Fragile X Syndrome

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New insights into Fragile X syndrome and the fetal brain

An illustration showing the symptoms of Fragile X syndrome. Tohoku University Graduate School of Medicine

Researchers at Tohoku University have revealed further insight into the fetal development of our brain and the potential causes of Fragile X syndrome (FSX).

During brain development, the fetal period is vital in creating neurons from neural stem cells to build up a functional adult brain. Any impairment in the developmental program could result in severe defects in the brain.

FSX is a genetic disorder characterized by intellectual disability and autistic symptoms. Children with FSX will generally suffer from developmental delays as well as social and behavioral problems.

FSX patients have a defect in the fragile X mental retardation 1 (FMR1) gene, a gene that codes for the fragile X mental retardation protein (FNRP)–the critical factor in normal brain development.

“Our study illustrated the possible molecular mechanism that causes FXS in the fetal brain and furthers our understanding of hereditary developmental disorders in the brain’s developmental stage,” said Noriko Osumi, professor at the Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine.

Using next-generation sequencing, Osumi and her team identified hundreds of FMRP regulated molecules in mice fetal brains. These molecules were associated not only with neurogenesis but also autism and intellectual disability.

Their findings showed that specific groups of molecules were involved in the intracellular signaling pathways such as Ras/MAPK, Wnt/β-catenin, and mTOR.

The mTOR activity was significant in the fetal brain of FMR1 deficient mice, suggesting that increased mTOR activity may lead to abnormal proliferation and differentiation of neural stem cells in the fetal brain. Ultimately, these molecular mechanisms could be responsible for developing the brain during the fetal period and contribute to the causes of FXS.

The research team hopes this new information will serve as an essential resource for future studies of neurodevelopmental disorders.

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Posted on Autism

Scientific breakthrough toward treatment of Fragile X syndrome

Fragile X Syndrome - YouTube


Scientists at the Hotchkiss Brain Institute (HBI), Alberta Children’s Hospital Research Institute (ACHRI), and Owerko Centre at UCalgary’s Cumming School of Medicine (CSM) have made a breakthrough discovery that could lead to treatment of Fragile X syndrome (FXS), the leading genetic cause of Autism Spectrum Disorder. The study, involving mouse models, shows promise of translating to treatment for people diagnosed with FXS.

FXS causes intellectual disabilities and hyperactive behaviour, usually more commonly seen in males than females. Children and adults with FXS are missing a protein vital to brain development called FMRP. Among other functions, FMRP helps develop synapses between neurons in the brain.

Dr. Raymond W. Turner, PhD, and members of his study team including Drs. Xiaoqin Zhan, PhD, Hadhimulya Asmara, PhD, and Ning Cheng, PhD, made the discovery while studying ion channels in the brain – special proteins that conduct currents through cells, enabling communication within the brain.

“If I had to make an analogy, it might be akin to insulin and diabetes. With FXS, individuals are missing this protein – let’s try putting it back in,” says Turner, study lead, and professor in the departments of Cell Biology & Anatomy, and Physiology & Pharmacology at the CSM. “In 30 minutes, the protein distributed throughout the brain, and accomplished what it’s supposed to do at the single-cell level.”

Unlike injected insulin, which helps someone with diabetes control their blood sugar for a few hours, the FMRP injection helps restore protein levels in the cerebellum and brain for up to one day after the injection. “Hyperactivity was reduced for almost 24 hours,” says Zhan, a postdoctoral scholar in the Turner lab. “We did one injection and we tested for it one day later, and three key proteins that are known to be in Fragile X were still at restored normal levels.”

In other, unsuccessful attempts to inject mouse models with FMRP to mitigate FXS, scientists used the entire molecule. But Turner and his colleagues used a fragment of FMRP which was able to cross the blood-brain barrier. “It’s not a full FMRP molecule at all but rather a fragment with important structural features and functional components that are active in doing things like controlling ion channels or the levels of other proteins,” says Cheng, a research associate in the Turner lab.

