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Jassiel Esli Hernandez Ontiveros Randall Fowler Bio 100 December 2012 Rett Syndrome Rett syndrome is an X-linked Dominant neurodevelopmental disorder that affects 1 in 100,000 males and 1 in 10,000/20,000 females. Although there are reported cases in boys, most dont survive the disease, making it the leading cause of mental retardation in women (Archer et al 2005). The disorder was first identified by the Austrian physician Dr. Andreas Rett in 1966. Unfortunately it wasnt until 1983 that the researcher Dr. Bengt Hagberg published a second article that the disease started to get recognition (National Institute of Neurological Disorders and Stroke). The following 6 to 18 months after the child is born, her psychomotor development is normal and no evident symptoms show. It is after that period that children with the syndrome experience a regression in language and motor skills. Other symptoms include repetitive hand movements, panic attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly (Christodoulou 2001). One other symptom is autistic-like behaviors (Preuss 2004), one which could have made it difficult to diagnose in the early days of treating the disease. Although medicine has come a long way since first discovering the disease, the means to diagnose it are still tentative at times. The reason being that though some children may experience regression

or some features of Rett syndrome, they do not necessarily have all of them. It is because of this that the terms Atypical or Variant Rett syndrome are used (Neul et al 2011).
There are 4 main criteria when it comes to diagnose Rett syndrome physicians use: 1 2 3 4 Partial or complete loss of acquired purposeful hand skills. Partial or complete loss of acquired spoken language Gait abnormalities: Impaired (dyspraxic) or absence of ability. Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms To diagnose typical Rett a period of regression followed by recovery or stabilization, and all main criteria are required. Although some exclusions for typical Rett syndrome would be Brain injury secondary to trauma, peri- or postnatally, neurometabolic disease, or severe infection that causes neurological problems. To diagnose atypical or variant Rett syndrome a period of regression followed by stabilization or recovery, 2 out of the 4 main criteria and 5 out of 11 supportive criteria are required. Supportive criteria for atypical or variant Rett: 1 2 3 4 5 6 7 8 9 10 11 Breathing disturbances when awake Bruxism when awake Impaired sleep pattern Abnormal muscle tone Peripheral vasomotor disturbances Scoliosis/kyphosis Growth retardation Small cold hands and feet Inappropriate laughing/screaming spells Diminished response to pain Intense eye communication - eye pointing (Neul et al 2011) Aside from diagnosis, there is also genetic testing, Prenatal diagnosis and preimplantation genetic diagnosis (Van Esch 2008).

In 1999, Rett syndrome was discovered to be related and linked to mutations in the MeCP2 protein producing MECP2 gene in the X chromosome. MeCP2 stands for Methyl CpGbinding protein 2. Something that puzzled scientists worldwide since MECP2 was not related to anything in the brain. In recent years, new discoveries and studies show that MECP2 remodels chromatin (Preuss 2004). So-called CpG "islands" are found at the promoter regions of many housekeeping genes, which code for proteins essential to cell function. They contain high densities of cytosine and guanine base pairs, known as CpG dinucleotides. MECP2, being a binding protein, can bind to these base pairs when methyl groups are attached to them. Normally, CpG dinucleotides in CpG islands are not methylated and the genes are active. However,if CpG islands are methylate, they attract MeCP2 proteins, which bind additional proteins that repress gene transcription and turn the promoter off. Thus MeC2P is thought to be a key player in assembling the protein factors that silence transcription. Because MeCP2 binds to methylated CpG dinucleotides, its effects are not dependent on the primary sequence of DNA. (Preuss 2004)

How does this relate to Rett syndrome? It has been found that a mutated MECP2s failure to regulate transcription on the DLX5 gene of which one allele is imprinted under normal circumstances. The production of the Dlx5 protein is increased due to the lack of the MeCP2 protein, influencing the production of the neurotransmitter GABA. All this also affects the

