Fall is Party Time for Rett Research!

This fall, there are several social events being held around the country to raise awareness and dollars for Rett Syndrome research. This past June, the New York City Picture a Cure Benefit kicked off the social event season with a bang - raising over $430,000 for research.  We will be adding to that total this fall in the following cities - Miami, Boston, Chicago and Washington D.C.  We need your help making these events a success. If you would like more information on these events or would like to serve on the event committee, please contact Craig Robertson, RSRF Executive Director, at 518.373.0687 or monica@rsrf.org.  You can also find more information on these events by clicking here.

	Miami, FL		Sep. 28th		Ferragamo's (Bal Harbour)		Picture a Cure Benefit
	Boston, MA	Nov. 3rd	The State Room	Festival of Food & Wine
	Chicago, IL	Nov. 4th	Bristol Court	New Year, New Hope Charity Dinner
	Washington D.C.	Nov. 18th	Mandarin Oriental Hotel	Festival of Food & Wine

 

Strollathon Program Rolls On

RSRF's Strollathon program is off to a wonderful start this summer. To date, events have been held in Stamford, CT, Harrisburg, PA and Cape Cod, MA.  In all, these three events have been attended by over 1,500 people and have raised over $335,000! That is a lot of awareness being generated and a great deal of money being raised for research. Congratulations to Event Chairs Kristy Kramer (PA), Monica Coenraads (CT) and Jennifer & Justin Endres (MA) on their fabulous efforts.

Four more Strollathons are scheduled over the next few months. Below is a listing of the events. If you would like more information or would like to support these events, please contact the respective Event Chair or Craig Robertson, RSRF Executive Director, at monica@rsrf.org or click here to go to the RSRF website.

Still to Come in 2005

	City		Location		Date		Event Chairs		Contact Info
	Seattle, WA	Bradley Park	Aug 27	Jeff & Laurie Huisingh	quadrifon@aol.com
	Roanoke, VA	Garst Mill Park	Sept 11	Karin Shuck	shuckstar@cox.net
	Charlotte, NC	Pineville Park	Oct 1	Debbie Devere Ricki O'Connor	ddevere@guaranteeins.com
	Cincinnati, OH	Bicentennial Commons	Oct 8	Kay Maynard	kmayn31@yahoo.com

Rett Syndrome Research Foundation Commits A Record $2.2 Million for 2005 Research Awards

Over $ 8.75 Million Invested in High-Impact Research Since 2000

August 15, 2005 - The Rett Syndrome Research Foundation (RSRF) announced today that it has awarded $2.2 million to fund 17 cutting edge projects aimed at accelerating treatments and a cure for Rett Syndrome, a devastating neurological disorder diagnosed almost exclusively in girls. Awards include Grants of Excellence to Accelerate Rett Research (G.E.A.R.), Research Grants and Post-Doctoral Fellowships. Click here for more information.

NIH Funding Table for  Various Diseases Available Online

The National Institutes of Health has posted on its Web site a revised table displaying funding levels for various diseases, conditions and research areas based on actual grants, contracts and research conducted at NIH. Rett Syndrome appears on this list after much lobbying on the part of RSRF. The table also provides funding estimates for FY2005 and FY2006. To view the table click here.  

Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome

This European research group, with funding from RSRF, studied 140 individuals with Rett Syndrome in an attempt to correlate mutations with symptoms. Click here to read the abstract and lay summary.

p.R270X MECP2 mutation and mortality in Rett syndrome

An Australian group found that the mutation pR270X was a common one. Recent analysis from other labs seemed to show an under-representation of this particular mutation. A study looking at over 500 individuals with Rett from Australia and the UK revealed that the underrepresentation of this particular mutation in older girls with Rett is probably due to a higher mortality rate associated with it. Click here to read the abstract.

Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males

A very interesting paper from a Belgian group showing that too much MECP2 causes a severe neurological disorder and may be a common cause of mental retardation in males. Click here to read the abstract and lay summary.

