NYC 6th Annual Rett Syndrome Symposium Will Gather Scientists From Around The World

Each year RSRF organizes the premiere Rett Syndrome meeting. At the end of this month 100 researchers and clinicians will come together for 3 days in Chicago to discuss the latest findings. RSRF wishes to thank co-chairs, Drs. Huda Zoghbi and Adrian Bird, for their leadership role. The symposium is notable for successfully promoting open dialogue and facilitating a generosity of spirit and the sharing of unpublished data. The agenda and list of participants are available on our website. Highlights of the meeting will be made available through the RSRFNewsAlert and website.

Research Update Featuring Dr. Jeffrey Neul Scheduled for June 26th in Chicago

Join us on Sunday, June 26th at the Eaglewood Resort and Spa and learn about the latest research developments from physician scientist, Dr. Jeffrey Neul of Baylor College of Medicine. To learn more please click here or contact Monica Coenraads at monica@rsrf.org. Please note that to attend you must RSVP.

NYC Picture a Cure Benefit Set for June 16th

The New York City Picture a Cure Benefit will be held on Thursday, June 16th at Sotheby's. The event, which hopes to raise over $400,000 for Rett Syndrome research, will feature fabulous food, live entertainment and a remarkable array of silent and live auction packages. Among the incredible auction items up for bid will be: luxury trips to Italy and Mexico; Sting autographed guitar; beautiful artwork; coveted sports tickets, golf at some of the tri-state area's premiere courses; a chartered yacht excursion to the British Virgin Islands; U2 concert tickets to Madison Square Garden and much, much more. Tickets are still available. To get more information or to see photos of last year's event, click here or contact Craig Robertson, RSRF Executive Director, at monica@rsrf.org.

Strolling and Rolling to Raise Funds for Research

RSRF would like to congratulate Event Chairs, Kristy Kramer and Monica Coenraads for the amazing job they did with their Strollathon events this past month. On May 14th, families from Pennsylvania came out to Harrisburg to show their support for Rett Syndrome. Over 300 people participated in the event helping to raise awareness and upwards of $40,000 for research. On May 22nd, RSRF supporters came from all over the tri-state New York area to Stamford, CT for the third annual Strollathon. Despite the rainy weather the event drew a crowd and raised over $140,000 for research. Please visit our website for more information and to see pictures of the event. RSRF would like to thank all of the families and donors whose generosity and commitment is helping us moving closer to cures and treatments.

Strollathon season, however, is just getting underway. This weekend, the Inaugural Cape Cod, MA Strollathon will be held in South Yarmouth, MA. Event Chairs, Jennifer and Justin Endres, have done an incredible job and will, no doubt, see the fruits of their labor this Saturday. To make a donation to the event in support of Rett research, contact Jennifer Endres at capecodstrollathon@yahoo.com or click here. Also, please be on the lookout for Strollathons coming to town in Seattle, WA (August 27th), Roanoke, VA (Sept. 11th), Charlotte, NC (Oct 1st) and Cincinnati, OH (Oct 8th). For more information on these events, click here.

Share Your Love for a Child with Rett Syndrome

Amy Schomburg, a mom from the Houston, TX area, is asking for your help. Amy, whose daughter Hannah has Rett Syndrome, is starting a project and needs your support compiling photos, stories, poems, letters, thoughts, etc. Her plan is to complete a book that will give the girls a voice to be shared with the world. Those interested in submitting stories or items to the book should contact Amy at neiamy@aol.com.

CDKL5 Belongs to the Same Molecular Pathway of MeCP2 and it is Responsible for the Early Seizure Variant of Rett Syndrome

Mutations in a gene called CDKL5 (also known as STK9) seem to cause symptoms very similar to Rett Syndrome. A common symptom associated with CDKL5 mutations are seizures within the first few months of life. The authors discuss possible interactions between MECP2 and CDKL5. Click here or on the title above to read the abstract and lay summary.

REST and Its Corepressors Mediate Plasticity of Neuronal Gene Chromatin throughout Neurogenesis

Like MECP2, the REST gene is a transcriptional repressor, meaning it regulates other downstream genes. This paper discusses functions of REST and provides an interesting hypothesis of why Rett Syndrome symptoms are neurological in nature even though MECP2 is found throughout the body. Click here or on the title above to read the abstract and lay summary.

Widened clinical spectrum of the Q128P MECP2 mutation in Rett syndrome

A cases study describing a child with an MECP2 mutation accompanied by some atypical traits who had seizure reduction through the ketogenic diet. Click here or on the title above to read the abstract.

Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome

This paper discusses a child with Rett Syndrome symptoms who had a chromosome translocation (where 2 different chromosomes exchange segments of DNA). The translocation affected a particular gene called NTNG1 which led the authors to hypothesize that mutations in this gene might also cause Rett Syndrome. Click here or on the title above to read the abstract and lay summary.

Another Patient With MECP2 Mutation Without Classic Rett Syndrome Phenotype

This paper describes a child with Angelman Syndrome symptoms who was found to have an MECP2 mutation. Click here or on the title above to read the abstract.

Increased dendritic complexity and axonal length in cultured mouse cortical neurons overexpressing methyl-CpG-binding protein MeCP2

Since individuals with Rett Syndrome are known to have immature neurons the authors decided to culture mouse neurons and expose them to an increased amount of MECP2 as well as mutant MECP2. Click here or on the title above to read the abstract and lay summary.

Rett Syndrome Featured in the Dana Foundation's Brain Work

The latest issue of the popular newsletter, Brain Work, distributed by the Dana Foundation includes an article on autism, Rett and Angelman Syndromes. Click here to read the article on page 5.

New data suggests efficacy of Lamictal as add-on treatment for primary generalized tonic-clonic seizures associated with epilepsy

Click here for more information.

Drug Warning for Trileptal

The FDA warns of serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) that have been reported in both children and adults in association with Trileptal use. For more information click here.

Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Most patients affected by classic RTT and a smaller percentage of patients with the milder form "preserved speech variant" have either point mutations or deletions/duplications in the MECP2 gene. Recently, mutations in the CDKL5 gene, coding for a putative kinase, have been found in female patients with a phenotype overlapping with that of RTT. Here we report two patients with the early seizure variant of RTT, bearing two novel CDKL5 truncating mutations, strengthening the correlation between CDKL5 and RTT. Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes. We show here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps that of MeCP2, during neural maturation and synaptogenesis. Importantly, we demonstrate that MeCP2 and CDKL5 interact both in vivo and in vitro and that CDKL5 is indeed a kinase, which is able to phosphorylate itself and to mediate MeCP2 phosphorylation, suggesting that they belong to the same molecular pathway. Furthermore, this paper contributes to the clarification of the phenotype associated with CDKL5 mutations and indicates that CDKL5 should be analyzed in each patient showing a clinical course similar to RTT but characterized by a lack of an early normal period due to the presence of seizures.

Lay Summary
Recently several labs have reported individuals with Rett like symptoms with mutations in a gene called CDKL5 (also knows as STK9). However, unlike classic Rett cases these individuals all have early onset seizures. This lab, which is currently funded by RSRF, analyzed how MECP2 and CDKL5 might interact. CDKL5 is a kinase, which means its function is to add a phosphate group to other genes in order to turn them on or off. The authors found that CDKL5 can facilitate the phosphorylation of MECP2. The authors point out that individuals with Rett symptoms but no MECP2 mutations should be analyzed for mutations in CDKL5, especially if they had seizures as infants. RSRF is also funding the lab of John Christodoulou to investigate how CDKL5 might be involved in Rett. The lead author of this paper as well as Dr. Christodoulou will be presenting at the upcoming RSRF symposium in Chicago.

Regulation of neuronal gene expression is critical to central nervous system development. Here, we show that REST regulates the transitions from pluripotent to neural stem/progenitor cell and from progenitor to mature neuron. In the transition to progenitor cell, REST is degraded to levels just sufficient to maintain neuronal gene chromatin in an inactive state that is nonetheless poised for expression. As progenitors differentiate into neurons, REST and its corepressors dissociate from the RE1 site, triggering activation of neuronal genes. In some genes, the level of expression is adjusted further in neurons by CoREST/MeCP2 repressor complexes that remain bound to a site of methylated DNA distinct from the RE1 site. Expression profiling based on this mechanism indicates that REST defines a gene set subject to plasticity in mature neurons. Thus, a multistage repressor mechanism controls the orderly expression of genes during development while still permitting fine tuning in response to specific stimuli.

Lay Summary
This paper describes the function of a gene called REST, which like MECP2, regulates other downstream genes. The author finds that REST regulates the transition of brain cells from immature to mature. Dr. Mandel, who serves on the RSRF Scientific Advisory Board, found that REST works in concert with partners, one of which is CoREST. In some cases the level of expression (the degree to which a gene is on or off) is fine tuned by a partnership between CoREST and MECP2. The paper offers an interesting hypothesis of why Rett Syndrome symptoms are mostly neurological despite the fact that MECP2 is found in all parts of the body.

