The natural history of the CDKL5 disorder: development of an international database

[Truncated] In 2003 disruption of the Cyclin-dependent Kinase-like 5 (CDKL5) gene was identified as the underlying genetic defect in two deceased females who had early-onset seizures and severe intellectual disability. The following year mutations were identified in individuals who had previously been diagnosed with the early onset-seizure variant of Rett syndrome, West syndrome, or X-linked Infantile Spasms syndrome. The majority of literature on these individuals had consisted of case studies or small case series and little was known about the natural history of those affected with a CDKL5 mutation. Key clinical features appear to include early-onset intractable seizures, severe intellectual disability and severe gross motor impairment. But a few individuals were described as having a milder phenotype including the ability to walk, use of spoken language and absence of seizures. Therefore it appears that variability exists in the clinical presentation of those with a CDKL5 mutation, but larger studies were needed to fully investigate this variability.

One of the aims of this thesis was to investigate the relationship between the clinical features of individuals with a CDKL5 mutation and those with Rett syndrome who have a MECP2 mutation and investigate whether CDKL5 mutations account for the presentation of the early-onset seizure variant of Rett syndrome. This thesis also aimed to establish an international data collection to better inform the clinical presentation and natural history of the CDKL5 disorder. In doing so, this thesis examined the attainment of developmental milestones, investigated the current gross motor, hand function and communication abilities, and described the onset, burden and management of seizures in affected children and adults.