Research Papers

We are happy to share this section as a joint effort of our Scientific Advisory Board to bring the latest scientific knowledge closer to human language. Thus, for every article shared here you will find a short and simple lay summary, provided either by the authors of the articles, or some short reviews by our SAB of recently published articles of other authors, as well as a link to an original article.

For an easier search and navigation, you will find these articles grouped by the main subject. Just click on the title, read the lay summary or review and look out for the full article in case you want to deepen your knowledge even more.

Living with Rett syndrome: therapies, communication, movement and more

“Why don’t they talk to our daughter?”: Eye-tracking AAC and medical communication in Rett syndrome. By Usree Bhattacharya, Wisnu A. Pradana, Xing Wei, Bukunmi Ogunsola (2023)


This investigation explores medical advocacy for Rett syndrome—a rare neurological disorder causing loss of speech and hand function—through the lens of eye-tracking augmentative and alternative communication (AAC) technology. We gathered data from five individuals with Rett syndrome and their caregivers, encompassing semi-structured virtual interviews, video analyses of AAC device usage, and examination of AAC pageset screenshots. The findings reveal diverse AAC strategies employed to express discomfort or illness and highlight caregivers’ pivotal role in processing medical information. Notwishstanding challenges like cost, time limitations in medical contexts, training needs, and the lack of standardized AAC symptom descriptions, eye-tracking AAC technology has the potential to enhance symptom assessment, foster patient autonomy, and facilitate personalized medical care. This study illuminates the transformative power of this AAC technology in medical communication, showcasing its promise in tackling communication challenges and underscoring its capacity to enhance quality of life for those with Rett syndrome and similar health conditions.

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The Impact of Eye-gaze Controlled Computer on Communication and Functional Independence in Children and Young People with Complex Needs – A Multicenter Intervention Study. By Borgestig M., Al Khatib I., Masayko S., Hemmingsson H. (2021)

Lay Summary:

This article reports on an international multi-centre intervention study, investigating the use of eye gaze controlled computers (EGCC) and their impact on communication, functional independence and participation. The study focuses on 17 children and young people (aged 3-26 years) with complex needs (severe motor impairments and no speech), receiving services from Assistive Technology (AT) Centres in Sweden, Dubai and USA. Five participants had Rett syndrome. All participants were provided with eye gaze equipment (Tobii products) to use at school and/or home for six months, with support from AT Centre staff. They were assessed at before provision of EGCC (baseline), at 3 and 6 months after baseline (with EGCC), and also 6-7 months (without EGCC). Assessments were conducted over 2 weeks at each measurement point, using a mix of questionnaire and observation-based formal measures and diaries. A range of software and language programmes was included on the EGCCs. Goals during the intervention period included: communication and social interaction (e.g. making choices, expressing needs, responding to questions), learning to control an EGCC with eye gaze, performing school tasks (literacy, writing and learning), and engaging in play and activities. Support included planning and follow-up meetings, joint sessions using the EGCC in everyday contexts, and technical support. Results showed an increase in expressive communication, functional independence (competence), repertoire of computer activities, and frequency and duration of use over the six-month period (although interestingly maximum use of EGCC was limited to 2 hours a day for almost all participants in school and at home). In conclusion, the authors found that the study strengthened the research evidence that EGCC can be an effective intervention in daily life for children and young people with complex needs. They recommend future research to follow participants over several years, to learn about long-term effects and continuity in EGCC use.

The full list of assessments is:
Communication Function Classification System and Gross Motor Function Classification System (baseline measures of overall severity); Communication Matrix (expressive communication); Psychosocial Impact of Assistive Devices Scale (PIADS) (functional independence); Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0) (parent and teacher satisfaction); KIDSCREEN-10 by proxy (health-related quality of life); diary (participation in computer activities).

Comment: This study offers an interesting model for others to follow, for example, to assess and evidence progress during supported EGCC loans, and to argue for funding and long-term provision of EGCCs.

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Aided language modelling, responsive communication and eye-gaze technology as communication intervention for adults with Rett syndrome: three experimental single case studies. By H. Wandin, P. Lindberg, K. Sonnander. (2021)

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.  

