Key Research Papers

Development of consensus-based guidelines for managing communication of individuals with Rett syndrome

Gillian S. Townend, Theresa E. Bartolotta, Anna Urbanowicz, Helena Wandin and Leopold M.G. Curfs

Lay summary

This paper describes how the Rett Syndrome Communication Guidelines were developed.
Difficulties with communication have a profound impact on the lives of children and adults with Rett syndrome and their parents/caregivers. Across the world, many families report difficulties in being able to access appropriate and timely information and services from professionals with expertise in Augmentative and Alternative Communication (AAC), especially those who can also understand the complexities of Rett syndrome. To address this need, international guidelines for managing the communication of individuals with Rett syndrome were created. They were developed using a “consensus” process. This process combined research evidence with lived experience and expert opinion. In the first two stages over 300 research articles were analysed and surveys were completed by over 500 communication professionals and caregivers. In the third stage, a two-phase Delphi survey was conducted with an expert panel to validate the statements and recommendations that had been extracted from the literature and surveys. All statements that reached a pre-determined level of 70% agreement were incorporated into the guidelines. The final, published guidelines consist of 268 statements and recommendations relating to (a) rights of the individual; (b) beliefs and attitudes of communication partners; (c) professional knowledge and team work; (d) strategies to optimize engagement; (e) assessment; and (f) intervention (targets and goals, techniques), including the use of AAC.
To date, this project is the largest of its kind, with 650 participants from 43 countries contributing to development of consensus-based guidelines for Rett syndrome.


Phenotypes in adult patients with Rett syndrome: results of a 13-year experience  and insights into healthcare transition

Angela Peron, Maria Paola Canevini, Filippo Ghelma, Rosangela Arancio, Miriam Nella Savini, Aglaia Vignoli

Lay summary

This informative paper has the purpose of describing the common profile of an adult patient with Rett syndrome, as a result of previous data combined with a study conducted at San Paolo University Hospital in Milan (Italy), currently hosting the only adult RTT clinic in Northern Italy. The study focused the analysis on 50 patients aged ≥18 years with MECP2 pathogenic variants or a clinical diagnosis of typical RTT. 
The main problems experienced by these patients were: first of all epilepsy, showing that seizure remission is not so common as was believed; moreover, drugs often need to be changed with ageing (i.e. carbamazepine seems more effective than valproic acid in adult patients).
Some of the girls maintain the ability to walk when adults, especially the ones showing mild neurological signs since childhood.  Older women can be affected by Parkinsonism and other neurological impairments; stereotypic hand movements persist throughout life. 
Other common issues are sleep problems and behavioural disorders. Night laughing and screaming tend to decrease with age, while waking remains similar across age groups. A significant deterioration in mood as individuals aged is reported, so depression should be assessed. 
Scoliosis and low bone density (anticonvulsant therapy, especially with valproate, is an additional risk factor) are common in adult women with RTT.
Breathing problems are frequent. Adults tend to have fewer episodes of hyperventilation,  while breath holding tends to persist. Gastrointestinal (GI) problems are common but, while children present with vomiting or regurgitation and GERD, underweight along with prolonged feeding time and swallowing difficulty – thus considering the need of gastrostomy placement — are typical of older individuals. Cholelithiasis seems relatively frequent in adults with RTT.
In conclusion, the clinical manifestations associated with this syndrome vary with age, therefore referring to a multidisciplinary clinic is very useful, so that all the main comorbidities are addressed. 
CDKL5 disorder and FOXG1 mutations.
Adults with CDKL5 disorder almost always present epilepsy, which is frequently drug-resistant also in adulthood, as in two patients in the study. Sleep difficulties as well as GI problems seem to be very common in the CDKL5 disorder. Breathing abnormalities seem much less common than in classic RTT.
Less than 10 adults with FOXG1 mutations have been described so far. GI problems, scoliosis and severe osteopenia with fracture were the main problems in two patients in this study, in addition to ID.


Potent hERG channel inhibition by Sarizotan, an investigative treatment for Rett syndrome

Hongwei Cheng, Chunyun Du, Yihong Zhang, Andrew F. James, Christopher E. Dempsey, Ana P. Abdala, Jules C. Hancox

Abstract

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder associated with respiratory abnormalities and, in up to ~40% of patients, with prolongation of the cardiac QTc interval. QTc prolongation calls for cautious use of drugs with a propensity to inhibit hERG channels. The STARS trial has been undertaken to investigate the efficacy of Sarizotan, a 5-HT1A receptor agonist, at correcting RTT respiratory abnormalities. The present study investigated whether Sarizotan inhibits hERG potassium channels and prolongs ventricular repolarization. Whole-cell patch-clamp measurements were made at 37 °C from hERG-expressing HEK293 cells. Docking analysis was conducted using a recent cryo-EM structure of hERG. Sarizotan was a potent inhibitor of hERG current (IhERG; IC50 of 183 nM) and of native ventricular IKr from guinea-pig ventricular myocytes. 100 nM and 1 μM sarizotan prolonged ventricular action potential (AP) duration (APD90) by 14.1 ± 3.3% (n=6) and 29.8 ± 3.1% (n=5) respectively and promoted AP triangulation. High affinity IhERG inhibition by Sarizotan was contingent upon channel gating and intact inactivation. Mutagenesis experiments and docking analysis implicated F557, S624 and Y652 residues in Sarizotan binding, with weaker contribution from F656. In conclusion, Sarizotan inhibits IKr/IhERG, accessing key binding residues on channel gating. This action and consequent ventricular AP prolongation occur at concentrations relevant to those proposed to treat breathing dysrhythmia in RTT. Sarizotan should only be used in RTT patients with careful evaluation of risk factors for QTc prolongation.


Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012

Anne-Marie Bisgaard, Bitten Schonewolf-Greulich, Kirstine Ravn, Gitte Rønde

Lay summary 

Rett syndrome (RTT) is a neurodevelopmental disorder that results in multiple disabilities. It also carries a risk of medical comorbidities. It is important to establish the diagnosis as soon as possible to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms.  
We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious. We therefore conducted a study in our Danish Center for Rett Syndrome.  
We analysed the development and symptoms before and at the time of the RTT diagnosis in a cohort of 24 girls with RTT born in Denmark between 2003 and 2012. Furthermore, we looked at the symptoms that led to a suspicion of RTT resulting in a MECP2mutation analysis. 
Nearly 90% of these girls were diagnosed when the classical RTT symptoms as regression of hand function and development of hand stereotypies were recognized. However, it turned out that parents were concerned about their daughters between 3 and nearly 5 years prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements. A third of the girls had been referred to psychiatric evaluation because of a suspicion of autism.  
We concluded that many individuals with a MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to the evolution of the core clinical symptoms. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT. 


Aided language modelling, responsive communication and eye-gaze technology as communication intervention for adults with Rett syndrome: three experimental single case studies 

H. Wandin, P. Lindberg, K. Sonnander

Lay Summary 

Three adult women with Rett syndrome took part in this communication intervention study using single case experimental design. This research design is a good way to allow the researchers to judge whether or not an intervention is effective.  
During the whole study, the participants interacted with a communication partner with experience and knowledge of eye gaze technology, responsive communication and aided language modelling. Responsive communication includes incorporating wait time and following the participant’s lead, and aided language modelling means that the communication partner points at symbols while speaking. In this study they used symbols in an eye gaze device; in total 12 pages with 15 symbols on each page. All interactions took place during leisure such as book reading, playing board games or using play apps on a tablet.    
In all sessions, responsive partner strategies were used, and the participants had access to the eye gaze device. During two intervention phases, aided language modelling (and individualised dwell time) was also used.  
Results: Two of the participants increased their use of the eye gaze device throughout the study and all three participants used a larger variety of words during the intervention. If the communication partners respond to this consistently it may potentially stimulate language learning. One participant had more gazes lasting one second or longer. The participants were reported to enjoy the interactions and their support persons, who observed the sessions, perceived that they had learned to support communication better only while watching the sessions.  
Conclusion: It is possible in adulthood to increase expressive communication with interventions that include a larger number of communication symbols. This type of study is accepted by the participants and their support persons.  


Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice

Yann Ehinger, Julie Bruyère, Nicolas Panayotis, Yah-Se Abada, Emilie Borloz, Valérie Matagne, Chiara Scaramuzzino, Hélène Vitet, Benoit Delatour, Lydia Saidi, Laurent Villard, Frédéric Saudou, Jean-Christophe Roux

Lay summary 

Rett syndrome is a severe and intractable neurological disorder caused by mutations of the MECP2 (Methyl CpG binding protein 2) gene, located on the X chromosome. The MECP2 protein fine-tunes the expression of many genes, including brain-derived neurotrophic factor BDNF. BDNF plays a key role in the brain to help neurons survive and connect together. Normalization of BDNF expression only partially rescues the Mecp2 KO (knock out) mouse phenotype. Huntingtin, the protein mutated in Huntington’s disease, serves as a carrier for BDNF vesicles. We used a combination of state-of-the-art technological approaches and found that genetic activation of Huntingtin increases BDNF axonal transport in neurons deficient for Mecp2 protein. We demonstrated that a very slight modification of Huntingtin (phosphorylation) improves the quality of life of a mouse model of Rett syndrome. This study identifies Huntingtin and its phosphorylation as a new therapeutic target in Rett syndrome and demonstrates that activating endogenous BDNF in the appropriate neuronal circuits is more effective than non-specific BDNF overexpression. This treatment increases BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of a mouse model of Rett syndrome even though the treatment was initiated after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of people with Rett syndrome. 


