Tag Archives: Gene Mutation

Question?: Rett Syndrome Treatment

Carol asks…

Pervasive Developmental Disorder…?

What is it??? What are the causes? What does it do? How to get rid of it if you can……

THANKS !
PLEASE ANSWERRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

admin answers:

Pervasive developmental disorders cause abnormal development, including social and communication development. The symptoms appear early on – by the age of 3 at least, except in one of the disorders – and last throughout the lifetime. There are five of them: autism, Asperger’s syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS). Autism, Asperger’s, and PDD-NOS are called the autism spectrum.

Symptoms of autism include difficulty socializing and communicating with others, delayed speech, lack of eye contact, difficulty interpreting nonverbal signals, intense fixations and interests, repetitive or compulsive movements, poor motor coordination, and abnormal sensory processing. The severity of these symptoms varies considerably. Asperger’s syndrome is a mild and high-functioning form of autism. The symptoms are the same except there is no speech delay. PDD-NOS is when someone has some autistic traits and significant impairment, but does not meet the diagnostic criteria for another PDD. These disorders have a genetic basis, but researchers have not yet uncovered the specifics. Some people believe environmental factors also play a role.

Childhood disintegrative disorder is when a child appears to be developing normally, then suddenly regresses sometime after the age of 3. The cause of this disorder is unknown. Rett syndrome occurrs almost exclusively in females. Infants with this disorder experience regression between 6-18 months of age. Symptoms include lack of speech, seizures, sensory problems, poor motor coordination, growth abnormalities, and repetitive movements. It is caused by a gene mutation on the X chromosome.

None of the PDDs are curable. There are many treatments available, including occupational therapy, cognitive behavioral therapy, applied behavior analysis, speech therapy, social skills training, behavior therapy, and certain medications.

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Question?: Rett Syndrome In Boys

Helen asks…

What is Rett Syndrome?

What is the disorder and how do you get it?
What are the symptoms and how is it diagnosed?
How is it treated? Are there any possible cures?

admin answers:

Its a genetic mutation in the MEPC2 gene on the x-chromosome (which is why most boys who have it will die before birth or in ealry infancy, b/c they only have one x & girls have 2 so if one is “bad” the other still one keeps her alive)

usually diagnosed through a blood test, looking for said gene mutation. If mutation is not found it can be diagnosed thorough the “stages” criteria (go on there website retthelp or rett.org) there are 4 stages- the first one usually over looked b/c the symtpoms are usually milder then the rest.

Treatment is according to sympotoms but can range from scoliosis surgery, GI tube being put in, Anti-seizure medicines, physical therapy, eye gaze communication, & many more
People also try alternative/holistic treatments like accupuncure, massage therapy, etc..

There is no cure…YET!!
They have been able to genetically engeneer a mouse to have Rett syndrome & have been successful in reversing it 100%
& there is always hope that one day I will wake up & hear that its been cured in a living human being. Also they are trying to raise money to try EVERY drug on the market on Rett syndrome mice to see what effects it may have on the syndrome.

I believe there are possible cures..but as of right now we just dont have it

Also as a side note: the range of severity greatly depends on how many of the mutated x’s are activated/deactivated

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Mice With Dravet Syndrome Mutation Given Low-Dose Sedative Show Improvements In Autism-Like Behavior

Main Category: Autism
Also Included In: Pain / Anesthetics;  Neurology / Neuroscience;  Genetics
Article Date: 24 Aug 2012 – 0:00 PDT Current ratings for:
Mice With Dravet Syndrome Mutation Given Low-Dose Sedative Show Improvements In Autism-Like Behavior
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A low dose of the sedative clonazepam alleviated autistic-like behavior in mice with a mutation that causes Dravet syndrome in humans, University of Washington researchers have shown.

Dravet syndrome is an infant seizure disorder accompanied by developmental delays and behavioral symptoms that include autistic features. It usually originates spontaneously from a gene mutation in an affected child not found in either parent.

Studies of mice with a similar gene mutation are revealing the overly excited brain circuits behind the autistic traits and cognitive impairments common in this condition. The research report appears in Nature. Dr William Catterall, professor and chair of pharmacology at the UW, is the senior author.

Dravet syndrome mutations cause loss-of-function of the human gene called SCN1A. People or mice with two copies of the mutation do not survive infancy; one copy results in major disability and sometimes early death. The mutation causes malformation in one type of sodium ion channels, the tiny pores in nerve cells that produce electrical signals by gating the flow of sodium ions.

The Catteralll lab is studying these defective ion channels and their repercussion on cell-to-cell signaling in the brain. They also are documenting the behavior of mice with this mutation, compared to their unaffected peers. Their findings may help explain how the sporadic gene mutations that cause Dravet syndrome lead to its symptoms of cognitive deficit and autistic behaviors.

The sodium ion channels in question malfunction in specific nerve cells, called inhibitory neurons, whose job is to send messages to hush the electrical signaling of neighboring cells. If only transmissions that excite nearby cells get through, the balance of cell signals that excite or inhibit the brain is seriously tilted toward excessive excitability.

