Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome

Abstract

Background: Initially 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.

Methods: Data 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.

Results: The 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.

Conclusion: This 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.

Keywords: CDKL5 disorder; Comorbidities; Cyclin dependent kinase-like 5 gene; MECP2; Rett syndrome.

Fig. 1

Estimated time-to-event functions of gastrostomy insertion for males and females with the CDKL5 disorder

Fig. 2

Mean subscale scores of the SDSC in CDKL5 positive individuals (n = 124) and published controls (n = 1157). Figure legend: DIMS, disorders of initiating and maintaining sleep; SBD, sleep breathing disorders; DA, disorders of arousal; SWTD, sleep-wake transition disorders; DOES, disorders of excessive somnolence; SHY, sleep hyperhidrosis. Subscale scores ranges from 1 to 5 with highest score possible is 5 with higher scores indicating more problematic sleep. The group data describing the healthy controls were derived from Bruni et al. [36]

Fig. 3

Estimated time-to-event functions of developing scoliosis for males and females with the CDKL5 disorder

Fig. 4

Estimated time-to-event functions of developing seizures for females with CDKL5 and Rett syndrome

Fig. 5

Estimated time-to-event functions of gastrostomy insertion for females with CDKL5 disorder and Rett syndrome

Fig. 6

Estimated time-to-event functions of developing scoliosis for CDKL5 and Rett syndrome females