Early onset seizures and Rett-like features associated with mutations in CDKL5

Mutations in a gene called CDKL5 (also known as STK9) can cause symptoms very similar to those seen in Rett. This international group analyzed CDKL5 in 94 indiviuals with a Rett or Rett-like clinical diagnosis. The paper reports on the outcome of the analysis. Click here to read the abstract.

Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome

This European group, with RSRF funding, identified two genes, Sgk1 and Fkbp5, that are either directly, or indirectly, regulated by MeCP2. Click here to read the abstract and lay summary.

Spinal fluid 5-methyltetrahydrofolate levels are normal in Rett syndrome

This paper reports on the findings of a multicenter study to test levels of 5-methyltetrahydrofolate in the spinal fluid of 76 girls and women with Rett. Click here to read the lay summary.

Buspirone in Rett syndrome respiratory dysfunction

This study details a case of Rett Syndrome where the patient's respiratory dysfunction was improved after buspirone was administered. Click here to read the abstract.

Survey on ketogenic diet and VNS

RSRF is conducting surveys to gather information on the efficacy of the ketogenic diet and Vagal Nerve Stimualtion (VNS) for children and adults with Rett Syndrome who suffer from intractable seizures. If your child has tried the ketogenic diet please participate in our survey by clicking here. If your child has a VNS please click here. Data compiled from this survey will be shared with you via the RSRFNewsAlert, website and quarterly newsletter. The data will also be made available to the research community. We thank you in advance for your help.

Eur J Hum Genet. 2005 Aug 3; [Epub ahead of print]
Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome

Charman T, Neilson TC, Mash V, Archer H, Gardiner MT, Knudsen GP, McDonnell A, Perry J, Whatley SD, Bunyan DJ, Ravn K, Mount RH, Hastings RP, Hulten M, Orstavik KH, Reilly S, Cass H, Clarke A, Kerr AM, Bailey ME.

1Institute of Child Health, University College London, London, UK.

Abstract
We aimed to improve the understanding of genotype-phenotype correlations in Rett syndrome (RS) by adopting a novel approach to categorising phenotypic dimensions - separating typicality of presentation, outcome severity and age of onset - and by classifying MECP2 mutations strictly by predicted functional attributes. MECP2 mutation screening results were available on 190 patients with a clinical diagnosis of RS (140 cases with classic RS, 50 with atypical RS). 135 cases had identified mutations. Of the 140 patients, 116 with classic RS (82.9%) had an identified mutation compared with 19 of 50 patients (38%) with an atypical presentation. Cases with early onset of regression and seizures, and those with clinical features that might indicate alternative aetiologies, were less likely to have mutations. Individuals with late truncating mutations had a less typical presentation than cases with missense and early truncating mutations, presumably reflecting greater residual function of MECP2 protein. Individuals with early truncating mutations had a more severe outcome than cases with missense and late truncating mutations. These findings held when restricting the analysis to cases over 15 years of age and classic cases only. Previous findings of variation in severity among the common mutations were confirmed. The approach to phenotypic and genotypic classification adopted here allowed us to identify genotype-phenotype associations in RS that may aid our understanding of pathogenesis and also contribute to clinical knowledge on the impact of different types of mutations.European Journal of Human Genetics advance online publication, 3 August 2005; doi:10.1038/sj.ejhg.5201471.

Lay Summary
From the time MECP2 mutations were discovered to cause Rett Syndrome there has been considerable interest in trying to correlate specific mutations with specific symptoms and their severity. Not only could this be of interest to parents but this knowledge could also teach scientists more about the MECP2 gene. This study was undertaken by several European research groups, with funding from RSRF, IRSA and others. They studied 190 individuals, 140 who were classic Rett and 50 with atypical Rett. Of the 140, 83% had MECP2 mutations while only 38% of the atypica had mutations. The following conclusions were drawn:

• early onset correlated with lack of identifiable mutation
• early truncating mutations (which would disrupt the protein to a greater extent) correlate with a more classic Rett presentation and more severe symptoms
• late truncating mutations correlated with a less typical presentation, presumably reflecting greater residual function of the MECP2 protein

The authors conclude that larger studies with greater sample studies should be undertaken.

