Investigators: Helen Leonard, Jenny Downs, Yuka Mori
Project description
The CDKL5 disorder is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene. Clinical features include early-onset seizures (generally within the first three months of life), severe intellectual and motor impairment, abnormal muscle tone, hand stereotypies, gastrointestinal problems and bruxism. In the past this disorder was considered an atypical form of Rett syndrome, but from our research published in 2012 we now conclude that it is an independent disorder.
Since our 2012 publication, which included the largest cohort of individuals with the CDKL5 disorder, we have worked at establishing and further developing the International CDKL5 Disorder Database. This has been done in collaboration with the International Foundation for CDKL5 Research. Data collection commenced in September 2012 and involved families of individuals with the CDKL5 disorder completing a questionnaire either online or on paper. The questionnaire has now been translated into French, German, Spanish, Mandarin, Portuguese, Russian and Japanese. More than 350 individuals are now registered with the database, with 45 new families registering during 2018. The largest proportions of cases come from the USA, Canada, Australia, UK, Germany, France, the Netherlands and Brazil. However, we now have over 20 other countries represented.
The infrastructure of the database has allowed us to investigate important research questions. In the past we have examined developmental milestones, functional abilities, pattern of seizures, medical comorbidities and impact on family wellbeing. In 2018 we published a paper about families’ experience using vagus nerve stimulation for the management of their child’s seizures. We also collaborated with a large international group of clinicians, researchers and caregivers to develop the first clinical severity scale for this disorder.
In June 2018, Drs Leonard and Downs attended the International CDKL5 Family Congress in Denver. This was an opportunity to meet with the Medical Director of Marinus Pharmaceuticals, a company which is keen to assess the efficacy of ganaxolone, a neurosteroid with the potential to improve seizure control in the CDKL5 disorder. Dr Leonard subsequently met again with this group and others in London in October 2018, at the CDKL5 Forum, a meeting that brought together clinicians and researchers already working in the CDKL5 field as well as those with the potential to do so in the future. The Forum was organised and hosted by the Loulou Foundation, a private not-for-profit foundation which was established to accelerate research into CDKL5. As a consequence of this relationship Marinus has consulted with us on numerous occasions since and the Database has provided important data to guide the design of a multicenter clinical trial of ganaxolone. We have also assisted with the selection and provision of measurement tools to be used in the trial.
Finally during 2018 much work was undertaken on the design and implementation of a web capture system to collect longitudinal data on CDKL5 disorder through a follow-up questionnaire. Since April 2018 data have already been collected from 150 families and will provide state-of-the-art information on the natural history of the CDKL5 disorder.
External collaborators
- Heather Olson (Harvard Medical School, Boston)
- Ralph Hector (Glasgow University)
- Children's Hospital Colorado