RSRF Flash Available Online

The Fall 2005 issue of the RSRF newsletter, RSRFlash, which contains the latest research news, educational information and updates on RSRF events, is now available online. Please click here to view it. We encourage you to share this online resource with any interested party. In order to receive your own personal copy of the RSRFlash please fill out our online registration form.    

Discovery Provides New Clues about Causes of Rett Syndrome

On October 17th, RSRF distributed a press release regarding a discovery made by Dr. Huda Zoghbi and Juan Young of Baylor College of Medicine. The research was funded by RSRF and the Howard Hughes Medical Institute among others. To read the HHMI press release please click here. To read the press release distributed by Baylor College of Medicine please click here.

Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett Syndrome

A paper which describes testing techniques which enable labs to comprehensively detect mutations in MECP2. To read the abstract and lay summary click here.

Postnatal Loss of Methyl-CpG Binding Protein 2 in the Forebrain is Sufficient to Mediate Behavioral Aspects of Rett Syndrome in Mice

This study illustrates which symptoms of Rett are likely attributed to the forebrain region of the brain and which are probably attributed to hindbrain regions. To read the abstract and lay summary, please click here.

The journal Brain and Development devoted a section on Rett Syndrome in their online September 22, 2005 issue

Below is a sample of the article abstracts. A full listing is available on the journal website.

• Abnormal general movements in girls with Rett disorder: The first four months of life
• Music therapy as a tool for assessing hand use and communicativeness in children with Rett Syndrome
• Management of young children with Rett disorder in the controlled multi-sensory (Snoezelen) environment
• Learning ability in children with Rett syndrome
• Rett syndrome from a family perspective: The Swedish Rett Center survey
• Disorganized rhythm and synchrony: Early signs of autism and Rett syndrome
• Can we relate MeCP2 deficiency to the structural and chemical abnormalities in the Rett brain?

FDA warns of medication dispensing or prescribing errors between Toprol-XL and Topamax

FDA warns of medication dispensing or prescribing errors between Toprol-XL and Topamax. To read more please click here.

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.

J Med Genet. 2005 Sep 23; [Epub ahead of print]
Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett Syndrome
Archer HL, Whatley SD, Evans JC, Ravine D, Huppke P, Bunyan D, Kerr AM, Kerr B, Sweeney E, Davies SJ, Reardon W, Horn J, Macdermot KD, Smith RA, Magee A, Donaldson A, Crow Y, Hermon G, Miedzybrodzka Z, Cooper DN, Lazarou L, Butler R, Sampson JR, Pilz DT, Laccone F, Clarke AJ.
Cardiff University, United Kingdom.

Abstract
MECP2 mutations are identifiable in ~80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. METHODS: We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using MLPA or QF-PCR. RESULTS: Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193 p<0.0001). CONCLUSIONS: Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.  

Lay Summary
It is a statement we have read often - “mutations in the MeCP2 gene are found in ~80% of girls with classic Rett syndrome”.  In the majority of cases, these mutations were identified by directly reading the DNA sequence of the MeCP2 gene in the patient samples, and looking for DNA sequences different from the norm.  However, there are a significant number of patients whom no MeCP2 mutation has been found via direct DNA sequence reading.  In this study, the authors reinforce the limitation of doing sequence reads alone.  Specifically, large DNA deletions of the MeCP2 gene, which are common forms of MeCP2 mutations, are missed by performing sequence reads alone – that is, the deletions are masked by the presence of the DNA of other non-mutated copy of MeCP2 found in patients.  Here, the authors examined 110 patients with either classic or atypical RTT, whom no MePC2 mutation had previously been detected by sequence analysis.  By using techniques that examine the structure of the MeCP2 gene as a whole, 37.8% of classic RTT and 7.5% of atypical RTT patients were found to have deletions of the MeCP2 gene, thus confirming clinical diagnoses.  Indeed, the study reinforces the point that screening for MeCP2 mutations by DNA sequencing alone is not enough, and that analysis of the whole gene structure is important in diagnostic assessments.

Biol Psychiatry. 2005 Sep 28; [Epub ahead of print]
Postnatal Loss of Methyl-CpG Binding Protein 2 in the Forebrain is Sufficient to Mediate Behavioral Aspects of Rett Syndrome in Mice
Gemelli T, Berton O, Nelson ED, Perrotti LI, Jaenisch R, Monteggia LM.

Abstract
Mutations in the methyl-CpG binding protein 2 (MeCP2) gene cause Rett syndrome (RTT), a neurodevelopmental disorder that is accompanied by a broad array of behavioral phenotypes, mainly affecting females. Methyl-CpG binding protein 2 is a transcriptional repressor that is widely expressed in all tissues. METHODS: To investigate whether the postnatal loss of MeCP2 in the forebrain is sufficient to produce the behavioral phenotypes observed in RTT, we have generated conditional MeCP2 knockout mice. RESULTS: These mice display behavioral abnormalities similar to RTT phenotypes, including hindlimb clasping, impaired motor coordination, increased anxiety, and abnormal social behavior with other mice. These mice, however, have normal locomotor activity and unimpaired context-dependent fear conditioning, suggesting that the behavioral deficits observed are the result of loss of MeCP2 function in postnatal forebrain and not the result of generalized global deficits. CONCLUSIONS: These data highlight the important role of MeCP2 in the forebrain and suggest that even partial loss of MeCP2 expression in these brain regions is sufficient to recapitulate features of RTT.

