Tag Archives: Gene Function

Question?: Rett Syndrome Research

Chris asks…

Does anyone know why Rett Syndrome girls start off “normal” & then regress?

Okay I’m aware of what Rett Syndrome is & how it works (for the most part anyway) but what has me confused the most is that most of these girls develope normally for about the first 6-18 minths & then start to regress/lose skills they’ve already learned (i.e. talking, walking, eye contact) . I know this is due to a mutation in the MEPc2 gene but why/how is it they can learn things & then lose them later on. I relize the gene is responsible for turning on/off certian protiens but what is making these girls funtion properly in the beginning then? another gene maybe?

admin answers:

To quote a passage from wikipedia:
“The recent studies demonstrating that neurological deficits resulting from loss of MeCP2 can be reversed upon restoration of gene function are quite exciting because they show that neurons that have suffered the consequences of loss of MeCP2 function are poised to regain functionality once MeCP2 is provided gradually and in the correct spatial distribution. This provides hope for restoring neuronal function in patients with RTT. However, the strategy in humans will require providing the critical factors that function downstream of MeCP2 because of the challenges in delivering the correct MeCP2 dosage only to neurons that lack it, given that the slightest perturbation in MeCP2 level is deleterious. Thus, therapeutic strategies necessitate the identification of the molecular mechanisms underlying individual RTT phenotypes and picking out the candidates that can be therapeutically targeted. The next phase of research needs to assess how complete the recovery is. Clearly, lethality, level of activity, and hippocampal plasticity are rescued, but are the animals free of any other RTT symptoms such as social behavior deficits, anxiety, and cognitive impairments? Since postnatal rescue results in viability, it will be important to evaluate if even the subtler phenotypes of RTT and MECP2 disorders are rescued when protein function is restored postnatally. This is particularly important given emerging data about early neonatal experiences and their long-term effects on behavior in adults.”

What I get from that is that the nerves become damaged by the defective gene, resulting in a loss of abilities that have already been learned.

Sorry if you’ve already read this, but this is just about all I could find as far as the reason for the decline period.
Hope this helps!

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Seizure Susceptibility In Angelman Syndrome May Be Due To Brain Cell Activity Imbalance

Main Category: Epilepsy
Also Included In: Autism;  Genetics
Article Date: 08 Jun 2012 – 0:00 PDT Current ratings for:
‘Seizure Susceptibility In Angelman Syndrome May Be Due To Brain Cell Activity Imbalance’
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New research by scientists at the University of North Carolina School of Medicine may have pinpointed an underlying cause of the seizures that affect 90 percent of people with Angelman syndrome (AS), a neurodevelopmental disorder.

Published online in the journal Neuron, researchers led by Benjamin D. Philpot, PhD, professor of cell and molecular physiology at UNC, describe how seizures in individuals with AS could be linked to an imbalance in the activity of specific types of brain cells.

“Our study indicates that a common abnormality that may apply to many neurodevelopmental disorders is an imbalance between neuronal excitation and inhibition,” Philpot said. This imbalance has been observed in several genetic disorders including Fragile X and Rett syndromes, both of these, like AS, can be associated with autism.

Angelman syndrome occurs in one in 15,000 live births. The syndrome often is misdiagnosed as cerebral palsy or autism. Its characteristics, along with seizures, include cognitive delay, severe intellectual disability, lack of speech (minimal or no use of words), sleep disturbance, hand flapping and motor and balance disorders.

The most common genetic defect of the syndrome is the lack of expression of the maternally inherited allele of gene UBE3A on chromosome 15.

This loss of gene function in AS animal models has been linked to decreased release of an excitatory neurotransmitter which increases the activity of other neurons. But that seems at odds with the high seizure activity observed in AS patients. The new study may clarify this issue.

In his lab in UNC’s Neuroscience Research Center, Philpot and graduate student Michael L. Wallace, the study’s first author, explored the neurocircuitry of an Angelman syndrome mouse model. These mice show behavioral features similar to humans with AS, including seizures.

The researchers used electrophysiological methods to record excitatory and inhibitory activity from individual neurons. These involved highly precise recording electrodes, microscopic tips attached to individual neurons. “In this way you can record from precise neuron types and tell which neuron you’re recording from and what its activity is,” explained Philpot.

“You can stimulate it to drive other neurons and also record the activity on other neurons onto it.”

The researchers found that neurotransmitters sent from inhibitory neurons and carrying chemical messages meant to stop excitatory neurons from increasing their activity were defective.

In addition, they found that AS model mice have a defect in their inhibitory neurons which decreases their ability to recover from high levels of activity. “One of the reasons why inhibition is so important is that it’s needed to ensure that brain activity is regulated,” Philpot said. “Inhibition plays an important role in timing of information transfer between neurons, and if the timing is messed up, as you might observe if you had a decrease in inhibition, then a lot of information is lost in that transfer.”

“We found a disproportionately large decrease in inhibition to excitation,” Wallace said. “We think that the circuit we investigated is in a hyperexcitable state and may be underlying some of the epileptic problems observed in the AS animal model. This improperly regulated brain activity might also underlie cognitive impairments in AS.”

Philpot says one of their goals is to understand exactly how these changes in the connections between neurons underlie seizures in AS. “A very long term goal is to try to get better treatments for these individuals because their epilepsy is very hard to treat.”

Article adapted by Medical News Today from original press release. Click ‘references’ tab above for source.
Visit our epilepsy section for the latest news on this subject. Along with Wallace and Philpot, other UNC co-authors are Alain C. Burette and Richard J. Weinberg from the department of cell and developmental biology.
Support for the research came from a National Institute of Neurological Disorders and Stroke, the Angelman Syndrome Foundation, the Simons Foundation, the National Eye Institute, and the National Institute of Mental Health.
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‘Seizure Susceptibility In Angelman Syndrome May Be Due To Brain Cell Activity Imbalance’

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