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

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.

Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients

“…Previous studies have recommended using an all-liquid KD to facilitate compliance, ensure sufficient ketosis, and minimize certain side effects such as acidosis and dehydration. 3,9 Behavioral improvements in areas such as attention and social functioning have been reported as additional therapeutic effects of the KD. 28 Our findings suggest some advantages in liquid-based KD, as those who received gastrostomy feeding maintained the diet for a longer duration, although there still may be benefit in appropriately selected orally fed children.…”

“…It functions to maintain normal synapse activity within the central nervous system (CNS). 7,8 Seizure onset occurs at a median age of 6 weeks, 7,9 and seizure types may include infantile spasms, myoclonic seizures, tonic, and generalized tonic-clonic seizures, often with a complex semiology including multiple seizures types in one epoch. 4 Furthermore, its association with the phosphorylation of MeCP2 and DNA methyl-transferase 1 suggests a role of CDKL5 in the epigenetic regulation of gene expression.…”

“…4 Furthermore, its association with the phosphorylation of MeCP2 and DNA methyl-transferase 1 suggests a role of CDKL5 in the epigenetic regulation of gene expression. 3,8,9 Despite the use of intensive polypharmacy, the intractable nature of CDKL5-associated epilepsy may prompt clinicians to consider employing nonpharmacological interventions. 7,8 Seizure onset occurs at a median age of 6 weeks, 7,9 and seizure types may include infantile spasms, myoclonic seizures, tonic, and generalized tonic-clonic seizures, often with a complex semiology including multiple seizures types in one epoch.…”

“…However, no information was provided on which seizure types responded to the KD, and overall the quality of the evidence was poor. 9,20 Methods The ICDD, established in 2012, collects information from caregivers of individuals with the CDKL5 disorder through either paper or online-based questionnaires, which families can complete at their own pace, or alternatively by telephone interview. 15 Early commencement of KD has also been associated with a good seizure response, especially in children with infantile spasms.…”

“…Nevertheless, a recent randomized control trial reported improvements in seizure frequency and severity at 4 months when KD was prescribed in addition to regular AEDs. 7,9,20 The ICDD questionnaire was designed to capture comprehensive data pertaining to aspects of childhood development, phenotypic features, and natural history of the disorder. 16,17 This suggests potential therapeutic benefits in patients with the CDKL5 disorder, where seizure onset occurs early in infancy and includes infantile spasms in a substantial proportion.…”