Towards evidence based care for Rett syndrome: a research model to inform management of rare disorders
Investigators: Helen Leonard, Jenny Downs, Yuka Mori
Rett syndrome is a rare neurological disorder usually affecting females and caused by a mutation in the MECP2 gene. AussieRett, as the Australian Rett Syndrome Study is known, is a population-based study which, since 1992, has followed a cohort of Australian Rett syndrome cases born since 1976. The study aims to describe the natural history of Rett syndrome and assess the impact of the condition on resource utilisation as well as to examine the economic and social burden for families and the community.
We have continued to exploit the data collected through an earlier NHMRC project grant which aimed to:
- develop recommendations for the diagnosis process for Rett syndrome
- identify longitudinal changes in gross motor abilities, hand function and development of scoliosis and
- evaluate the clinical effectiveness of scoliosis and gastrostomy surgery in children and adults with Rett syndrome.
For the diagnostic study we asked clinicians to complete questionnaires relating to the characteristics of their patients for whom they requested MECP2 testing at one of the three Australian accredited laboratories. These were completed prior to the result of genetic testing being known. During the study period there were 297 referrals where a clinician could be contacted and agreed to participate. Pathogenic MECP2 mutations were identified in 14.8% of female and in no male patients (12.8% positive overall). We found that the core features of regression of hand function and communication and the development of hand stereotypies persisted as important predictors of a positive molecular diagnosis and that the supportive criteria were of less value. It remains to be seen whether in the future Next Generation Sequencing will take over from conventional mutation testing making a clinical diagnosis less necessary.
As part of the longitudinal study follow-up questionnaires had been administered to 269 families enrolled in the study and families could return data online, on paper or during a telephone interview. The response fraction from parents and care-workers was excellent at over 86%. Information has been collected on the affected individual’s functional ability in daily living, behaviour, hand function, medical conditions, use of health and education services, and family health and functioning. We also collected video data and by year end 2014, 175 families had provided video footage of their daughter’s functional abilities.
In the course of 2015 and 2016 we had evaluated the clinical effectiveness of scoliosis surgery and found that that survival was better in those with severe scoliosis who had surgical compared to conservative management. During 2017 we focused on evaluating the impact of gastrostomy surgery on nutritional status, physical health and parental well-being but did not identify benefit in all areas. During this period Dr Yuka Mori also examined the wellbeing of caregivers of children with Rett syndrome and compared it with that of those of children with Down syndrome and the CDKL5 disorder. She also investigated the family factors and child morbidities which affected parental physical and mental health specifically in Rett syndrome and the impact of these factors over time.
The AussieRett study has continued to involve consumers through the Consumer Reference Group, biannual newsletters and online via the new website and Facebook page. The Consumer Reference Group, involving family members from across Australia via regular teleconferences, is an opportunity to discuss and give valued feedback on all facets of the study. Our investigative team is multi-disciplinary from the fields of medicine, physiotherapy, epidemiology, biostatistics, dietetics and occupational therapy. It has national collaborations with the Children’s Hospital at Westmead and the Children’s Hospital Randwick, Sydney, the Royal Children’s Hospital, Melbourne, the Mater Children’s Hospital, Brisbane and the Royal Children’s Hospital, Brisbane and the Children’s Hospital, Adelaide. During 2018 we recruited 11 new cases to participate in the national-wide Australian Rett Syndrome Database providing a total of 462 cases (90 of whom have died) since onset of registry in 1993.
We have conducted a qualitative investigation in relation to quality of life in children with Rett syndrome, a more recent direction for our research. We identified the domains of quality of life that are important for Rett syndrome and these data form a framework to understand quality of life. Subsequently, these data were combined with similarly collected data in relation to children with other causes of intellectual disability including Down syndrome, severe cerebral palsy and autism to develop and validate a quality of life outcome measure for children with intellectual disability.
During 2018, seven articles relating to Rett syndrome, three of which used the Australian Rett Syndrome Database as a data source, were published by our group. These included the results of the study evaluating the impact of gastrostomy surgery on nutritional status, physical health and parental well-being, another investigating the family factors and child morbidities which affected parental physical and mental health in Rett syndrome over time and a third describing choice-making by girls and women with Rett syndrome.
- John Christodoulou (Murdoch Children's Research Institute)
- Gordon Baikie (University of Melbourne)
- Carolyn Ellaway (Westmead Children's Hospital)