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A comparison of formal and informal methods for assessing language and cognition in children with Rett syndrome. By Callie Ward, Shula Chiat, Gillian S. Townend. (2021)


Background: Opinions about the cognitive and receptive language skills of people with Rett syndrome (RTT) range from severe intellectual impairment to near-normal development. Assessment is challenging because most are non-verbal, with no purposeful hand use. Clarkson et al. (2017) adapted the Mullen Scales of Early Learning for use with eye gaze technology (MSELA/ET) for people with RTT. Aims: To investigate and compare the performance of children with RTT on formal and newlydesigned informal assessments of language and cognition using eye gaze/tracking technology.

Methods and procedures: Ten children with RTT aged 4:0–6:8 were assessed on the MSEL-A/ET for Visual Reception (VR) and Receptive Language (RL), and standard MSEL for Expressive Language (EL). Informal assessments of the same skills were embedded in activities such as reading and cake-decorating.

Outcomes and results: Standard scores on MSEL-A/ET VR and RL subtests ranged from ‘very low’ to ‘above average’. All children scored ‘very low’ on standard EL assessment. Informal assessments added information about EL, with children producing 1–3 word utterances and a range of communicative functions through an eye gaze device.

Conclusions and implications: Combining low-tech augmentative and alternative communication, eye gaze technology, informal activities and formal assessment, yields greater insight into children’s abilities. This is important in informing suitable support and education for the individual.

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Development of consensus-based guidelines for managing communication of individuals with Rett syndrome. By Gillian S. Townend, Theresa E. Bartolotta, Anna Urbanowicz, Helena Wandin and Leopold M.G. Curfs. (2020)

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.

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Implementing telehealth support to increase physical activity in girls and women with Rett syndrome-ActivRett: Protocol for a waitlist randomised controlled trial. By Jenny Downs, Meir Lotan, Cochavit Elefant, Helen Leonard, Kingsley Wong, Nicholas Buckley, Michelle Stahlhut. (2020)

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.  

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Eye-Gaze Control Technology as Early Intervention for a Non-Verbal Young Child with High Spinal Cord Injury: A Case Report. By Helena Hemmingsson, Gunnar Ahlsten, Helena Wandin, Patrik Rytterström and Maria Borgestig. (2018)


Assistive technology (AT) can be used as early intervention in order to reduce activity limitations in play and communication. This longitudinal case study examines eye-gaze control technology as early intervention for a young child with high spinal cord injury without the ability to make sounds. The young child was followed by repeated measures concerning performance and communication from baseline at 9 months to 26 months, and finalized at 36 months by field observations in the home setting. The results showed eye-gaze performance and frequency of use of eye-gaze control technology increased over time. Goals set at 15 months concerning learning and using the AT; naming objects and interactions with family was successfully completed at 26 months. Communicative functions regarding obtaining objects and social interaction increased from unintentional actions to purposeful choices and interactions. At 36 months, the toddler was partly independent in eye gazing, used all activities provided, and made independent choices. In conclusion, the results show that a 9-month-old child with profound motor disabilities can benefit from eye-gaze control technology in order to gradually perform activities, socially interact with family members, and make choices.

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The Time is Now: The Need for an Intensive, Appropriate Individual Intervention for Individuals with Rett Syndrome. By Nissanholtz-Gannot R, Zigdon A, Lotan M. (2015)

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.  

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Basic research

Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome. By Edilene Siqueira, Aida Obiols-Guardia, Olga C. Jorge-Torres, Cristina Oliveira-Mateos, Marta Soler, Deepthi Ramesh-Kumar, Fernando Setién, Daniëlle van Rossum, Ainhoa Pascual-Alonso, Clara Xiol, Cristina Ivan, Masayoshi Shimizu, Judith Armstrong, George A. Calin, R. Jeroen Pasterkamp, Manel Esteller, and Sonia Guil. (2022)

Lay Summary:

In this work, the fraction of the human genome that does not code for proteins but has important regulatory roles (what is known as the noncoding transcriptome) is explored in RTT. By combining experiments in mouse animals and human cell models, together with data obtained from patient’s brains post-mortem samples, changes in the noncoding transcriptome have been revealed. Some key changes are linked to altered control in the formation of important neural structures, including the cytoskeleton (the scaffold of the cells) and some of the membrane receptors that are crucial for the glutamatergic (excitatory) signalling in neurons. Strikingly, by acting through different cellular pathways, different classes of noncoding transcripts influence nevertheless the same key processes down the road, which highlights the potential for this type of transcripts (traditionally overlooked in RTT studies) to reveal important aspects in RTT pathogenesis. Their utility as therapeutic targets and/or disease biomarkers will be further assessed in future studies.