expression of other DLX genes resulting with consequences relating to brain development (Shinichi et al 2005). It has to be mentioned that although there are various theories of how the gene and proteins work, there is still no definite explanation for what exactly causes the mutation and how does it relate to the brain and other genes. Although Rett syndrome is categorized as X-linked dominant, in most cases, girls affected by the disorder have no family history linking them to the syndrome. The syndrome is mostly caused by the mutation in the different genes and alleles mentioned before, Although there have been some cases with more than 1 reported family member affected by the disease (Genetics Home Reference). In essence, this disorder can be viewed as a kind of domino effect during translation and transcription and genetic coding, as one single genes fails or mutates, a whole series of events is triggered just by a single mutation. A clear example of how a mutation can be both our salvation or demise. Unfortunately, direct treatment of the disease does not exist. Only the symptoms and resulting afflictions can be dealt with, by using medication such as low doses of Risperidone for agitation, Melatonin for sleep disturbances and Topiramate to help improve seizures and respiratory problems. Therapeutic and psychological treatment is also highly necessary or highly recommended to improve the way of life of the person affected by the syndrome such as augmentative communication techniques, speech therapy, motor skills therapy, swimming, music therapy and even horseback riding can provide therapeutic stimuli (Christodoulou 2001). Even if there are no cures today, the future may hold the key to unlocking Retts mysteries by research done in the present. Bone marrow transplant has shown promise in

experiments done with mice by treating the brain-dwelling immune cells known as microglia, which deteriorate with Rett syndrome (Callaway 2012). Another therapy that might hold a promise for the future is genetic modification. Studies in labs using mice as subjects to the modification have shown some promise, though most of the results are not seen as achievable in a real surgical environment at the moment (Arnold 2012). There are many reasons why I chose this disorder, including its link to other diseases and how it demonstrates the brains dominance over the rest of the body. But in a more personal standpoint I chose Rett syndrome for its subtlety it presents itself and how its a clear example of how precise and amazing our bodies and genetics can be when properly orchestrated and how disastrous it can be if not. Also the support and places where people with and without Rett syndrome can go and gain information from and the amount of researchers working on it is amazing and heartwarming at times. As far as science has advanced, it has not yet fully revealed the mysteries of this disease, but as the world evolves and moves forward, everyday people help science to help us discover and achieve a better life in the future.

Sources Cited
Archer, H.L. et al. Gross rearrangement of the MECP2 gene are found in both classical and

atypical Rett syndrome patients. J Med Genet. Journal of Medical Genetics. 14 Oct. 2005. Web. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564520/ Arnold, Paul. The Prospects for Future Therapies for Rett Syndrome. Bright Hub. Bright Hub Inc. May 12, 2012. Web. Available from: http://www.brighthub.com/science/genetics/articles/71074.aspx Callaway, Ewen. Bone Marrow Transplant Reverses Rett Syndrome in Mice. Nature. Nature Publishing Group. March 18, 2012. Web. Available from: http://www.nature.com/news/bone-marrow-transplant-reverses-rett-syndrome-in-mice1.10243 Christodoulou J, Ho G. MECP2-Related Disorders. Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews .University of Washington, Seattle 1993-.2001 Oct 3. Web Available from: http://www.ncbi.nlm.nih.gov/books/NBK1497/ Neul, Jeffrey L. et al. Rett Syndrome: Revised Diagnostic Criteria and Nomenclature. Ann Neurol. National Institute of Health. 1 December 2011. Web. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058521/pdf/nihms214759.pdf Preuss, Paul. Solving the Mechanism of Rett Syndrome: How the First Identified Epigenetic Disease Turns On the Genes That Produce its Symptoms. Berkeley Lab. University of California. 20 December 2004. Web. Available from: http://www.lbl.gov/ScienceArticles/Archive/LSD-Rett-syndrome.html

Rett Syndrome. Genetics Home Reference. US. National Library of Medicine. December 2, 2011 Web. Web. Available from: http://ghr.nlm.nih.gov/condition/rett-syndrome Rett Syndrome Fact Sheet. National Institute of Neurological Disorders and Stroke. National Institutes of Health. November 2009. Web. Available from: http://www.ninds.nih.gov/disorders/rett/detail_rett.htm

Shin-ichi Horike et al. Loss of Silent Chromatin Looping and Impaired Imprinting of DLX5 in Rett Syndrome. Nature. Nature Publishing Group. January 2005.Web. Available from: http://www.lbl.gov/Science-Articles/Archive/assets/images/2004/Dec-20/DLX5-RettSyndrome. Van Esch H. MECP2 Duplication Syndrome. Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews . Seattle (WA): University of Washington, Seattle 1993-.2008 Jan 18. Web Available from: http://www.ncbi.nlm.nih.gov/books/NBK1284/