NYC Picture A Cure Benefit scheduled for June 16th

The New York City Picture A Cure Benefit will be held on June 16th at Sotheby's in New York City. The event, which was attended by 400 people and raised over $425,000 last year, hopes to raise $500,000 for Rett Syndrome research. The event will include wonderful food, fabulous live entertainment and very exciting live and silent auctions. For more information or to view photos from last year's event, please click here or contact Craig Robertson, RSRF Executive Director, at monica@rsrf.org.

Kentucky Families Making a Difference

A "Family Fun Night for Rett Syndrome" was recently organized by Vanessa and Tony Cox of Mt. Washington, KY in honor of their daughter, Vanessa, who has Rett Syndrome.  The March 5th event featured food, drinks, games, prizes, live entertainment, an auction, raffle and door prizes!  The event brought lots of awareness of Rett Syndrome to the community and raised almost $6,000 which was shared between RSRF and IRSA.  Congratulations to the Cox Family on a wonderful event! 

The Walls Family of Shepherdsville, KY has been very busy this spring raising funds for Rett research.  Frank, whose daughter Michaela has Rett Syndrome, is a member and past-president of the Robinson Lodge #266 F. & A.M. in Louisville, KY.  They recently sponsored a Fish Fry Night on March 19th.  The event raised $2,275 which the Lodge will use for a Gold Sponsorship in the 2005 Ohio-Kentucky-Indiana Strollathon to be held October 8th in Cincinnati.    On April 9th, Lauren, Michaela's mom, held her annual Yard Sale.  Though her daughter had just been released from the hospital, Lauren exclaimed, "the show must go on".  The Walls family is not stopping there.  They also are planning a "Birthday Bash" for June 4th where a number of local families with daughters affected by Rett Syndrome will come together to celebrate their daughters' birthdays.  We would like to thank the Walls family for their extraordinary efforts!

Strollathons on tap in PA, CT and MA

With spring now here, the Strollathon program will soon be rolling out in Pennsylvania, Connecticut and Massachusetts.  In all, eight Strollathon events will be held this year across the country.  The first event of the season will be held on May 14th in Harrisburg, PA.  The third annual event, chaired by Kristy Kramer, hopes to raise over $50,000 for Rett research.  The second event on the calendar will be held on May 22nd in Stamford, CT.  Chaired by Monica Coenraads, RSRF Director of Research, the event hopes to exceed last year's incredible total of $190,000.  On June 4th, the Inaugural Cape Cod, MA Strollathon will be held in South Yarmouth.   This event, chaired by Jennifer and Justin Endres, is off to a great start and looks like it will be a huge success. 

The Strollathon program is RSRF's signature event and a wonderful opportunity for families to show their support for Rett Syndrome (RTT) research.  We hope that you will join us in our fight to find treatments and a cure for RTT.  For more information on the Strollathon program or to register for any of the events previously mentioned, click here or contact the respective Event Chair listed below.  Thank you for your support!

	Harrisburg, PA			Kristy Kramer			strollathon@aol.com
	Stamford, CT		Monica Coenraads		monica@rsrf.org
	Cape Cod, MA		Jen & Justin Endres		capecodstrollathon@yahoo.com

Sangamo BioSciences Announces Success in Gene Correction Technology

The April 4th issue of the journal Nature contained a paper by scientists at Sangamo BioSciences announcing that their gene correction technology was successfully used in manipulating the mutation found in "Bubble Boy" disease, X-linked Severe Combined Immunodeficiency Disease. Simply stated, the erroneous DNA was spliced out and the correct DNA was spliced in. The gene correction took place in a previously unheard of rate of 18% of the cells. It is important to note that these experiments took place in tissue culture (as in petri dish). Future experiments will hopefully move this research into the clinical trial phase. Click here to read Sangamo's press release. More information on this exciting work is available here.

The lead author of the paper, Dr. Fyodor Urnov, is currently funded by RSRF to do similar work on Rett Syndrome. He proposes to create mouse models for several of the most common point mutations found in Rett Syndrome and then attempt to use gene correction technology. To read more about this study please click here. Dr. Urnov will be attending RSRF's 6th Annual Rett Syndrome Symposium and will update the participants on his work.

The A140V mutation in the MECP2 gene is not a common etiological factor among Brazilian mentally retarded males

We now know that mutations in MECP2 can lead to disorders beyond classic Rett Syndrome. One such example is a particular mutation that causes autistic symptoms in males. Click here or on the title above to read the abstract and lay summary.