The Time is Now: The Need for an Intensive, Appropriate Individual Intervention for Individuals with Rett Syndrome

Nissanholtz-Gannot R, Zigdon A, Lotan M

Lay summary

Rett syndrome (RTT) is a complex neurological disorder caused by an affected MECP-2 gene, primarily affecting females. In 2007, a reversal of typical clinical characteristics of MECP2 mice was performed successfully. The results suggest that similar reversals might be achieved in human patients with RTT in a foreseeable future. Nonetheless, this future cure will not be able to reverse already acquired disabilities and limitations, such as osteoporosis, muscle degeneration, orthopedic contractures, and functional loss attributed to a long sedentary life typical for this group of clients. Evidence suggests that many aspects of clients’ well-being and functional status depend on the therapeutic interventions they receive. Findings from diverse, intensive therapeutic programs implemented both with mice and individuals with RTT imply that such programs can enhance longevity, communications, learning, well-being, functional ability, and other life aspects characterizing this syndrome.  
The authors therefore urge that individuals with this syndrome should be treated with an intensive intervention programs from childhood to maintain their optimal functional performance and medical condition so that maximal gains will be achievable for those individuals with the availability of the forthcoming genetic cure.  


Implementing telehealth support to increase physical activity in girls and women with Rett syndrome-ActivRett: Protocol for a waitlist randomised controlled trial.  

Jenny Downs, Meir Lotan, Cochavit Elefant, Helen Leonard, Kingsley Wong, Nicholas Buckley, Michelle Stahlhut

Lay summary 

Individuals with Rett syndrome (RTT) experience impaired gross motor skills, limiting their capacity to engage in physical activities and participation in activities. Use of gross motor skills as physical activity during everyday living is an important component of health and quality of life. Still, we have limited knowledge of the effectiveness of supported physical activity interventions. Programmes of support for increasing participation in meaningful physical activities in small groups of individuals with RTT have been proven to be feasible and increase function. This study aims to evaluate the effects of a telehealth-delivered physical activity programme on physical activity, sedentary behaviour and quality of life in RTT. 
This is a multicentre study, conducted in Australia, Denmark and Israel. It is a randomised waitlist-controlled trial comparing an intervention to support physical activity with usual care. When a participant enters the study, he/she will be allocated to either immediate intervention or waitlist. Participants on the waitlist will then later complete the intervention. Participants are approximately 60 children and adults with RTT, recruited from the Australian Rett Syndrome Database, the Danish Center for Rett Syndrome and the Rett Syndrome Association of Israel. All participants are able to walk either independently or with assistance. The intervention duration is 12 weeks, including fortnightly telephone contact to plan, monitor and develop individual activity programmes. The activity programme aims to increase standing and walking activities, also known as ‘uptime’ activities. The increased ‘uptime’ activities will be determined by goals set in collaboration with caregivers and service providers for use in their own environments (home, school, community) and supported by the usual caregivers and service providers in those environments. Outcomes are measured at baseline, at 13 weeks and then at 25 weeks. The primary outcomes are sedentary behaviour assessed with an activPAL accelerometer and the number of daily steps measured with a StepWatch Activity Monitor. Secondary outcomes include sleep, behaviour and quality of life. Caregiver experiences will be assessed immediately after the intervention using a satisfaction questionnaire.  
For the involved participants and families, this study will build on available resources and strengths, respond to locally identified needs and empower those working in the local communities to improve physical activities and participation of the individuals with RTT under their care. Results from the study will be presented at conferences and consumer forums. We will develop an online resource that presents strategies of how to evaluate and support individuals with RTT to live physically active lives.   
This study will be the first clinical trial investigating strategies to increase physical activity in RTT. It is also one of the first studies to apply a telehealth approach in RTT. Telehealth can bring specialist skills to the affected individual in his/her own environment and is a particular attractive approach in light of the social isolation and disruption to traditional therapy delivery caused by the ongoing COVID-19 pandemic.  


Regression in Rett syndrome: Developmental pathways to its onset

Christa Einspieler, Peter B. Marschik

Lay summary

This article summarizes findings of various behavioural phenomena in early infancy, and thus prior to regression, in Rett syndrome. The clinical picture associated with Rett syndrome is defined by core and supportive consensus criteria, where a period of behavioural regression and the loss of previously acquired functions is outlined as a typical clinical trajectory. This review sheds light on early neuro-functions and alterations from expected infant behaviours, aiming to highlight their potential to serve as behavioural biomarkers before the onset of regression. In other words, this article outlines the current knowledge about behavioural phenomena that might inform earlier diagnosis. The main focus lies on different behavioural domains: (a) motor development, especially on purposeful hand movements and the occurrence of stereotypies prior to the loss of functions; and (b) speech-language and socio-communicative development. We outline potentially specific atypical behavioural patterns in these domains (e.g., vocalisations on inspiratory airstream; i.e. infants vocalize while they are inhaling) and different developmental traits of regression. Do infants achieve certain milestones and if so, what is the qualitative realization (e.g., walking): (1) ‘regression’, here, might point to the fact that the lack of respective behavioural patterns appeared more and more worrisome with increasing age; and (2) developmental milestones were achieved and functions deteriorate or even get lost during regression. In this article, we conclude that we are not quite there yet, but seem to be on the right track towards defining new and reliable neuro-functional markers for early detection of Rett syndrome. Based on these findings and the current ongoing studies, we expect to contribute to an earlier detection of Rett syndrome in the future.


Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Olga C. Jorge-Torres, Karolina Szczesna, Laura Roa, Artur Llobet, Sonia Guil, Manel Esteller

Abstract

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.

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