New insight into Rett syndrome severity

A research collaboration between Australia and Israel has identified a genetic variation that influences the severity of symptoms in Rett syndrome.
The finding is published in the latest edition of the international journal Neurology.

Dr Helen Leonard, who heads the Australian Rett Syndrome Study at the Telethon Institute for Child Health Research, said the finding was exciting in that it identifies a potential new target for treatment of the debilitating neurological disorder.
"We know that there is a wide range in the onset and severity of symptoms in patients with Rett syndrome but it has been difficult to give families a firm idea of how the disorder would progress," Dr Leonard said.
"This information is potentially helpful in predicting the clinical progression, but importantly, gives us another area to explore for potential therapies."

In the study, clinical information and DNA samples were gathered from 125 patients from the Australian Rett Syndrome Database and an Israeli cohort coordinated by Dr Bruria Ben Zeev at the Safra Pediatric Hospital, Sheba Medical Centre, Sackler School of Medicine, Tel Aviv. The genetic testing was undertaken by Professor John Christodoulou, from the NSW Centre for Rett Syndrome Research at the Children's Hospital at Westmead in Sydney and Dr Eva Gak from the Sagol Neuroscience Center at the Sheba Medical Centre.
Professor Christodoulou said while it has been established that Rett syndrome is caused by mutations in the MECP2 gene, these new findings have established a correlation between the severity of clinical symptoms and a common brain-derived neurotrophic factor (BDNF) polymorphism.

"Those patients with the normal BDNF genetic variant had less severe symptoms, with later onset and frequency of seizures," Dr Christodoulou said.
"We know that BDNF plays a major role in the development, survival and function of brain cells. What we now have to establish is the nature of the interaction between MECP2 and BDNF."
"It may be that if we can stimulate BDNF within patients with Rett syndrome, there is a chance that we can delay the onset of seizures and reduce some of the more debilitating aspects of the disorder."

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Rett gene in amygdala linked to fear and learning

Deleting the gene associated with Rett syndrome from the amygdala region of mouse brains triggers anxiety and problems with learning and memory, according to research published today in the Journal of Neuroscience 1.

Researchers at the University of Texas Southwestern Medical Center at Dallas selectively deleted the MeCP2 gene, mutations in which cause Rett syndrome, from the amygdala — a clustering of cells in the brain that regulates the processing of emotions — of 3- to 5-month-old mice.

These mice, which express roughly 50 percent of normal MeCP2 levels in the amygdala, freeze when placed in a maze task routinely used to assess anxiety, the researchers found. The mice also have trouble remembering to anticipate a brief shock after an auditory tone — a task that control mice learn and remember after two tries — suggesting that MeCP2 regulates fear-dependent learning and memory.

Rett syndrome is a rare neurodevelopmental disorder that predominantly affects girls, and is characterized by distinctive hand movements, abnormal gait, seizures and mental retardation. Girls with the syndrome also often show features of autism, including anxiety, deficits in social skills and repetitive behavior.

Intriguingly, mice lacking MeCP2 in the amygdala show normal patterns of social interaction. “We were sort of surprised because it does suggest you can separate out anxiety from social interaction deficits,” says lead investigator Lisa Monteggia.

“For autism spectrum disorder, one of the most debilitating aspects is the social deficit,” Monteggia says. “So if we go back to other brain regions, could we recapitulate the social interaction deficits?”

A research team led by Huda Zoghbi in 1999 first linked mutations in the MeCP2 gene to Rett syndrome2, but the gene’s exact role is still unknown. Last year, the same group reported that the gene is a master regulator, controlling the activation and repression of thousands of other genes3.

Because MeCP2 is found throughout the body, it has been difficult to tease apart its contribution to the collection of symptoms seen in Rett syndrome. For example, mice that don’t have any MeCP2 are normal until 5 weeks of age, when they begin to develop Rett-like symptoms, and then die between 6 and 12 weeks of age4.

“When this protein is missing everywhere in the brain, the animals are so sick that you may miss hidden phenotypes,” Zoghbi says. “By looking at the gene just in specific areas, you might be able to learn the symptoms emanating from those specific brain regions.”

Regional deletions:
In 2001, Rudolf Jaenisch and colleagues created mice that lack the gene in the forebrain, a large region of the brain that includes the amygdala and performs a gamut of functions from sensory processing to memory, beginning at postnatal day 14, when neuronal connections are actively forming.

Monteggia’s group showed in 2006 that these mice have a broad array of Rett-like symptoms, including anxiety, learning and memory problems, deficits in motor coordination and social deficits5. The researchers then decided to focus specifically on the amygdala because anxiety, learning and memory tasks are regulated by the region.

Because some of Rett’s symptoms, including difficulty breathing and sleeping and elevated response to stress, implicate the hypothalamus, Zoghbi and her colleagues in September 2008 selectively deleted MeCP2 from the mouse hypothalamus and found that the mice are more aggressive and tend to eat more than do control littermates6.

In the new study, Monteggia and her colleagues also exposed normal mice to a histone deacetylase inhibitor — a chemical that enhances gene expression — and found that these normal mice and the MeCP2-deficient mice show similar behavioral deficits.

“To us, it suggested that these behavioral processes that we think MeCP2 is involved in were mediated through transcriptional repression,” Monteggia says.

Deletions from specific brain regions allow researchers to dissociate different brain functions that might involve different brain regions, says Mriganka Sur, chief of brain and cognitive sciences at the Massachusetts Institute of Technology. Still, to treat Rett syndrome, it will be important to intervene broadly in the brain, he notes.

Sur and his colleagues have found that treating mice that lack MeCP2 throughout the brain with insulin-like growth factor 1, a chemical that improves cell survival and maturation, improves the lifespan and locomotor activity7. The growth factor also strengthens connections between neurons, which is likely to be relevant to MeCP2’s role in regions like the amygdala.

“To my mind [the new study] argues that the MeCP2 gene is really involved in the kind of function that we postulated,” says Sur, “that MeCP2 is involved in synaptic maturation and regulating plasticity.”

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European Rett Syndrome Congress, June 5-7, Milan, Italy

1st European Congress on Rett Syndrome - Università degli Studi di Milano, June 5-7, 2009

Rett Syndrome is a rare disease which springs from a genetic mutation of a specific gene, the MECP2, and provokes severe problems to the "girls with beautiful eyes", including neurological disfunctions in movement and development of the brain, cardiac problems, gastric disfunctions and many others.

We need your help to substain AIR (Associazione Italiana Sindrome di Rett) and RSE (Rett Syndrome Europe) and divulgate the results of recent researches on the disease.
Please help us make Rett Syndrome a studied and well-known disease, registering to the congress and bringing your contribution through submittance of an abstract through the web site www.aimgroup.it/29009/airett.

AIR
RSE
The Organizing Secretariat

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