In the next phase, the researchers will investigate using other parts of the FMRP molecule to mitigate cognitive disorders associated with FXS. “Unlike a lot of drug therapies where you hope you can get your drug to one specific group of cells, FMRP is expressed in just about every cell in the brain, so an all-encompassing wide-based application is what you want,” says Turner.

Beyond potential treatments for FXS, the research could help develop treatments to offset behavioural symptoms characteristic of other Autism Spectrum Disorders.

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Posted on Autism

Behavioral intervention, not lovastatin, improves language skills in youth with fragile X

Researchers recommend focusing on nonmedical interventions while the search for helpful drugs continues


UC Davis MIND Institute researcher delivering the behavioral intervention PILI to parents with youth with fragile X syndrome. UC Davis Health

A UC Davis Health study found more evidence for the efficacy of telehealth-delivered behavioral intervention in treating language problems in youth with fragile X syndrome (FXS). The authors, however, could not establish efficacy for the drug lovastatin as a treatment for learning or behavior problems in individuals with FXS.

Fragile X syndrome is a single-gene disorder affecting approximately one in every 3,600 to 5,000 males and one in every 4,000 to 6,000 females. It is considered the leading inherited cause of intellectual disability. Individuals with FXS frequently have speech and language delays, behavior challenges, anxiety and symptoms of autism spectrum disorder.

Lovastatin is a widely used FDA-approved treatment for reducing cholesterol levels. It has been considered promising as a treatment for patients with FXS, based on an unblinded study and preclinical work. The UC Davis investigators assessed whether the benefits of lovastatin combined with Parent-Implemented Language Intervention (PILI) would be greater than the benefits of PILI alone.

There have been numerous demonstrations of the role a verbally responsive style of parental interaction can play in supporting the language development of children with FXS. PILI is an intervention model that aims to enhance parent’s use of this style of interaction. In a verbally responsive interaction, parents:

  • Talk about and follow the child’s focus of attention
  • Respond to the child’s communicative overtures in affectively positive and contingent ways
  • Solicit the child’s participation in the interaction
  • Provide examples of language that are slightly more advanced than the child’s current level

“This is one of the first published studies to combine behavioral and medication treatment in fragile X syndrome,” said Angela John Thurman, lead author and assistant researcher in the Department of Psychiatry and Behavioral Sciences and member of the UC Davis MIND Institute faculty.

Behavioral intervention helps youth with FXS

The study was a 20-week randomized, double-blind controlled trial. It included 30 participants between the ages of 10 and 17 with FXS. Fourteen participants took lovastatin capsules orally, starting at 10 mg and increasing weekly or as tolerated by 10 mg increments, up to a maximum dose of 40 mg daily. Sixteen participants took a placebo.

A researcher delivered PILI through video teleconferencing to the families of all participants for 12 weeks, with four activities per week. Parents were taught to use PILI language-facilitation strategies when interacting with their children during a shared storytelling activity.

The study found that both groups demonstrated significant improvements in several outcome measures. It showed significant increases, over the course of the treatment period, in the number of child’s story-related utterances, the number of different words produced by the child and the number of parent’s story-related utterances.

Parents in both groups were able to learn and use the PILI language facilitation strategies. They reported significant improvements in the severity of spoken language and social impairments of their children.

“We found evidence that the behavioral intervention using telehealth to train parents to deliver therapy to their kids works,” Thurman said. “This is consistent with our other published studies on the intervention.”

The magnitude of change observed across the two groups was comparable, providing support for the efficacy of the use of PILI in youth with FXS. The medication, however, showed no evidence of efficacy.

“The study suggests that while we pursue medical treatments, we must also do more to develop behavioral and other nonmedical interventions,” said Leonard Abbeduto, director of UC Davis MIND Institute, professor of psychiatry and behavioral sciences and co-author on the study.