“Imagine New York City traffic without any red lights, just green lights,” said Catterall. This kind of electrical traffic jam might explain the heightened brain state of children with the Dravet mutation. These children suffer from frequent electrical storms, called epileptic seizures, in their brains. They are hyperactive, anxious and have difficulty sleeping. Their problems in learning, remembering and reasoning often follow a downhill course through childhood. The children also show several symptoms of an autistic spectrum disorder, including withdrawing from social interactions, repeated movements, and restricted, intense interests. The brain mechanisms behind this disorder have been poorly understood, Catterall said.

In observing the behavior of mice with the same genetic variation, Catterall and his team saw that they did not display many normal social interactions of mice. Mice are naturally curious about a mouse they haven’t met before, and will approach and sniff it. Sometimes they will attack, wrestle and playfully bite the stranger. Usually mice are more interested in mice they haven’t met before than those they already know. Mice with the Dravet syndrome were not interested in meeting strangers or acknowledging acquaintances, and did not approach them either aggressively or with mild manners. In fact, they froze when confronted with new mice, the scent of male mouse urine, or new food smells like banana oil, which usually attracts mice unfamiliar with the scent.

These altered behaviors suggested that the Dravet mice were unable to have normal social interactions with recently introduced mice and were repelled by new experiences, even new food odors. The Dravet mice also had problems in spatial learning and memory. They were unable to learn and remember the location where fearful events occurred or to learn and remember how to escape a brightly lighted area. In an open field test and maze running comparisons with mice without the mutation, the Dravet mice traveled more, spend less time in the center, and walked in circles. They also groomed themselves and wiped their whiskers excessively.

“Like many children with autism, the mice seemed overwhelmed by changes in their environment and unable to interact socially with other mice,” Catterall said. “They also showed stereotypic movements and repetitive behaviors common in autism.”

His team went on to explore the cellular and biochemical underpinnings of the autism-related traits and spatial learning deficits in the Dravet mutation mice. They tested the hypothesis that the condition arises from decreased activity of particular sodium ion channels in the brain cells that relay inhibitory information to other nerve cells in the forebrain.

They found that the deep layer of the prefrontal cortex of the brain was the most affected by the mutation. Among the core components linking thinking and emotion circuits of the brain are the interneurons. These cells release a neurotransmitter called GABA, a brain chemical signal that inhibits neighboring cells. On the other hand, excitatory nerve cells release a different neurotransmitter that activates neighboring nerve cells. Normally, these excitatory and inhibitory nerve cells balance each other.

The researchers found that the Dravet mutation mice had the normal number of the GABAergic interneurons, the cells that fire a “turn it down” signal to their neighbors. However, a significant percentage of these cells lacked a specific type (type-1 or Nav1.1) of gated sodium channel. This deficit kept these cells from firing enough electrical signals. As a consequence, excitatory signals dominated circuits in critical areas of the brain.

“We reasoned that the decreased in sodium channel activity in these GABAergic interneurons could be rescued by increasing the strength of the GABAergic transmissions,” Catterall said.

His team decided to treat both the normal and the Dravet mutation mice with the benzodiazepine clonazepam. This drug is often given to people suffer from moderate, debilitating anxiety, such as fear of flying. Benzodiazepines also control some forms of epileptic seizures. The researchers lowered the dose to make sure they were not sedating the mice or removing their anxious state.

“The treatment with a single low dose of clonazepam completely alleviated the impaired social interactions of the Dravet mice. It also removed the freezing reaction to novel situations. They were willing to approach mice that were strangers to them and to explore new odors. They behaved just like their peers,” Catterall observed. “This dose of the drug had no effect on the behavior of their normal peers.” The effects of the drug wore off after it cleared completely from the body, which takes a few days in mice.

“The results showed that a single low dose of clonazepam can reversibly rescue core autistic traits and cognitive deficits in mice with the Dravet mutation,” Catterall said. Additional measurements of cell firing in brain tissues from affected mice showed that the behavioral effects were likely based on decreased strength of the inhibitory signals, which caused an overall increase in brain electrical signaling by releasing the restraint on excitatory neurons. Their research also suggested that the cognitive and behavioral impairments in Dravet syndrome are not the result of damage from epileptic seizures, but are due to an innate shortage of a certain type of sodium ion channel and the resulting failure of inhibitory electrical signaling.

Catterall added that the research indicates that low-dose benzodiazepine treatment could be a potential drug intervention for cognitive deficits and autistic symptoms in Dravet syndrome patients, if clinical trials show they are effective in humans, and perhaps more broadly in certain other types of autism spectrum disorders.

“Interestingly, mutations in many other autism spectrum disorders also cause an imbalance of excitatory over inhibitory electrical activity in the brain,” the research team noted. Perhaps autistic traits in some other conditions within the realm of autism spectrum disorders might also be caused by a reduction in GABAergic signaling between brain cells.

Dravet syndrome is not the only genetic disorder that has autistic traits accompanying other physical and developmental disabilities. Rett, fragile X, and Timothy syndromes also have autistic features.