Lay Summary
Several different mouse models of Rett syndrome have now been generated, and are widely used in Rett research.  One mouse model has the normal MeCP2 gene replaced with a truncated MeCP2 gene (Huda Zoghbi's group), another mouse model has MeCP2 missing in all of the cells of the mouse (Adrian Bird's group), and another mouse model has MeCP2 is missing in just the forebrain – that is, the most forward section of the brain, which is responsible for emotions, thought process, self-awareness, memory, and motor movement (Rudolph Jaenisch’s group).  In this paper, the authors describe in detail the observable behaviour characteristics of the latter mouse model.  Like the other mice models, these mice display behavioural abnormalities common to Rett syndrome, including limb clasping, impaired coordination, increased anxiety, and abnormal social behaviour with other mice. Most interestingly, unlike the other mouse models, these mice have normal movement and a normal response to some tests of fear.  Thus, this study illustrates which of those behaviours common to Rett syndrome are attributed to the forebrain region of the brain (limp clasping, coordination, anxiety, social behaviour), and which are probably attributed to hindbrain regions (overall movement and some fear conditioning).   

Abnormal general movements in girls with Rett disorder: The first four months of life
Einspieler C, Kerr AM, Prechtl HF.
Section Developmental Physiology and Developmental Neurology, Institute of Physiology, Center for Physiological Medicine, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria.

An apparently normal early development was one of the initial criteria for classical Rett syndrome. However, several investigators considered Rett syndrome to be a developmental disorder manifesting very soon after birth. Videos of 14 infants with Rett disorder were carefully assessed for their spontaneous movements, in particular general movements (GMs), during the first 4 months of life. A detailed analysis clearly demonstrated that none of the infants had normal GMs. However, a specific abnormal GM pattern could not be detected for Rett disorder. The abnormal GMs described here, and their individual developmental trajectories are different from the abnormal GMs described in infants with acquired brain lesion. Our study is the first to apply specific standardised measures of early spontaneous movements to infants with Rett syndrome, proving conclusively that the disorder is manifest within the first weeks of life.  

Music therapy as a tool for assessing hand use and communicativeness in children with Rett Syndrome
Wigram T, Lawrence M.
Department of Music and Music Therapy, University of Aalborg, Institut 10, Kroghstraede 6, 9220 Aalborg O, Denmark; Harper House Children's Service, Hertfordshire Partnership NHS Trust, 15 Forest Lane, Harperbury, Harper lane, Radlett, Herts WD7 9HQ, UK.

A six-year-old girl with Rett syndrome was assessed in a multi-disciplinary specialist therapy clinic and aspects of her responsiveness and developmental potential were found in the music therapy assessment. Functional hand use, eye-referencing, motivated and intentional communication were observed and reported through video analysis of a 30min session of music therapy employing improvisational methods. Absent or reduced hand clasping/plucking, interactive turn-taking, primary and secondary inter-subjectivity, and vocalisation with appropriate emotional expression were evident. Stable truncal positioning and occasional gentle restraint of either hand improved both spontaneous and prompted activity.  

Management of young children with Rett disorder in the controlled multi-sensory (Snoezelen) environment
Lotan M, Shapiro M.
Therapeutic Department, Zvi Quittman Residential Center, The Millie Shime Campus, Israel Elwyn, Jerusalem, Israel.

Rett syndrome is a neurological disorder resulting from an X-linked dominant mutation. It is characterized by a variety of physical and perceptual disabilities, resulting in a need for constant therapy programs to be administered on a regular basis throughout the client's life. As the child with Rett disorder (RD) is entering the more obvious, hectic phase of this syndrome (stage II), signs of extreme agitation and discomfort are usually exhibited. This behavior is suspected to reflect damaging chaotic processes accruing in the brain at that time. Experts advise that calming techniques might be helpful for children with Rett during this period. This may be our earliest opportunity to change the course of the disorder. Now that our knowledge of RD has increased and children are being diagnosed at a substantially earlier age, new intervention methods should be introduced for parents and therapists. This may ensure more suitable treatment. The multi-sensory environment may provide a soothing haven, which appeals to the child with RD. This article provides a short review of RD typical phenotype and suggests suitable activities that could take place in the multi-sensory environment with this population at the early stages of appearance of the Rett disorder.  

Learning ability in children with Rett syndrome
Elefant C, Wigram T.
Sogn and Fjordane University College, Sandane, Norway.