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Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice. By 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. (2020)

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. 

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Sleep problems in Rett syndrome animal models: A systematic review. By Xinyan Zhang, Jian-Sheng Lin, Karen Spruyt. (2020)

Lay summary:

Disturbed sleep is a supportive diagnostic criterion of Rett Syndrome (RTT). Our aim was to explore in more detail such sleep disturbances. Up to now, we published two review articles, both animal and human research, investigating sleep. Since the discovery of the pathogenicity of the genetic mutations in RTT, 13 sleep studies involving animal models of mostly mice, but also cynomolgus monkeys and Drosophila have been developed. These animal models reported highly fragmented sleep in the 24-hour sleep/wake cycle with distinct differences and arrhythmicity. Combined, they illustrate disturbed efficacy and continuity of sleep. Although these animal models may mimic sleep complaints reported in individuals with RTT, contrary to human studies, in mutant mice attenuated deep sleep as well as occurrences of sleep apneas in non-rapid eye movement sleep were reported. In the review paper summarizing case data reported in the literature, we collected 74 RTT cases from eleven studies and did a stratified analysis per RTT-related gene, comorbidities of epilepsy and scoliosis, and the history of adeno(tonsil)ectomy surgery. Regarding the sleep macrostructure, we mainly found a significantly longer total sleep time and non-rapid eye movement sleep stage 1 (or lighter sleep) in CDKL5 mutant RTT cases compared to the MECP2 mutant ones. We also compared the sleep macrostructure of RTT cases to the normative values from the literature, phenotyping their sleep as longer wakefulness after sleep onset, enhanced deep sleep and reduced rapid eye movement sleep. In terms of sleep respiratory events, sleep disordered breathing was confirmed by an abnormal apnea/hypopnea index. Sleep and breathing during sleep was disturbed since early age. Our ongoing work are a meta-analysis of the sleep problems and polysomnographic parameters reported in the literature and analyzing polysomnographic recordings of RTT cases collected from the clinic. 

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Potent hERG channel inhibition by Sarizotan, an investigative treatment for Rett syndrome. By Hongwei Cheng, Chunyun Du, Yihong Zhang, Andrew F. James, Christopher E. Dempsey, Ana P. Abdala, Jules C. Hancox. (2019)


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.

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Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice. By Olga C. Jorge-Torres, Karolina Szczesna, Laura Roa, Carme Casal, Louisa Gonzalez-Somermeyer, Marta Soler, Cecilia D. Velasco, Pablo Martínez-San Segundo, Paolo Petazzi, Mauricio A. Sánchez, Raúl Delgado-Morales, Stephane Fourcade, Aurora Pujol, Dori Huertas, Artur Llobet, Sonia Guil, and Manel Esteller (2018)

Lay summary

Rett syndrome (RTT) is a severe neurodevelopmental disorder characterised by loss-of-functions mutations in MeCP2 gene. In this research article, Jorge-Torres et al. show that mice models of RTT display hyperactivation of the molecular pathway controlled by Gsk3b kinase and neuroinflammation. The administration of a specific inhibitor of Gsk3b reduces motor deficits and improves the general wellbeing of the mice. Analysis of the resulting neuronal morphology indicates restoration of the cellular complexity in vitro and in vivo, together with an impact on excitatory synapses upon treatment. Altogether, this indicates that inhibition of Gsk3b pathway partially rescues the Rett phenotype and impacts on neuronal morphology and synaptic activity, suggesting that Gsk3b is a potential therapeutical target in Rett syndrome treatment. 

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Clinical research

Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome. By Helen Leonard, Wendy Gold, Rodney Samaco, Mustafa Sahin, Timothy Benke and Jenny Downs. (2022).