Article adapted by Medical News Today from original press release. Click ‘references’ tab above for source.
Visit our autism section for the latest news on this subject. The study was supported by grants from the National Institutes of Health R01NS25704, R01MH075016, and R37MHO49428 and from the McKnight Foundation. This research was part of the doctoral research of Dr. Sung Han, now a postdoctoral fellow at UW, and involved scientists at the University of California at San Francisco and Seoul National University in Korea.
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‘Mice With Dravet Syndrome Mutation Given Low-Dose Sedative Show Improvements In Autism-Like Behavior’

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Hyperconnectivity In Brain’s Hearing Center Caused By Gene Mutation In Autism

Main Category: Autism
Also Included In: Genetics
Article Date: 02 Feb 2012 – 1:00 PST

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New research from Cold Spring Harbor Laboratory (CSHL) might help explain how a gene mutation found in some autistic individuals leads to difficulties in processing auditory cues and paying spatial attention to sound.

The study has found that when a suspected autism gene called PTEN is deleted from auditory cortical neurons – the main workhorses of the brain’s sound-processing center – the signals that these neurons receive from local as well as long-distance sources are strengthened beyond normal levels. These effects, the study shows, can be blocked by a drug currently in use as an immunosuppressant.

“It’s long been hypothesized that autism spectrum disorders (ASDs) arise from a partial disruption of long-range connections in the brain during development,” explains Professor Tony Zador, who led the study. “Our finding that PTEN-deficient neurons receive stronger inputs suggests that one way this disruption can be caused is by signal enhancement.” His team’s work appears in the Journal of Neuroscience.

Although ASDs could arise from mutations in any of dozens of candidate genes, a core triad of symptoms defines all cases: impaired language, impaired social interaction, and restricted and repetitive behaviors. “The challenge therefore has been to understand how this diverse set of candidate genes and the pathways they control converge to cause the common signature of ASDs,” Zador says.

The auditory cortex, which plays a critical role in auditory attention and perception, forms functional connections with other sensory cortices and critical brain areas. The neural network within the auditory cortex has therefore been a target of studies aimed at understanding how alterations in neural circuits contribute to dysfunction in ASDs.

Zador’s team focused for several reasons on the role of one suspected autism candidate gene, PTEN, on circuit alterations within the auditory cortex. Well known for its role as an anti-cancer gene that powers down cell growth, proliferation and survival, this gene has also been linked to ASDs by a slew of studies in humans and mice. PTEN mutations have been found in autistic individuals with extreme macroencephaly – an increase in brain volume. PTEN loss in mice has been found to boost cell size and the number of neuronal connections in the brain.

To decipher the role of PTEN on functional connectivity in the auditory cortex, Zador’s group selectively disrupted the function of the PTEN gene in adult mice, only in a subset of neurons of the auditory cortex, while leaving the gene intact in neighboring neurons. The scientists then assessed the effect of the loss of PTEN on connectivity within the auditory cortex using techniques that involve stimulation by laser or flashes of blue light to trigger neuronal activity either locally or in other brain areas that send neuronal projections into the auditory cortex.

The rapid and robust increase in the strength of both long-range and local inputs observed following PTEN loss could possibly be explained by an increase that the scientists observed in the length and density of dendritic spines – the tiny, knob-like structures jutting out of a neuron that act like signal-receiving antennae.

These effects could be blocked, however, by chemically negating the effect of PTEN loss. One of the pathways regulated by the PTEN protein involves shutting down an intracellular enzyme called mTORC1, which promotes cell growth, among other things. Zador’s group found that treating the PTEN-deficient mice for 10 days with the mTORC1-inhibitor rapamycin prevented an increase in dendritic spine number and signal strength.

While Zador is excited about “this finding that suggests that mTORC1 could be a good therapeutic target for some cases of PTEN-mediated brain disorders,” he is also keen to further pursue his team’s new evidence that cortical hyperconnectivity could be the “final pathway” by which diverse ASD genetic pathways lead to a single ASD phenotype. “Using cortical connectivity as a paradigm for assessing ASD candidate genes could provide insights into the mechanisms of the disorders and perhaps even give us clues to formulate new therapeutic strategies,” he states.

This work was supported by grants from the National Institutes of Health and Autism Speaks.

Article adapted by Medical News Today from original press release. Click ‘references’ tab above for source.
Visit our autism section for the latest news on this subject. “PTEN regulation of local and long-range connections in mouse auditory cortex” appears in the Journal of Neuroscience on February 1. The full citation: Qiaojie Xiong, Hysell V. Oviedo, Lloyd C. Trotman, and Anthony M. Zador.
Cold Spring Harbor Laboratory Please use one of the following formats to cite this article in your essay, paper or report:

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Cold Spring Harbor Laboratory. “Hyperconnectivity In Brain’s Hearing Center Caused By Gene Mutation In Autism.” Medical News Today. MediLexicon, Intl., 2 Feb. 2012. Web.
9 Mar. 2012. APA

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‘Hyperconnectivity In Brain\’s Hearing Center Caused By Gene Mutation In Autism’

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View the original article here