RxPG News : Rett Syndrome

Differences in swallowing mechanism of Rett syndrome patients

Mon, 04 Aug 2008 12:48:57 PST

( from http://www.rxpgnews.com ) Researchers at Wake Forest University Baptist Medical Center have found that the reflux and swallowing problems that are common symptoms in patients with Rett syndrome and other neurological impairments, may be caused by a different mechanism than they are in healthy individuals. The finding leaves researchers to wonder if these patients truly benefit from anti-reflux surgery commonly performed in these children.

In a study published in this quarter's issue of the Journal of Applied Research, John E. Fortunato, M.D., lead researcher and an assistant professor in the Department of Pediatrics, found that the esophagus of children with Rett syndrome demonstrates different movements than it does in patients without the neurological disorder, which may explain why so many Rett patients experience persistent reflux and swallowing issues even after undergoing surgery meant to correct those problems.

"The significance of this is for other groups of patients with neurological impairment," Fortunato said. "Do all of these patients have the same mechanism for reflux and swallowing disorders? If not, performing a fundoplication (anti-reflux surgery) may not help. In fact, it may make things worse like it did in the Rett girls."

Previous studies have shown that children with neurological impairments have increased complications after anti-reflux surgery. In this study, Fortunato found the same to be true of Rett syndrome patients who underwent fundoplication. The finding leads researchers to believe that there may be something different causing the reflux and swallowing problems in Rett syndrome patients and possibly other patients with neurological impairments, such as cerebral palsy, brain injury and autism, than the accepted mechanism for the same problems in otherwise healthy adults and children.

Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene MECP2 located on the X chromosome. It is the only Autism spectrum disorder with a known genetic cause and is characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, walking abnormalities, seizures, and mental retardation. Early symptoms may also include toe walking, sleep problems, teeth grinding, difficulty chewing and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing.

Rett syndrome affects one in every 10,000 to 20,000 live female births and is associated most closely with gastroesophageal reflux disease (GERD) and difficulty and /or pain swallowing (dysphagia). Most patients affected by the mutation have trouble eating, so they often are shorter and weigh less than other children their age. To maintain proper nutrition, some children need to be fed through tubes placed in their noses or stomachs. Boys who inherit the mutated gene usually don't survive infancy, according to the National Institute of Neurological Disorders and Stroke.

The study included 32 Rett patients between the ages of 2 and 14 with prior history of feeding problems. Researchers looked at the movement (or peristalsis) of the esophagus in the girls and found unusual esophageal movement disorders.

As a result of the study's findings, Wake Forest Baptist has approved further research to look at esophageal movement and swallowing function before and after reflux surgery, comparing children with and without neurological impairment.

"This issue is of particular interest to pediatricians who refer these patients for their 'reflux' problems," Fortunato said. "If we develop a better understanding of the mechanisms behind the problems being experienced by these children, we just might be able to find a way to make life a little more comfortable for them."

MeCP2 - Rett Syndrome protein binds only to specific genes

Sun, 04 Sep 2005 07:26:38 PST

( from http://www.rxpgnews.com ) Adrian Bird of the University of Edinburgh and colleagues report today in the online issue of Molecular Cell that the "Rett Syndrome protein", MeCP2, only binds to genes with a specific sequence of nucleotide bases. This knowledge will aid in the identification of the genes that are regulated by the gene MECP2. This work was supported, in part, by the Rett Syndrome Research Foundation (RSRF).

Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.

The instructions needed to make the cells of all living organisms are contained in their DNA, which is organized as two complementary strands with bonds between them that can be "unzipped" like a zipper. DNA is encoded with building blocks called bases which can be abbreviated A, T, C, G. Each base "pairs up" with only one other base: A-T, T-A, C-G, G-C create the bonds that connect the complementary strands. Long stretches of base pairs make up genes.

All genes found in the human body are present in every one of our cells. What allows the same cells to develop into a heart in one instance and a kidney in another? The answer is gene expression. In a typical human cell only one tenth of the genes are expressed; the rest are shut down.

One way that genes are shut down is by attaching a small "tag" called a methyl group to the C base. The number and placement of the methyl tags dictates when a gene should be silenced. The protein, MeCP2, binds to these methyl groups to silence particular genes.

