JAMA

Mutations causing syndromic autism define an axis of synaptic pathophysiology

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2+/− and Fmr1−/y mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.



What Causes Fragile X Syndrome?

Fragile X Syndrome

Fragile X is a group of genetic disorders that can affect individuals and their families in many ways because they are all caused by changes in the same gene, the Fragile X Mental Retardation 1 (FMR1) gene. The group of fragile X conditions includes:

  • Fragile X syndrome is the most common known cause of intellectual disability that can be inherited.
  • Fragile X-associated tremor/ataxia syndrome (FXTAS) involves tremors and problems with walking, balance, and memory. FXTAS occurs in some older men and women who carry certain changes in the FMR1 gene. (See people with a premutation.)
  • Fragile X-associated tremor/ataxia syndrome (FXTAS) can cause tremors and problems with walking, balance, and memory. FXTAS occurs in some older men who have changes in the FMR1 gene.

What is Fragile X Syndrome?

Fragile X syndrome is the most common known cause of intellectual disability, also known as mental retardation, that can be inherited (passed from one generation to the next).

Physical and behavioral signs that a child has fragile X syndrome include:

  • Not sitting, walking, or talking as early as other children (this is known as having developmental delays)
  • Learning disabilities
  • Speech and language delays
  • Behavioral problems such as attention-deficit/hyperactivity disorder (ADHD)

Children often have a typical facial appearance that gets more noticeable with age. These features include:

  • A large head
  • A long face
  • Prominent ears, chin, and forehead

Males who have fragile X syndrome usually have some degree of intellectual disability that can range from mild to severe. Females with fragile X syndrome can have normal intelligence or some degree of intellectual disability with or without learning disabilities.

Autism spectrum disorders also occur more frequently in children with fragile X syndrome.

How Many People Have Fragile X Syndrome?

The exact number of people who have fragile X syndrome is unknown, but it is estimated that about 1 in 4,000 males and 1 in 6,000 to 8,000 females have the disorder. Although fragile X syndrome occurs in both males and females, females usually have milder symptoms.

FXS is caused by a change (mutation) in a gene on the X chromosome. Genes contain codes, or recipes, for proteins. Proteins are very important biological components (parts) in all forms of life. The gene on the X chromosome that causes FXS is called the Fragile X Mental Retardation 1 (FMR1) gene. The FMR1 gene makes a protein that is needed for normal brain development. This protein is not made in individuals who have FXS.

How is Fragile X Syndrome Diagnosed?

Fragile X syndrome can be diagnosed by testing a person’s DNA from a blood sample. A physician or genetic counselor must order the test. Testing can also be done to detect changes in the FMR1 gene that can lead to the different conditions mentioned above.

What is CDC Doing about Fragile X Syndrome?

Since 2005, CDC and its partners have been working on several public health activities to find out more about fragile X syndrome.

These projects include:

  • Fragile X Clinic Consortium
    The fragile X community is linking together clinics that care for people with fragile X, FXTAS, and FXPOI. The purpose is to improve care, identify research projects, and develop a patient registry. CDC is providing support for this effort.
  • Fragile X Pilot Surveillance Projects
    CDC is supporting a project to estimate the prevalence of FXS in individuals who have autism and intellectual disability. Researchers at Johns Hopkins University and the Medical University of South Carolina are working on this project.
  • National Fragile X Survey
    CDC is working with researchers at Research Triangle Institute (RTI) on a national survey that will identify the needs of families with fragile X syndrome. A total of 1,221 families have enrolled in the survey. The results from this survey will help researchers find ways to better serve families with fragile X.
  • Fragile X syndrome cascade testing and genetic counseling protocols
    The 2005 National Society of Genetic Counselors guidelines for fragile X-related disorders were updated to include recent research on the different conditions that can affect people who have changes in the FMR1 gene. In addition, efforts were taken to help inform health care providers about these conditions.
  • Development of a newborn screening test for fragile X syndrome
    CDC has worked with researchers to develop a test to detect fragile X syndrome in newborns. This project will also find out how often fragile X syndrome occurs in newborns.
  • Single Gene Resource Center
    CDC is working with the Genetic Alliance to help people find quality information on single gene disorders, such as fragile X syndrome.