Pathogenic mutations in the CDKL5 gene were first described in 2005 in three members of an Australian family including a girl whose features resembled those of the neurodevelopmental disorder Rett syndrome, her identical twin sister with autism and her brother with a severe intellectual disability and epilepsy.(1)
The research was a collaborative effort between the Universities of Sydney and Adelaide and the Telethon Kids Institute in Perth. Subsequently many children with similar genetic mutations were identified in InterRett, the International Rett syndrome Database.
A comparison in 2012 of these individuals with a CDKL5 mutation with those with mutations in the MECP2 gene demonstrated that the CDKL5 disorder was an independent entity with specific characteristics including early onset epilepsy and severe gross motor delay.(2)
Need for Natural History Studies
Natural History Studies track the course of disease over time, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes when treatment is usual care.
A thorough understanding of disease natural history is the foundation upon which clinical development programs for treatments for rare diseases can be built. However, in 2012 little clinical research, let alone any natural history studies existed for the CDKL5 disorder.
Therefore, following the model of InterRett(3), an infrastructure which has had a major impact on the clinical understanding of Rett syndrome,(4) the International CDKL5 Database was first established in 2012 by a team at the Telethon Kids Institute in Western Australia.
To understand the diversity and variation in symptoms and their severity and how they may change over time, it was necessary to collect data from as many patients as possible and thus for the database to be international in scope.
Central to the philosophy of the Telethon Kids Institute, families and consumers were involved from day one and worked with us throughout the development phase to ensure that their views and need for information were incorporated at every step.
We needed to ensure that issues most important to this community in relation to their child’s health and wellbeing, as well as their own short and long-term wellbeing were covered.
We have already examined carer wellbeing(5) and are about to embark on a program investigating the domains that are important for the child’s quality of life.
We have also worked with families regarding data collection methods and have our instruments available in a variety of mediums and languages, particularly for those who do not have access to internet.
As pioneers in their use over a period of nearly two decades(6) we offer different web-based options according to the age of the child and needs and time constraints of the carer.
The database is still relatively young and only entering its second year of regular funding from the International CDKL5 Foundation for Research. However with the involvement of over 300 families from over 30 different countries, we have, in the five years since its initiation, been building and growing the database and have already achieved a great deal.
Furthermore we plan to use the data, as we have done for Rett syndrome, to develop best practice guidelines for aspects of clinical management in the CDKL5 Disorder. We are already working with specialist clinicians across the world using our data to investigate outcomes associated with particular treatment regimes.
One of the many reasons for setting up the International CDKL5 Disorder Database was to learn more about this condition so that we could make this information available to doctors who were managing and treating children with this disorder.
Many of these doctors may only have had one affected patient and could have been searching the medical literature for material to no avail. We wanted to change this situation. As a part of our effort to inform the clinical community about this burdensome disorder we have already published six articles in prestigious medical journals and presented our findings at national and international conferences in Australia and the US.
gastrointestinal (GI) problems and feeding difficulties,
sleep and respiratory problems,
and their relationships with age and type of genetic mutation.
Our data showed that the likelihood of experiencing some of these conditions did increase with age and that boys were more vulnerable to respiratory and sleep problems than girls. We believe that this information, now published in the medical literature, will be enormously helpful to the medical specialists who are providing clinical management to affected children.
We have also specifically examined epilepsy outcomes and what factors influence outcomes both positively and negatively(8). For instance we found that ability to walk and use of spoken language were associated with lower rates of current seizures when compared to those with less functional abilities.
We also found that, after adjusting for walking ability and confounders including use or otherwise of polytherapy, seizure rates were lower in those with truncating mutations occurring in certain regions of the gene (between aa172 and aa781).
Our team is always keen to collaborate with other groups in Australia and internationally to ensure that we are making the best use of the data we have collected to advance knowledge in the CDKL5 Disorder.
For over ten years we have worked with Professor John Christodoulou, now of the Murdoch Children’s Research Institute in Melbourne, Australia. In the latter half of 2016 we teamed up with a research group from the Centre of Genomics in Western Australia and hope very much that some of the funding applications we have submitted together will be successful and allow us to investigate the possibility of some potential cross-cutting genetic therapies for this disorder.
At the same time we have been working with Dr Richard Chin from the University of Edinburgh and Dr Heather Olson from the Centre of Excellence at the Boston Children’s Hospital in relation to the management of epilepsy and Dr Ralph Hector from the University of Glasgow in relation to the spectrum of different mutations which occur in this disorder.
Let’s Keep in Touch!
We would like to keep everyone up to date with our research progress. Let us know by emailing your updated contact details to CDKL5@telethonkids.org.au
Have you previously contributed to our research, but have forgotten your username or password? If so, please also do email us at CDKL5@telethonkids.org.au
How Can You Participate?
If you are interested in participating in the database, you can register using one of three ways:
(1)Weaving LS, Christodoulou J, Williamson SL, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet 2004;75:1079-93. (2)Fehr S, Wilson M, Downs J, et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet 2013;21:266-73. (3)Leonard H, Anderson A, Bebbington A, et al. Resourceful and creative methods are necessary to research rare disorders. Dev Med Child Neurol 2013;55:870-1. (4)Leonard H, Cobb S, Downs J. Clinical and Biological Progress over 50 Years in Rett syndrome. Nature Reviews Neurology Forthcoming 2016. (5)Mori Y, Downs J, Wong K, Anderson B, Epstein A, Leonard H. Impacts of caring for a child with the CDKL5 disorder on parental wellbeing and family quality of life. Orphanet Journal of Rare Diseases 2017;12:1-15. (6)Fyfe S, Leonard H, Gelmi R, Tassell A, Strack R. Using the Internet to pilot a questionnaire on childhood disability in Rett syndrome. Child Care Health Dev 2001;27:535-43. (7)Mangatt M, Wong K, Anderson B, et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis 2016;11:39. (8)Fehr S, Wong K, Chin R, et al. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology 2016;87:2206-13.
For further reports and findings, see our publications list.
Roisin Carbery suffers from a rare genetic disorder which causes her to have multiple seizures a day. Watch this story to learn what Telethon Kids Institute researchers are doing to help kids like Roisin.