Eur J Hum Genet. 2005 Aug 3; [Epub ahead of print]
p.R270X MECP2 mutation and mortality in Rett syndrome

Jian L, Archer HL, Ravine D, Kerr A, de Klerk N, Christodoulou J, Bailey ME, Laurvick C, Leonard H.

1Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.

Abstract
Among cases in the Australian Rett Syndrome Database, the nonsense mutation p.R270X is one of the most commonly occurring single pathogenic MECP2 mutations. In two recent published reports of the MECP2 mutational spectrum the p.R270X appeared to be under represented. We hypothesised that increased mortality arising from this mutation may underlie this apparent discrepancy. We investigated our hypothesis in two independent study groups from Australia and the UK with prospective data collections (total n=524). Only females with Rett syndrome and an identified MECP2 mutation were included. Significant differences in survival were detected among Rett syndrome cases grouped for the eight most frequent mutations (log-rank chi(2) (7)=15.71, P=0.03). Moreover, survival among cases with p.R270X, when compared with survival among cases with all the other mutations was reduced (log-rank chi(2) (2)=6.94, P=0.01). Our observation of a reduced survival associated with the p.R270X mutation offers an explanation for the under representation of p.R270X in older subjects with Rett syndrome.
European Journal of Human Genetics advance online publication, 3 August 2005; doi:10.1038/sj.ejhg.5201479.

Am J Hum Genet. 2005 Jul 29;77(3) [Epub ahead of print]
Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males

Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Marynen P, Fryns JP, Froyen G.

Centre for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium. Hilde.VanEsch@med.kuleuven.ac.be.

Abstract
Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.

Lay Summary
We know from recent work in Dr. Huda Zoghbi's lab that too much MECP2 is detrimental to mice and causes neurological problems. This paper proves that the same is true in humans. Instead of mutations in MECP2 these Belgian researchers found a group of males who have 2 copies of MECP2 on their X chromosome, thus they have too much MeCP2 protein being produced. Symptoms included: hypotonia, developmental delay, no speech or ambulation, seizures, recurrent infections and spasticity as they child aged. The duplications of MECP2 came from the mothers who for unknown reason were all asymptomatic due to extremely skewed X inactivation. It may be a bit early to determine that MECP2 duplication is a frequent cause of mental retardation in males but this paper certainly makes the case that males with the symptoms listed above should be tested for this possiblity.

Eur J Hum Genet. 2005 Jul 13; [Epub ahead of print]
Early onset seizures and Rett-like features associated with mutations in CDKL5

Evans JC, Archer HL, Colley JP, Ravn K, Nielsen JB, Kerr A, Williams E, Christodoulou J, Gecz J, Jardine PE, Wright MJ, Pilz DT, Lazarou L, Cooper DN, Sampson JR, Butler R, Whatley SD, Clarke AJ.

1Department of Medical Genetics, Cardiff University, Heath Park, Cardiff, UK.

Abstract
Mutations in the CDKL5 gene (also known as STK9) have recently been shown to cause early onset epilepsy and severe mental retardation (ISSX or West syndrome). Patients with CDKL5 mutations sometimes also show features similar to those seen in Rett Syndrome (RTT). We have screened the CDKL5 gene in 94 patients with RTT or a RTT-like phenotype who had tested negative for MECP2 mutations (13 classical RTT female subjects, 25 atypical RTT female subjects, 40 RTT-like female and 16 RTT-like male subjects; 33 of the patients had early onset seizures). Novel pathogenic CDKL5 mutations were identified in three girls, two of whom had initially been diagnosed with the early onset seizure variant of RTT and the other with early onset seizures and some features of RTT. In addition, the 33 patients with early seizures were screened for the most common mutations in the ARX gene but none were found. Combining our three new cases with the previously published cases, 13/14 patients with CDKL5 mutations presented with seizures before the age of 3 months.European Journal of Human Genetics advance online publication, 13 July 2005; doi:10.1038/sj.ejhg.5201451.