Lay Summary (by Gillian Townend):

In this article Leonard and colleagues explore some of the issues associated with clinical trials and the development of treatments to address symptoms of Rett syndrome. They look at common comorbidities and their management, and reasons behind difficulties to date in transferring preclinical research into human clinical trials. The article gives a neat overview of the three types of pharmaceutical trials that have so far focused on symptom relief (drugs to target neurotransmitters in the brain, drugs that promote brain growth, and drugs that target other systems) and the future prospects for gene therapy. The authors promote the concept of clinical trial readiness and look to the experience of other rare disease communities (e.g. Fragile X) for guidance in this. Most importantly, the article suggests the necessary ingredients for clinical trial readiness include: listening to the needs of families and patient advocacy groups; building harmonised registries/databases for sharing natural history data across countries; development and validation of suitable biomarkers and new (or existing) outcome measures; and developing coordinated trial networks. Overall the need for a collaborative and coordinated approach between all stakeholders is emphasised, with new types of trial design that are more efficient, less costly and less of a burden on families.

Review (by Aglaia Vignoli):

Over the last 50 years,  since the first description of  the syndrome by Andreas Rett and other colleagues around the world , and the discovery of  its cause by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene in 1999, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced the understanding of this rare disorder. Starting from that point, in the past 20 years preclinical research has extended the knowledge about the mechanisms at the basis of the different aspects of the syndrome, with some studies leading to human clinical trials. Despite this, few viable therapeutic options have emerged from this investment of effort. Also gene therapy, which has greater potential to change disease status rather than modify symptoms, is currently under investigation, but recent Mecp2 gene transfer studies have shown some concerns, where, despite showing extended lifespan, the studies identified dose-dependent toxicity and variability in safety and efficacy issues. Reasons for this lack of success may be relate both to preclinical research and to the clinical trial landscape: so that a positive and constructive approach should be taken and introduce the concept of clinical trial readiness. In order to achieve this goal, a series of different approaches are recommended such as listening to the needs of families; support from advocacy groups; optimizing use of existing clinic infrastructures and available natural history data; and, finally, the validation of existing outcome measures and/or the development and validation of new measures (e.g. specific biomarkers). The Authors conclude by reiterating the need for a collaborative and coordinated approach amongst the many different stakeholder groups and the need to engage in new types of trial design which could be much more efficient, less costly and much less burdensome on families.

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Sleep problems in individuals with Rett Syndrome: A systematic review and meta-analysis. By Karen Spruyt. (2022)


Importance: Prognosis and understanding of sleep disorders in rare genetic syndromes is limited, despite being a common complaint of caregivers. Rett Syndrome (RTT) is a rare, progressive neurodevelopmental disorder with problematic sleeping being a clinical feature yet inconsistencies exist in the literature.

Objective: To examine the strength of evidence of a sleep disorder in RTT. To investigate the complaints reported based on a sleep disorders classification approach and to determine differences in rates per the RTT main clinical features.

Data sources: PubMed, Web of Science, PsycINFO, Ebsco, Scopus, and Cochrane Library up to November 4 th 2021 with no time or language limitation (CRD 42020198099) were searched.

Study selection: Original research published in peer-reviewed journals, with RTT clinical or genetic diagnosis reported and stating a sleep complaint with prevalence rate, were selected.

Data Extraction and Synthesis: We followed the PRISMA guideline for abstracting data and assessed risk of bias with the NIH quality assessment tools. The prevalence rates were meta-analyzed applying the mixed-effects model with measures of consistency.

Main Outcome(s) and Measure(s): The International Classification of Sleep Disorders was used to summarize sleep complaints reported in the literature. Those that did not specify the precise sleep complaint were categorized as a not otherwise specified sleep problem. We further analyzed data per available RTT characteristics.

