Join us on Saturday, November 20th at Baylor College of Medicine in Houston and learn about the latest research developments from one of the key leaders in the field, Dr. Huda Zoghbi. To learn more please click here or contact Monica Coenraads at monica@rsrf.org. Please note that to attend you must RSVP.

This work, funded by RSRF, shows that MECP2 is involved in the maintenance and maturation of brain neurons rather than the early development or the movement of neurons as the brain is initially formed. Click here or on the title above to read the abstract and lay summary.

The above two papers discuss individuals who have symptoms that resemble Rett Syndrome but who have no discernable MECP2 mutations. Mutations in a gene called CDKL5 (also called STK9) were found in these individuals. A grant recently awarded by RSRF to Dr. John Christodoulou of Australia is aimed at investigating the relationship between MECP2 and CDKL5. Click here or on the title above to read the abstract and lay summary.

This paper discusses the benefits of a physical exercise program based on treadmill therapy for individuals with Rett Syndrome. Click here or on the title above to read the abstract.

Dr. Solomon Moshé, Vice-Chairman of the Department of Neurology at the Albert Einstein College of Medicine in NYC, is interested in studying the relationship of autonomic dysfunction and seizures in children with Rett Syndrome. If your child has been diagnosed with Rett Syndrome and either has seizures or you suspect seizures please click here for more information.

A study from The Netherlands shows that patients using anti-reflux medications are more susceptible to pneumonia. Click here for more information.

A study by reseachers at Texas Children's Hospital concludes that fundoplication surgery in children often doesn't work. Click here for more information.

Rett syndrome is a neurodevelopmental disorder and one of the causes of mental retardation and autistic behavior in girls, as well as in a small group of boys. It was recently discovered that mutation of the methyl-CpG-binding protein 2 (MECP2) gene encoding a transcriptional repressor on the X chromosome causes Rett syndrome. Although it is evident that phenotypes of MECP2 mutant mice that resemble those of Rett syndrome are attributable to lack of the MECP2 gene in the central nervous system (CNS), there is little understanding of the neuropathological abnormalities in the CNS of MECP2-null mice. Here, we investigated the developmental regulation and specific cellular expression of MECP2 during neural development both in vitro and in vivo. MECP2 is expressed in mature neurons, but not in astroglia or oligodendroglia, and is increasingly expressed during development of the mouse neocortex. In addition, in vitro culture studies suggest that MECP2 is expressed in more differentiated neurons rather than in less differentiated neuroblasts. Under in vitro conditions using neural precursor cultures, we find that MECP2 mutant neural precursors differentiate into morphologically mature neurons and glia, and no significant differences in differentiation are detected between cells from wild-type and MECP2 mutant mice, suggesting that MECP2 may play a different role in mice than it does in Xenopus embryos. In agreement with this hypothesis, neocortical projection layers in MECP2 -/y mice are thinner than those in wild-type mice, and pyramidal neurons in layer II/III in MECP2 -/y mice are smaller and less complex than those in wild-type mice. Taken together, our results indicate that MECP2 is involved in the maturation and maintenance of neurons, including dendritic arborization, rather than in cell fate decisions.

This study, which was funded by RSRF, investigates where and when MeCP2 is found in the brain. The investigators found that MeCP2 is only found in certain brain cells called neurons and was not found in glia. Furthermore, MeCP2 was found in more mature neurons. A healthy mature neuron looks like a tree with many branches. The investigators determined that neurons which lacked MeCP2 had many less branches. They conclude that MeCP2 is somehow involved in the maintenance of mature neurons.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

See below.

Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process. PMID: 15499549 [PubMed - as supplied by publisher]

Two independent labs identified mutations in a gene called CDKL5 in patients who have symptoms that overlap significantly with Rett Syndrome. RSRF is currently funding the Australian group to study what the relationship between MECP2 and CDKL5 is. If your child has Rett symptoms but no MECP2 mutations you may want to consider having the child tested for CDKL5 mutations. Please visit the RSRF website for more information.

To investigate the feasibility of a physical exercise programme with treadmill for persons with Rett syndrome (RS) in order to promote fitness and health. Methods A daily training programme on a treadmill was designed for four females with RS over a period of 2 months with tests performed in three intervals, at time 1, 2 and 3, 2 months apart with intervention taking place between tests 2 and 3. Participants were four girls with RS aged 8.5-11 years (mean: 10 years) attending the educational facility Beit Issie Shapiro, Raanana, Israel, all with independent mobility and with typical characteristics of RS stage III. The training took place at the educational facility, on a 1400 model treadmill (Trimline, capable of very low speeds < 0.5 k/h), with very long side rails. Special low side rails were adapted to the treadmill in order to fit the height of the children and velcro straps were added to assist in safely placing the hands. Pulse was monitored constantly during exercise by an A3 polar pulse belt. Pulse measurements at rest during training were considered as evaluators of aerobic physical condition. Functional measurement was based on a scale specially established for the present study. The scale was a 31-item motor-functioning tool that measures the ability of participants to knee walk and knee stand, to get up to a standing position, duration of walking different paths, and to go up and down stairs and slopes. Results The study showed that physical fitness of the children at the end of the training programme had improved considerably (P < 0.05). Tests showed that general functional abilities had improved considerably (P < 0.0001). Although all items of the functional ability measure showed impressive positive change, some of the 31 items on it showed statistically significant improvement (knee walking, going up and down stairs and speed of walking for 25 m. Pearson correlation showed high linkage (r = -0.76) between functional improvement and change in physical fitness. Conclusions Physical fitness programme executed on a daily basis is capable of improving functional ability of children with RS. Nonprofessional personnel can execute such a programme under supervision of a qualified physical therapist.

October 26, 2004 - Individuals who use gastric acid-suppressive medications may be at an elevated risk of developing community-acquired pneumonia, according to an article in the October 27 issue of JAMA.

According to background information in the article, 20 to 40 percent of the general population experiences at least one episode of indigestion or gastroesophageal reflux disease (GERD, a backflow of acid from the stomach into the swallowing tube or esophagus) and five percent consult a general practitioner for their ailment. In primary care, a common way to treat these symptoms is to reduce gastric (stomach) acid secretions with the use of acid-suppressive drugs. However, these medications can increase vulnerability to infections, as stomach acidity is a major defense mechanism against ingested pathogens.

Robert J.F. Laheij, Ph.D., from the University Medical Center St. Radboud, Nijmegen, Netherlands, and colleagues studied pneumonia rates of both patients who did and did not use acid-suppressing medication. Patients were identified from the Integrated Primary Care Information (IPCI) database between January 1995 and December 2002. The study population included 364,683 individuals from the Netherlands who developed 5,551 cases of pneumonia for the first time.

The researchers found that current use of all acid-suppressive drugs was associated with a 27 percent increase in the risk of pneumonia, with higher risks for specific classes of acid-suppressive drugs (such as proton pump inhibitors or H2-receptor antagonist drugs).

"The effectiveness of acid-suppressive drugs in the treatment of upper gastrointestinal tract symptoms is excellent. Acid-suppressive drugs nevertheless seem to have some significant drawbacks," write the authors. "Persons using acid-suppressive drugs more often develop a community-acquired pneumonia compared with those who do not use acid-suppressive drugs, which is in general not a problem because the risk for developing pneumonia is low. The increased risk for pneumonia is a problem for patients who are at increased risk for infection, especially because community-acquired pneumonia is potentially dangerous."

(JAMA. 2004; 292:1955-1960. Available post-embargo at www.jama.com)