The purpose of this article is to present results of a research study examining learning ability in individuals with Rett syndrome. The material for this article was drawn from a more extensive doctoral study, designed to investigate intentional communication in this population, through the use of songs in music therapy. Rett syndrome is a neurological disorder resulting from an X-linked mutation, affecting mainly females, and found across racial and ethnic groups worldwide. One of the main areas affecting functioning in individuals with Rett syndrome is a severe impairment of receptive and expressive communication. This creates difficulties when attempting to reveal their potential learning abilities. This population has been observed as very responsive to music hence music therapy intervention has been advocated in promoting and motivating them to communicate and to learn. Seven girls with Rett syndrome, between ages 4 and 10 participated in the study. A single subject, multiple probe design was applied during 30-min trials, three times per week and lasted 8 months. During the trials the participants were asked to choose from a selection of 18 familiar and unfamiliar songs, while their ability to learn was observed and measured. Findings revealed that all seven girls demonstrated an ability to learn and to sustain learning over time. This intervention demonstrated that individuals with Rett syndrome could be promoted and motivated to communicate and learn when therapeutically employed by a trained music therapists.  

Rett syndrome from a family perspective: The Swedish Rett Center survey
Larsson G, Lindstrom B, Engerstrom IW.
Swedish Rett Center, Froso Strand, Box 601, SE-832 23 Froson, Sweden.

The aim of this study was to make a description of the early development in individuals with the diagnosis Rett syndrome using parents' information. Information received from 125 cases of Rett syndrome in Sweden in 1997 provided us with families' description of early development in gross motor function, fine motor function and communication/social interplay. Best abilities before regression were presented, 62% lost their best abilities, 22% kept them and 5% kept them with deterioration. Seventy-three percent learnt to walk, 20% stopped walking and 2% retrained walking. Concerning feeding, 69% learnt to feed themselves, 57% lost this ability, 7% retrained the ability and 5% learnt to feed after regression. Sixty-four percent were one year or younger when there was a deviation in development. Sixty answers reported the girl was late in developing functions while 35 reported sudden loss of reached abilities. Seventy-four percent developed a scoliosis and 83% reported other deformities; of these, deformities in feet were the most common. Postural control was poor since all but 15 girls/women leant in different directions when sitting. Transitional movements were difficult to perform. In 80% of cases, the families were those who suspected early that something was wrong in the child's development. Because of this it is essential that medical staff is aware of the different ways RS develops in order to give families early appropriate support and a plan for intervention. Since there is not only loss of function in this group but also kept abilities, retrained abilities and abilities achieved after regression, more research has to be focused on management and treatment to help persons with Rett syndrome keep and develop abilities according to their individual resources.  

Disorganized rhythm and synchrony: Early signs of autism and Rett syndrome
Trevarthen C, Daniel S.
Department of Psychology, The University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, Scotland, UK.

We interpret early age-related developments in intentions and socially responsive behaviour with data from home videos of infants who later develop autism or Rett syndrome. Detailed evidence is given from a micro-analytic study of videos of monozygotic twin girls at 11 months, one of whom became autistic in the second year. Changes in this twin's attention, motor tonus, initiative and emotion reduce her prospective control of movements and her anticipations in awareness compared to her sister. These changes were reflected in the child's asynchronous social behaviour, which frustrated the father's attempts to support her attempts to walk, share toys, or play a game, confusing his anticipations, and this further reduced mutual attention and joint activity. Observations of the development of girls with Rett syndrome in the first year reveal changes in motor coordination, attention and communicative initiative, indicative of a failure of intrinsic core brain regulations of neural development and conscious activity. Notwithstanding that the two conditions show clear differences in both brain growth and early development of skills and sociability, the first signs of autism and Rett syndrome have important similarities. We conclude with recommendations for an approach to early diagnosis and treatment, applicable for the whole range of developmental brain disorders, including Rett syndrome and autism, that attempts to identify residual capacities for sympathetic motivation and collaborative learning-an approach that deliberately tries to support weakened rhythmic impulses for motor, perceptual and communicative functions in the growing infant brain.  

Can we relate MeCP2 deficiency to the structural and chemical abnormalities in the Rett brain?
Armstrong DD.
Department of Pathology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.

The mutated gene for Rett syndrome, MECP2, has now been identified in ninety percent of cases. Molecular biologists are immersed in the study of this gene's biology determining how its mutation could be responsible for such an enigmatic phenotype. In this paper the same question is considered, reexamining the structural phenotype of the Rett brain and asking; is MeCP2 present at the appropriate time and place in brain development to influence the structural and chemical abnormalities which characterize the Rett brain? Data from the literature and previous research suggest that MeCP2 is expressed during critical periods of brain development at several sites and in different neurons. It supports the idea that inadequate functioning of MeCP2 alters trophic factors and raises the possibility that replacement of these factors might improve brain function. The availability of mouse models now makes it possible to test such ideas.