Abstract
BackgroundInitially described as an early onset seizure variant of Rett syndrome, the CDKL5 disorder is now considered as an independent entity. However, little is currently known about the full spectrum of comorbidities that affect these patients and available literature is limited to small case series. This study aimed to use a large international sample to examine the prevalence in this disorder of comorbidities of epilepsy, gastrointestinal problems including feeding difficulties, sleep and respiratory problems and scoliosis and their relationships with age and genotype. Prevalence and onset were also compared with those occurring in Rett syndrome.MethodsData for the CDKL5 disorder and Rett syndrome were sourced from the International CDKL5 Disorder Database (ICDD), InterRett and the Australian Rett syndrome Database (ARSD). Logistic regression (multivariate and univariate) was used to analyse the relationships between age group, mutation type and the prevalence of various comorbidities. Binary longitudinal data from the ARSD and the equivalent cross-sectional data from ICDD were examined using generalized linear models with generalized estimating equations. The Kaplan-Meier method was used to estimate the failure function for the two disorders and the log-rank test was used to compare the two functions.ResultsThe likelihood of experiencing epilepsy, GI problems, respiratory problems, and scoliosis in the CDKL5 disorder increased with age and males were more vulnerable to respiratory and sleep problems than females. We did not identify any statistically significant relationships between mutation group and prevalence of comorbidities. Epilepsy, GI problems and sleep abnormalities were more common in the CDKL5 disorder than in Rett syndrome whilst scoliosis and respiratory problems were less prevalent.ConclusionThis study captured a much clearer picture of the CDKL5 disorder than previously possible using the largest sample available to date. There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics.
Highlights
Described as an early onset seizure variant of Rett syndrome, the cyclin dependent kinase-like 5 (CDKL5) disorder is considered as an independent entity
Sufficient mutation details were available for 164 cases to enable classification into mutation groups based on the structure and function of the CDKL5 gene
Epilepsy in the CDKL5 disorder Families of all (98.0 %, 145/148) but two females and one male reported that their child had experienced one or more episodes of seizures
Summary
Described as an early onset seizure variant of Rett syndrome, the CDKL5 disorder is considered as an independent entity. The CDKL5 disorder is a rare X-linked neurodevelopmental disorder caused by a disruption in the cyclin dependent kinase-like 5 (CDKL5) gene [1] Mutations in this gene were originally identified in children with West syndrome, X-linked infantile spasms and principally in those with the early seizure onset form of Rett syndrome [1, 2]. The CDKL5 disorder has been further defined as an independent disorder, characterized by early-onset intractable seizures, severely impaired gross motor skills and global developmental delay with sleep disturbances, abnormal muscle tone, bruxism and gastrointestinal issues occurring commonly [3]. Less common features are hand stereotypies, laughing and screaming spells, breathing disturbances, peripheral vasomotor disturbances and a range of dysmorphic features The latter include a broad/ prominent forehead, large “deep-set” eyes, full lips, tapered fingers and anteverted nares [3]
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