Outside of the brain REST can act as a compensatory mechanism for MECP2. So when MECP2 is mutated and doesn't function properly REST can pick up the slack. REST is not present in a mature brain (mature meaning around the time of birth) and therefore there is no compensatory mechanism to pick up the slack from the mutated MECP2. The first author, Nurit Ballas and Gail Mandel, lead author, will both be attending the RSRF symposium later this month to discuss their finding.

We describe a female patient with Arnold Chiari type I malformation, atypical Rett syndrome characterized by postnatal onset microcephaly, stereotypic hand movements, ataxia, severe developmental delay, intractable tonic-clonic seizures, and a MECP2 mutation with a unique set of clinical findings. Implementation of a ketogenic diet resulted in decreased seizure activity and an improvement in the patient's degree of social relatedness with her family members. DISCUSSION: An early diagnosis of Rett syndrome allows families to maximize utilization of existing treatment modalities and seek appropriate genetic counseling and prenatal diagnoses. This case also provides further evidence for the treatment benefit of ketogenic diets for seizures in patients with Rett syndrome.

We have identified a girl with characteristic features of Rett syndrome (RTT) who carries a de novo balanced translocation involving chromosomes 1 and 7. Both breakpoints were mapped by fluorescence in situ hybridization with selected genomic clones from the regions of interest. Southern blot hybridisations, utilizing probes derived from breakpoint spanning BACs, detected several aberrant fragments specific for the patient. Sequence analysis of the cloned junction fragment indicated that on chromosome 1 the predominantly brain-expressed Netrin G1 (NTNG1) gene is disrupted, whereas on chromosome 7 there was no indication for a truncated gene. The chromosome 1 breakpoint lies within the 3' part of NTNG1 and affects alternatively spliced transcripts, suggesting that the phenotype in this patient is the result of disturbed NTNG1 expression. In silico translation of the NTNG1 splice variants predicted protein isoforms with different C-termini: one membrane bound through a glycosylphosphatidylinositol anchor and the other soluble. The membrane-bound protein isoform would be affected by the breakpoint, whereas the soluble form would remain intact. Our results suggest that the central nervous system is sensitive to NTNG1 expression levels and that NTNG1 is a novel candidate disease gene for RTT.

Lay Summary
Most individuals with Rett Syndrome symptoms have mutations in MECP2. However since some do not the search for other potential causes of these symptoms continues. This group of doctors identified a child with Rett like symptoms who had a chromosome translocation. This means that DNA segments from 2 chromosomes, in this case chromosome 1 and 7, were switched. This switch caused a disruption in a gene called NTNG1 which led the authors to hypothesize that mutations in this gene might also contribute to the symptoms seen in Rett Syndrome.

Rett syndrome and Angelman syndrome are two neurodevelopmental disorders characterized by partial overlapping features. Rett syndrome is frequently caused by a mutation in methyl-CpG-binding protein (MECP2) gene, localized on chromosome Xq28, whereas Angelman syndrome is frequently caused by different genetic anomalies at chromosome 15q11-q13 (deletions, uniparental disomy, imprinting center mutations, ubiquitin E3 ligase [UBE3A] gene mutations). Recently, some patients with a clinical diagnosis of Angelman syndrome were found to have a mutation in MECP2 gene. This report describes another patient with an Angelman-like phenotype and with an MECP2 mutation.

Rett syndrome is caused by loss-of-function mutations in the gene encoding the methyl DNA-binding factor MeCP2. As brain mass and neuronal complexity tend to be diminished in Rett patients, we tested whether MeCP2 directly influences the morphological complexity of developing neurons. Our results show that cultured mouse neurons overexpressing MeCP2beta (MECP2A) develop more complex morphologies, having longer axonal and dendritic processes, and an increased number of axonal and dendritic terminal endings. We then tested whether overexpressing a mutant form of MeCP2beta lacking its carboxyl terminus would elicit the same effects. Interestingly, while neurons overexpressing this mutant failed to enhance axonal and dendritic process elongation, the complexity of their axonal and dendritic processes remained significantly elevated. Taken together, these data support the hypothesis that MeCP2 directly regulates neuronal maturation and/or synaptogenesis, and provides evidence that MeCP2 may influence neuritic elongation and process branching through different mechanisms.

Lay Summary
Neurons (brain cells) can be described like trees with complex branching. In Rett Syndrome the number and complexity of the branching is reduced. It's theorized that MECP2 may be involved in maintaining the complexity and maturity of neurons. The authors of this paper decided to grow mouse neurons in a Petri dish and expose them to "too much" MECP2. It was not surprising when these neurons grew branches that were longer and more complex then typical. The scientists then exposed the mouse neurons to mutated MECP2 and the neurons failed to develop appropriate branching. The findings support the hypothesis that MECP2 regulates neuronal maturation.