Results: We included 19 studies ( n = 4298, 0.3 to 57.2 years old) across five countries involving predominantly observational study designs. Overall, 54.1% (95%CI: 43.8% to 64.5%) of individuals with RTT exhibit problematic sleeping, in particular, excessive somnolence (67.5%; 95%CI: 47.5% to 82.7%) and difficulties initiating and maintaining sleep (61%; 95%CI: 49.6% to 71.4%). Disturbed sleep not otherwise specified was reported in 57.1% (95%CI: 34.5% to 81.3%). Although studies could improve details reported, females with MECP2 -RTT showed a higher prevalence rate of excessive somnolence and sleep-wake transition disorders than those diagnosed by CDKL5 -RTT. P revalence rates remain roughly unaltered across the lifespan. Sleep disorders are about two times more prevalent than in typically developing children.

Conclusions and Relevance: Findings indicate predominantly disorders regarding maintenance of sleep and wake state, which persist throughout their lifespan. Improved reporting of clinical features in cases with RTT pheno- types and of sleep behavior frequency and severity may lead to explicit prevalence rates. This is fundamental to progress in the pathophysiological investigation of altered sleep-wake mechanisms and to implement tailored sleep interventions for individuals with RTT, and families.

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Literature Cases Summarized Based on Their Polysomnographic Findings in Rett Syndrome. By Xin-Yan Zhang and Karen Spruyt. (2022)


Rett syndrome (RTT) is a severe and rare neurodevelopmental disorder affecting mostly girls. In RTT, an impaired sleep pattern is a supportive criterion for the diagnosis, yet little is known regarding the sleep structure and sleep respiratory events. Aiming to delineate sleep by aggregating RTT case (series) data from published polysomnographic studies, seventy-four RTT cases were collected from eleven studies up until 6 February 2022 (PROSPERO: CRD 42020198099). We compared the polysomnographic data within RTT stratifications and to a typically developing population. MECP2 cases demonstrated shortened total sleep time (TST) with increased stage N3 and decreased REM sleep. In cases with CDKL5 mutations, TST was longer and they spent more time in stage N1 but less in stage N3 than those cases affected by MECP2 mutations and a typically developing population. Sleep-disordered breathing was confirmed by the abnormal apnea/hypopnea index of 11.92 +/- 23.67/h TST in these aggregated cases. No association of sleep structure with chronological age was found. In RTT, the sleep macrostructure of MECP2 versus CDKL5 cases showed differences, particularly regarding sleep stage N3. A severe REM sleep propensity reduction was found. Aberrant sleep cycling, possibly characterized by a poor REM ‘on switch’ and preponderance in slow and high-voltage sleep, is proposed.

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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. (2020)

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.

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Regression in Rett syndrome: Developmental pathways to its onset. By Christa Einspieler, Peter B. Marschik. (2019)

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.

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Sleep Quality in Children and Adults with Rett Syndrome. By Y. Leven, F. Wiegand, B. Wilken. (2019)


Background: Over 80% of individuals suffering from Rett syndrome (RTT) are affected over their life period by sleeping disorders. Little is known about the impact of those on the quality of life and a clinical approach to the treatment of sleep disturbances is lacking.

Aims: Primary aim was to assess sleep quality in children and adults. Secondary aim was to assess behavioral disorders and their relationship to sleep quality. The medication taken by the subjects was also included.

Methods: Sleep quality and medication were assessed using the sleeping questionnaire for children with neurological and other complex diseases (SNAKE). Behavioral disorders were assessed by the Rett Syndrome Behavior Questionnaire (RSBQ). Questionnaires were sent to the 700 members of the Elternhilfe für Kinder mit Rett Syndromin Deutschland e.V. (Rett Aid) of which 287 were included. Questionnaires were filled out by the primary caregivers.

Results: Sleep quality was rated as very good to good by over 60% of caregivers in contrast to data available in the literature. Behavioral disorders related to regression such as loss of acquired hand skills (p¼0.046) and isolation (p¼0.002) were found to be associated with sleep quality.Melatonin showed a significant association (p¼0.007) with sleep quality.

Conclusion: Our study showed sleep dysfunction to be less prevalent in RTT-affected individuals than evidence frompast studies has suggested. Nevertheless, this remains a subjective assessment of sleep quality and therefore the need to find objective, disorder-specific parameters that measure sleep quality in RTT patients persists.

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Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012. By Anne-Marie Bisgaard, Bitten Schonewolf-Greulich, Kirstine Ravn, Gitte Rønde. (2015)

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. 

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