Hum Mol Genet. 2005 Jul 7; [Epub ahead of print]
Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome

Nuber UA, Kriaucionis S, Roloff TC, Guy J, Selfridge J, Steinhoff C, Schulz R, Lipkowitz B, Ropers HH, Holmes MC, Bird A.

Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.

Abstract
Rett syndrome (RTT) is a severe form of mental retardation in girls, which is caused by spontaneous mutations in the X-linked gene MECP2. How the loss of MeCP2 function leads to RTT is currently unknown. Mice lacking the Mecp2 gene initially show normal postnatal development but later acquire neurological phenotypes, including heightened anxiety, that resemble RTT. The MECP2 gene encodes a methyl-CpG-binding protein that can act as a transcriptional repressor. Using cDNA microarrays, we found that Mecp2-null animals differentially express several genes that are induced during stress response by glucocorticoids. Increased levels of mRNAs for plasma glucocorticoid-inducible kinase 1 (Sgk) and FK506-binding protein 51 (Fkbp5) were observed before and after onset of neurological symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 is bound to the Fkbp5 and Sgk genes in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, our data raise the possibility that disruption of MeCP2-dependent regulation of stress-responsive genes contributes to the symptoms of RTT.

Lay Summary
The Chairman of the RSRF Scientific Advisory Board, Adrian Bird, of the University of Edinburgh and colleagues have identified two genes, Sgk1 and Fkbp5, that are either directly, or indirectly, regulated by MeCP2.  Sgk1 seems to play a role in cell survival and neuronal excitability. Fkbp5 modulates glucocorticoids, a class of hormones produced by the adrenal gland in response to stress. Given the harmful effects of glucocorticoid exposure on brain development, this data raises the possibility that disruption of the glucocorticoid pathway may contribute to the symptoms of RTT.  The project was funded, in part, by RSRF.

Neurology. 2005 Jun 28;64(12):2151-2.
Spinal fluid 5-methyltetrahydrofolate levels are normal in Rett syndrome

Neul JL, Maricich SM, Islam M, Barrish J, Smith EO, Bottiglieri T, Hyland K, Humphreys P, Percy A, Glaze D.

Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

PMID: 15985595 [PubMed - in process]

No abstract is available.

Lay Summary
In 2003 a paper was published a paper in Neurology reporting low levels of a folate metabolite, 5-methyltetrahydrofolate, in the spinal fluid of 4 girls with Rett Syndrome. Treatment with folinic acid increased the levels of the folate metabolite and parents reported some improvements in the children. A multi-center study including the Blue Bird Circle Rett Center at Baylor College of Medicine, University of Alabama-Birmingham and Children's Hospital of Eastern Ontario, undertook spinal fluid analysis of 5-methyltetrahydrofolate in 76 girls and women with RTT.  The study does not support the earlier findings as all but 2 individuals had normal amounts of 5-methyltetrahydrofolate. The reason for the discrepancy between the studies is unclear.  These findings indicate that there is no gross abnormalities in the spinal fluid folate metabolites in Rett Syndrome and do not support the use of folinic acid as a treatment for Rett Syndrome.

Brain Dev. 2005 Jun 17; [Epub ahead of print]
Buspirone in Rett syndrome respiratory dysfunction

Andaku DK, Mercadante MT, Schwartzman JS.

Santo Amaro University Physical Therapy School, Sao Paulo, Brazil.

Abstract
This study details a case of Rett Syndrome where the patient's respiratory dysfunction was improved after buspirone was administered. Polygraphic studies in the waking state, before and after treatment with 5mg of buspirone twice a day, were obtained. Breathing movements, oxygen saturation and end-tidal carbon were monitored. Average oxygen saturation increased from 86.9 to 91%, and the period of saturation below 90% was reduced by 42.2%. The oxygen saturation improvement observed in this case suggests that buspirone might be useful in treating respiratory dysfunction associated with Rett Syndrome. Controlled clinical trials are needed to provide more evidence.