CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

Abstract

Objective The cyclin‐dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure‐free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. Methods This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. Results Ninety‐two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0‐11.0). Eighty‐one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor‐tonic‐spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty‐three percent of patients experienced a seizure‐free period ranging from 1 to >12 months, but only 6% were still seizure‐free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. Significance The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.

Deficiency of cyclin-dependent kinase-like 5 causes spontaneous epileptic seizures in neonatal mice

“…However, early-onset epilepsy, the symbolic trait in children with CDD, has not been reported in previous studies. Given that eighty percent of children with CDD have daily seizures, and the epileptic spasms onset at a median age of 6 weeks followed by a seizure-free honeymoon period (Fehr et al, 2016;Demarest et al, 2019;Olson et al, 2019), we reasoned that onset of epilepsy in mice with CDKL5 deficiency may occur during the early postnatal age and likely become alleviated later in life. By using a miniature telemetry system for wireless EEG recording in mouse pups, we identified robust epileptiform discharges in pups with CDKL5 deficiency selectively at P12.…”

“…6) suggest that the grasping behavior could be a robust trait representing an outcome measure for the hypermotor-tonic-spasms type of epilepsy in the frontocentral region (Gardella et al, 2006;Leiguarda et al, 2008;Klein et al, 2011;Melikishvili et al, 2019). In view of the expression of KCC2 in human, it reaches to the equivalent level as that in P10-15 rat at the early infancy stage (Kang et al, 2011), corresponding to the period of seizure occurrence in children with CDD (Fehr et al, 2016;Demarest et al, 2019). Our findings of epileptic discharges in Cdkl5 -/y mouse pups at P12, therefore could be temporally relevant to the time window of seizure onset in children with CDD, in terms of KCC2 expression.…”

“…The epileptic activities accompanied with developmental delays in children with CDD are frequently associated with devastating cognitive, psychiatric and behavioral disabilities later in life. Elimination of early-onset epilepsy may potentially ameliorate the consequent developmental delays of this disorder (Fehr et al, 2016;Scheffer et al, 2017;Demarest et al, 2019). Despite well-defined genetic cause, however, children with CDD are resistant to most of the anti-epileptic drugs (AEDs) and the pathogenic mechanisms for CDKL5 deficiency-induced seizures remain unclear.…”

“…Notably, all 5 the behavioral observations and EEG recordings for seizure activities in these studies were conducted in adult mice aged from 1 to 4 months. Considering that the median age of seizure onset in CDD patients is about 6 weeks after birth and a "honeymoon period" with seizure cessation can last up to 72 months (Bahi-Buisson et al, 2008;Fehr et al, 2016;Demarest et al, 2019), it is possible that early-onset spontaneous seizures were missed in these studies of adult mice.…”

Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?

“…Most individuals with variants in the CDKL5 gene display a phenotype consisting of early‐onset and refractory epilepsy with severe global developmental delay and markedly impaired gross motor function (Fehr et al, ). Additionally, they may experience cortical visual impairment (CVI) (Demarest et al, ), sleep disturbances, respiratory infections, hypotonia, gastrointestinal problems, and have subtle dysmorphic features (Mangatt et al, ). In the overwhelming majority of affected individuals, functional abilities are severely impaired, disability is marked, and the health implications of the disorder are pronounced (Fehr, Downs, et al, ; Mangatt et al, ).…”