Dr. Bird and colleagues found that the methyl groups alone were not enough to attract MeCP2 to a gene. In fact, what is needed is a stretch of at least four A-T bases flanking the methyl groups.

"We previously thought that MeCP2 only needed methyl groups to bind DNA. As there are about 30 million such sites in the genome, it seemed likely that MeCP2 was a rather indiscriminate repressor of gene expression all over the genome. The new data shows that the number of potential MeCP2 binding sites is in fact far less than we thought, making it easier to find new target genes that are mis-regulated in Rett Syndrome," said Adrian Bird.

Researchers hypothesize that the devastating cascade of symptoms seen in Rett Syndrome is caused by the inability of mutated MeCP2 to silence its target genes. To date, the genes DLX5 and BDNF have emerged as strong MeCP2 target candidates and are therefore implicated in the disease process of Rett Syndrome. Interestingly, both genes were found to have the required A-T stretch, strengthening the argument that MeCP2 is involved in regulating these genes.

"Finding the MeCP2 target genes is a crucial step in understanding what goes awry in Rett Syndrome. Unfortunately these genes have been elusive. Dr. Bird's discovery of the A-T stretch provides a much-needed clue which should aid in their identification," said Monica Coenraads, Director of Research for RSRF.

Spontaneous neuronal activity is reduced in cortex in Rett Syndrome

Tue, 23 Aug 2005 21:18:38 PST

( from http://www.rxpgnews.com ) Sacha Nelson of Brandeis University in Waltham, MA and Rudolf Jaenisch of the Whitehead Institute of Biomedical Research in Cambridge, MA and their colleagues report online today in the Proceedings of the National Academy of Sciences Early Edition that spontaneous neuronal activity is reduced in the cortex of a knockout mouse model for the childhood neurodevelopmental disorder, Rett Syndrome. The Rett Syndrome Research Foundation (RSRF) and the McKnight Foundation funded this project.

Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.

The nervous system consists of billions of neurons that communicate with each other. Neurons don't touch and the gap between them is called a synapse. This gap is bridged by neurotransmitters that are released by the generation of electrical signals. Some neurotransmitters are excitatory and increase activity in the brain and others are inhibitory and decrease activity. In healthy brains, a balance between excitation and inhibition is essential for nearly all functions, including representation of sensory information, cognitive processes such as decision making, sleep and motor control.

The electrical signals that neurons generate can be measured using microelectrodes. Using a technique called, whole cell patch clamp, Vardhan Dani, a graduate student in Dr. Nelson's lab and Qiang Chang a post doctoral fellow from Rudolf Jaenisch's lab tested the electrical impulses in the cortex of the Rett Syndrome knockout mouse model. The cortex is one of the regions of the brain affected in patients with RTT. These mice are genetically manipulated so they lack the "Rett gene", MECP2. Like individuals with Rett Syndrome, they are seemingly normal at birth and begin to exhibit Rett-like behaviors by 5 weeks of age.

Interestingly, the groups found that the excitatory-inhibitory balance in the cortex of the mice was shifted towards inhibition (decreased brain activity). They surmise that this shift toward inhibition in the cortex and perhaps other brain regions could underlie some of the cognitive, motor, linguistic and social symptoms seen in RTT.

The spontaneous firing of L5 pyramidal neurons in 5 week-old mice was decreased 4-fold when compared to normal mice. This reduction is progressive, since two weeks earlier, in presymptomatic mice, the reduction was only 2-fold. This finding represents the first experimental evidence for a physiological abnormality that exists before symptoms appear.

"It's important to note that since this defect is seen so early it suggests that the reduced cortical activity may be a primary cellular defect that may lead to other neuropathologies," shared Qiang Chang, co-first author on the paper.

Future work will focus on elucidating the mechanisms by which the lack of MECP2 leads to increased inhibition and reduced excitation. "The next step is to use a technique called paired recording to look at the properties of individual synaptic connections between pairs of cortical neurons to find out more precisely which connections change and how. We are also trying to understand which other neural genes are regulated by Mecp2 by measuring gene expression in neurons from knockout mice and their normal siblings," said Sacha Nelson, the corresponding author of the paper.