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Autism linked to egg cells’ difficulty creating large proteins




Image result for Autism Linked to Egg Cells’ Difficulty Creating Large Proteins




Carnegie’s Ethan Greenblatt and Allan Spradling discuss their work, which focuses a gene called Fmr1. Mutations in this gene create problems in the brain as well as the reproductive system. They can lead to the most-common form of inherited autism, fragile X syndrome, as well as to premature ovarian failure. They found that Fmr1 serves as a sort of a helper, which boosts the production of critically important large proteins that are difficult for eggs or neurons to manufacture. A higher quality video is available on request.

 

New work from Carnegie’s Ethan Greenblatt and Allan Spradling reveals that the genetic factors underlying fragile X syndrome, and potentially other autism-related disorders, stem from defects in the cell’s ability to create unusually large protein structures. Their findings are published in Science.




Their work focuses on a gene called Fmr1. Mutations in this gene create problems in the brain as well as the reproductive system. They can lead to the most-common form of inherited autism, fragile X syndrome, as well as to premature ovarian failure.

It was already thought that Fmr1 plays a pivotal part in the last stages of the process by which the recipe encoded by a gene is used to construct a protein.

Here’s how it works:

Our genetic information is stored in DNA molecules, which are bound up tightly in the nucleus of each cell. Think of this as a master list of instructions. Before the cell can read one of the protein recipes, it must be copied over–or transcribed–by the more-mobile RNA. Think of RNA molecules as runners, carrying bits of code from the nucleus to the place where the protein will be manufactured. The RNA’s code is then translated into a string of amino acids by a special protein-making assembly line.

In most instances, these steps–transcription from DNA to RNA and translation from RNA to protein–occur in rapid succession. However, in some highly specialized kinds of cells, including neurons and eggs, it is necessary for RNA to be created and then stored for future use.

Previous work had suggested that Fmr1 prevents the stored RNA molecules from overproducing new proteins. But since many of these studies were done with brain cells, in which the results were very complicated to analyze, Greenblatt and Spradling set out to solve the problem by studying Fmr1’s effects on the protein-manufacturing process in a much simpler type of cell–fruit fly eggs.

“Our results surprised us,” Spradling said. “We found that egg cells lacking Fmr1 were at first completely normal; but over time, if they were stored, they lost function much faster than stored eggs with normal Fmr1, which is reminiscent of the human ovarian failure syndrome. What’s more, when fertilized, these Fmr1-lacking eggs created offspring with severe nervous system defects, which is reminiscent of fragile X syndrome.”

Expanding their analysis, Greenblatt and Spradling revealed that Fmr1 mutant egg cells produce reduced amounts of several hundred proteins, many of which, if missing completely, are associated with autism.

A common denominator among the affected proteins is that they encode some of the largest proteins constructed by our bodies. Even in normal eggs, large proteins, including those affected by Fmr1, are produced inefficiently, reflecting the challenge of stringing together a very long protein chain under conditions of RNA storage.

“We think that Fmr1 serves as a sort of a helper, which boosts the production of critically important large proteins that are difficult for eggs or neurons to manufacture,” Greenblatt said. “Without Fmr1, egg cells have inadequate supplies of specific large proteins and prematurely start to fail. Since Fmr1 is also important in the brain, the loss of certain large proteins associated with autism could explain the autism-like symptoms of fragile X syndrome patients.”

Future research should investigate whether problems related to the manufacture of large proteins is linked to aging or other disorders such as Alzheimer’s disease and ALS.

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Posted on Autism

What are the health conditions associated with autism?




Autism Tattoo from Laure Letitia

Autism Tattoo from Laure Letitia

What are the health conditions associated with autism?




Below are some other conditions known to be associated with ASD:

muscular dystrophy – a group of inherited genetic conditions that gradually cause the muscles to weaken

Down’s syndrome – a genetic condition that typically causes a learning disability and a range of physical features

cerebral palsy – conditions that affect the brain and nervous system, causing problems with movement and co-ordination

infantile spasms – a type of epilepsy that develops while a child is still very young (usually before they’re one year old)

neurofibromatosis – a number of genetic conditions that cause tumours to grow along the nerves (the main types are neurofibromatosis type 1 and neurofibromatosis type 2)

the rare genetic conditions fragile X syndrome, tuberous sclerosis and Rett syndrome