Managing scoliosis in a young child with Rett Syndrome: a case study

An interesting case study which illustrates how scoliosis was reversed in a child with Rett Syndrome through an intense physical therapy regimen. Click here or on the title above to read the abstract.

MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affect UBE3A expression

Since Angelman Syndrome shares many symptoms with Rett the authors of this paper hypothesized that MeCP2 may regulate the Angleman gene, UBE3A. The results are intriguing. Click here or on the title above to read the abstract and lay summary.

Topiramate May Impair Cognitive Function

In a study published in the medical journal Neurology, Dr. M. C. Salinsky, of Oregon Health and Sciences University, Portland, and colleagues examined the cognitive effects of topiramate in 39 healthy volunteers. Click here to learn more.

In mammals, methyl-CpG binding proteins play a significant role in the control of gene expression through their association with chromatin-remodeling complexes. Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome and have also been reported in a number of X-linked mental retardation diseases. In this study, DNA samples from 363 male individuals with syndromic and non-syndromic mental retardation and other psychiatric diseases were screened for A140V (419C>T) mutation in the MECP2 gene, considered the most frequent MECP2 mutation in males. No 419C>T was found suggesting that the A140V mutation in the MECP2 gene is not a common cause of mental retardation in males. Recently, a new and abundant isoform of MECP2 was described, which has an alternative N-terminus, translated from exon 1, that was previously thought to be non-coding and has been excluded from many mutational screening, as well, the 5' and 3' UTR regions. We consider essential proceeding further screening in the whole extension of the MECP2 gene using clinically well-documented and larger sized sample to assure the overall contribution of MECP2 to mental retardation.

Lay Summary
We now know that mutations in MECP2 can lead to disorders beyond classic Rett Syndrome. One such example is a point mutation at nucleotide number 419 which, in males, can cause autistic symptoms. The authors analyzed blood samples of 363 males with mental retardation and other psychiatric disorders for this particular mutation. They found none and conclude that this mutation is not a common cause of mental retardation in males. However, they recommend analzying a larger sample size and screening both isoforms of MECP2 (please visit our website for more information on MECP2 isoforms). www.rsrf.org/about_rsrf/1.5.3.html and www.rsrf.org/about_rsrf/1.5.2.html.

Rett syndrome is a genetic disorder primarily affecting females. One of its most disabling features is the severe and rapid progression of scoliosis. So far, only surgical intervention has succeeded in reversing the development of scoliosis in Rett syndrome. The present study describes a new management approach implemented with a girl with Rett syndrome. The core of the management regime was intensive: asymmetrical activation of trunk muscles through equilibrium reactions. The X-rays accompanying the article (evaluated by four experienced orthopedic surgeons blinded to the intervention process) suggested that the intervention was successful in reversing the progress of the scoliosis for the above-mentioned child. Discontinuation of treatment led to severe and rapid deterioration of the spinal curve. Due to the fact that this was a case study, generalization is limited, but we suggest further investigation and studies with this method.

Anyone interested in reading the entire article should contact Monica Coenraads at monica@rsrf.org

Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder, caused by heterozygous mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2). MeCP2 is a nuclear protein that binds specifically to methylated DNA and functions as a general transcription repressor in the context of chromatin remodeling complexes. Rett syndrome shares clinical features with those of Angelman syndrome (AS) an imprinting neurodevelopmental disorder. In AS patients, the maternally expressed copy of UBE3A that codes for the ubiquitin protein ligase 3A (E6-AP) is repressed. The similar phenotype of these two syndromes led us to hypothesize that part of the RS phenotype is due to MeCP2 associated silencing of UBE3A. Indeed, UBE3A mRNA and protein are shown here to be significantly reduced in human and mouse MECP2 deficient brains. This reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MeCP2 deficiency resulted in elevated acetylation of histone H3 and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center with no effect on DNA methylation or SNRPN expression. We conclude therefore that MeCP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications result in loss of imprinting (LOI) of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and consequently reduction in UBE3A production.

Lay Summary
Angelman Syndrome is a disorder that share many symptoms with Rett. It is caused by mutations in a gene called UBE3A on chromosome 15. Expression of UBE3A is "imprinted", a phenomenon in which the disease phenotype depends on which parent passed on the disease gene. When the father's complement of 15 is missing, the child has Prader-Willi, but when the mother's complement of 15 is missing, the child has Angelman syndrome. Due to the shared symptoms the authors hypothesized that MeCP2 may be regulating UBE3A. In fact the authors found that in the mouse model of Rett Syndrome the levels of UBE3A protein were lower then normal. These findings have also been corroborated by RSRF-funded Janine LaSalle of UCDavis. This is another example of how studying Rett will shed light on other disorders.