Society for neuroscience article: Brain breifings (Rett Syndrome)

APRIL 2007 Traditionally, children affected by Rett Syndrome have had few options for treatment. But research has uncovered the genetic causes behind the disease, providing possible targets. Also, scientists have made significant progress with animal studies, including effectively reversing symptoms of the disorder. These advances give hope to researchers developing new treatments. -------------------------------------------------------------------------------- A little girl suddenly stops walking and talking. Soon, she can't use her hands. Later, she can't breathe very well, begins having seizures, and eventually may die. It can be difficult to understand how this can happen to a seemingly normal child, but such is the case of those with Rett Syndrome (RTT), an incurable neurological disorder that targets girls almost exclusively. RTT is a rare disease -- it affects approximately 1 in every 10,000 to 12,000 females -- and seemingly strikes at random. Those with RTT develop normally at first, but between 6 and 18 months of age, symptoms begin to appear. The child stops achieving normal developmental milestones, such as acquiring verbal skills. She begins wringing her hands in anxiety. About 50 percent of girls with RTT become wheelchair-bound, but the degree of a person's developmental skills depends largely on the severity of the disease. Many live into adulthood, but their average life expectancy falls below the national average. Current treatments merely manage the symptoms with medications, various forms of speech and physical therapy, and support for families. But research has made strides, including the discovery that RTT also can strike males with no family history of the disorder. More than 40 years of research have led to: The discovery that RTT is caused by specific genetic mutations, providing a potential target for researchers. The identification of more than 200 associated mutations. Clinical trials focusing on drugs to enhance the quality of life for those affected. RTT is caused by a mutation in the gene that encodes methyl cytosine-binding protein 2 (MeCP2), which is located only on the X chromosome. This is part of the reason for RTT's prevalence in girls, who inherit one X chromosome from each parent. Most boys born with RTT die so soon after birth that statistics on such cases are hard to obtain. MeCP2 regulates the production of proteins generated by other genes by shutting off the genes like a switch. Normally in girls, one of the two MeCP2 genes is permanently in the "off " position. But in children with RTT, one is defective, so the ability to shut down other genes fails. This causes an overabundance of certain proteins from other genes, and RTT symptoms begin to appear. Recent advances from research in animals have successfully reversed the symptoms of full-blown RTT. In one experiment using genetically engineered mice, researchers silenced MeCP2 by inserting a "roadblock" into the gene. Once RTT symptoms appeared, researchers removed the roadblock to reactivate MeCP2. Symptoms of RTT began to reverse or decrease within four weeks. This gives scientists hope that treatments for children and adults are not too far off. Anxious behavior and high stress levels are common in girls with RTT. The culprit, researchers suspect, are hormones related to stress that become altered by abnormal regulation by MeCP2 genes. Studies of mice show that high levels of corticotrophin-releasing hormone, a stress hormone, occur in the brain areas responsible for controlling stress. This finding may lead to drugs that target stress hormones and reduce the anxiety seen in girls with RTT. The discovery that MeCP2 interacts with a protein that helps support new and existing brain cells has led researchers to question whether this protein contributes to RTT symptoms. When altering levels of this protein in laboratory animals, they found that deleting it caused an earlier onset of RTT symptoms, whereas increasing the level caused later onset and slower disease progression. Further studies will focus on how much of the protein should be used and which parts of the brain should be targeted in order to successfully reduce symptoms. Advances from clinical tests have been small, with only three trials completed since 1999. These trials focused on medications to improve sleep, energy levels, and communication skills. Alternative treatments have used music therapy in efforts to improve hand use, eye contact, and communication, but with little success. A new study is using the drug dextromethorphan to target the receptors of the brain chemical glutamate, which plays a key role in communication between brain cells. Excessive numbers of glutamate receptors can lead to seizures, behavioral problems, and respiratory abnormalities. Researchers hope to determine the most effective dosage needed to control these symptoms and open the way to improved treatments. For additional information, check out: Neuron. 2006 Feb. 2; 49 (3):341-8. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Chang Q, Khare G, Dani V, Nelson S, Jaenisch R. Proceedings of the National Academy of Sciences. Nov. 15, 2006; 103; 18267-18272. Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. McGill B, Bundle S, Yaylaoglu M, Carson P, Thaller C, Zoghbi H. Science. 2007. Feb 23; 315(5815):1143-7. Reversal of neurological defects in a mouse model of Rett syndrome. Guy J, Gan J, Selfridge J, Cobb S, Bird A. Neurology. 2006 July 11; 67(1):164-166. Early progressive encephalopathy in boys and MECP2 mutations. Kankirawatana P, Leonard H, Ellaway C, Scurlock J, Mansour A, Makris CM, Dure LS 4th, Friez M, Lane J, Kiraly-Borri C, Fabian V, Davis M, Jackson J, Christodoulou J, Kaufmann WE, Ravine D, Percy AK. Source: Society for Neuroscience 1121 14th Street, Suite 1010 | Washington DC 20005 Phone: (202) 962-4000 http://www.sfn.org/index.cfm?pagename=brainbriefings_rett_syndrome