International Rett syndrome study: InterRett

Helen Leonard, Jenny Downs, Kingsley Wong, Amy Epstein, Nada Murphy, Barbara Anderson, Nan Hu, Jessica Mackay, Sharolin Boban

Rett syndrome is a rare neurological disorder affecting approximately 1:9000 females and is associated with a mutation in the MECP2 gene. Given the low number of cases at a national level (~415 in Australia) international collaboration and data collection are imperative. The InterRett database project allows clinicians and families caring for an individual with Rett syndrome to directly contribute to the global research effort by completing web or paper-based questionnaires. The project, which is funded by Rettsyndrome.org (formerly the International Rett Syndrome Foundation), was established in 2002 and continues to grow and expand with online questionnaires available in Mandarin and six European languages. The database currently contains more than 2,600 cases representing more than 50 different countries. New participants register using a form on the project website (also available in different languages). International support for the InterRett project continues to strengthen, particularly in China and we have a Chinese national, Nan Hu who is providing translational expertise and assisting families in submitting their information. The website also allows users to: generate graphs based on summary data; download clinical guidelines for the management of scoliosis and gastrointestinal issues; and to read snapshots of the over 20 peer-reviewed publications arising from analyses of the InterRett data. Our research covers a wide range of topics such as: pain sensitivity; the characteristics that influence diagnosis; diagnostic challenges in China; the influence of mutation type or DNA variations in the BDNF gene on clinical severity; and ageing in Rett syndrome. To allow families to contribute at all levels of the research process, from study design to the dissemination of findings, a Consumer Reference Group (CRG) has been established. In 2014 we were awarded a further two years ongoing funding from Rettsyndrome.org to continue the management of the database. Our current aims are to:

• To give families a strong voice in research about Rett syndrome,
• To expand data collection to facilitate evidence-based management,
• To focus on families who live in under-represented majority world countries, and
• To further develop the InterRett infrastructure to enable linkage with other Rett syndrome and international rare disease database initiatives.

There has been little research investigating which girls and women with Rett syndrome may be particularly at risk either of specific breathing problems or of sleep disturbances. Although we hypothesise that both comorbidities are particularly burdensome both for those affected and their families, there has been no such investigation and neither do we know what treatments may be effective for these conditions. During 2015 we undertook a major project with English-speaking InterRett families living mainly in the US, Canada and the UK. We aimed:

• To identify how commonly specific breathing and sleep abnormalities are occurring in girls and women with Rett syndrome.
• To identify what may be risk factors and what may be protective factors for sleep and breathing problems in Rett syndrome.
• To find out whether there are treatments that are working for these conditions.

Using for the first time, the web-based electronic data capture system Redcap we invited English-speaking families with whom we had recent contact, to fill out a questionnaire specifically designed to answer these questions. We have had a very gratifying 83% response from the 570 families we have invited.

We found that breathing irregularities such as hyperventilation and breath-holding affected girls and women of all ages and with most mutation types. However, the impact especially for breath-holding was worse for those with a p.Arg294* mutation, one of the generally milder mutations. We also found that respiratory infections, often involving hospital admission were common, but less likely to occur in those who were ambulant. A manuscript describing the breathing irregularities is currently under review and one describing respiratory infections in preparation.

Night waking was the most prevalent sleep problem affecting over 80% with nearly half (48.3%) currently waking often at night. Night laughing also occurred but was less common. Using standardized sleep disturbance scales we also found that sleep problems were much more prevalent in Rett syndrome than in a normal control population. In particular, we found that those with Rett syndrome had particular difficulties with initiating and maintaining sleep and also excessive somnolence (falling asleep during the day). Once again we found relationships with the p.Arg294* mutation, a mutation usually associated with a mild phenotype. Severe seizure activity was also associated with poor sleep after adjusting for age group, mutation type and mobility. Our findings highlight the complexities of aberrant MECP2 function in Rett syndrome and explain some of the variation in manifestation of sleep disturbances. One manuscript describing these findings was published in 2016 while a further manuscript is in an advanced state of preparation.

One aim of InterRett is to focus on families who live in under-represented majority world countries. With materials translated into Mandarin and with collaborations dating back to 2002, a country with strong growth for InterRett is China. Dr Downs and Dr Leonard have visited families affected by Rett syndrome in Shenzhen, China on several occasions since 2013 and developed a collaboration with the Rett Syndrome Comprehensive Research Institute (RSCRI). Together with colleagues from the RSCRI, Shenzhen Children’s Hospital, they were awarded a grant by Rettsyndrome.org in 2015 to conduct a randomized stepped wedge design trial investigating the effects of an intensive environmental enrichment program on primarily functional abilities in girls with Rett syndrome younger than six years. This study is being led by Dr Jenny Downs and the InterRett database has formed the infrastructure for recruitment. Data collection and analyses are complete and the findings will be prepared for publication over the course of 2017.

We have received continued funding through 2017 and 2018 and plan to continue building the database including majority world countries, as well as administer additional questionnaire modules on the topics of behavior and dental health.

Plain Language summary:

We have continued to recruit families to the InterRett database. Families have participated in new questionnaires on breathing and sleep disturbances. We conducted a study in China that has assessed whether an intensive therapy program helps the health and functional abilities of young girls with Rett syndrome. Two Honours students have worked on our InterRett data in 2016.  

Funder: rettsyndrome.org

External collaborators:

• Andrew Wilson, Princess Margaret Hospital, Perth
• Dr Chen Li, Shenzhen Children’s Hospital, China
• Mr Tam Cruise, Rett Syndrome Comprehensive Research Institute, Shenzhen, China
• Professor Sean Huang, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, China