Functional abilities in children and adults with the CDKL5 disorder

Abstract

Functional abilities in the CDKL5 disorder have been described as severely impaired, yet some individuals are able to run and use phrases for speech. Our study investigated gross motor, hand function, and expressive communication abilities in individuals with the CDKL5 disorder. Data for 108 females and 16 males registered with the International CDKL5 disorder database and with a pathogenic CDKL5 mutation were analyzed. Relationships between functional abilities, age, genotype, and gender were analyzed using regression models. Over half of the females could sit on the floor and nearly a quarter could walk 10 steps. Fewer males could complete these tasks although one boy was able to sit, walk, and run. Most females and few males were able to pick up a large object. Females mostly used gestures to communicate while males mostly used other forms of non-verbal communication. Compared to those with no functional CDKL5 protein, individuals with truncating variants after aa 781 were more likely to be able to stand (OR 5.7, 95%CI 1.2, 26.6) or walk independently (4.3, 95%CI 0.9, 20.5), and use more advanced communication methods such as words (OR 6.1, 95%CI 1.5-24.2). Although abilities were markedly impaired for the majority with the CDKL5 disorder, some females and a few males had better functional abilities. This variability may be related to underlying gene variants, with females with a late truncating variant having better levels of ability than those with no functional protein. © 2016 Wiley Periodicals, Inc.

Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder

“…Since the 2004 genetic discovery, molecular genetic diagnosis has identified nearly 200 patients carrying mutations in CDKL5 (Fehr et al, 2016). The types of mutations include translocations, deletions, insertions, nonsense and missense mutations, and the majority of CDKL5 mutations are located within the N-terminal kinase domain, suggesting that the kinase function of CDKL5 is particularly important for brain function (Bahi-Buisson et al, 2008, 2012; Fehr et al, 2016).…”

“…The types of mutations include translocations, deletions, insertions, nonsense and missense mutations, and the majority of CDKL5 mutations are located within the N-terminal kinase domain, suggesting that the kinase function of CDKL5 is particularly important for brain function (Bahi-Buisson et al, 2008, 2012; Fehr et al, 2016). Moreover, genotype-phenotype correlation study has found mutations in the N-terminal kinase domain are associated with more severe clinical symptoms than mutations in the C terminus (Fehr et al, 2016). Furthermore, it becomes clear that mutations in CDKL5 exons 19-21 are unlikely pathogenic, because the isoform of CDKL5 that predominantly expresses in the brain does not include exons 20-21 (Hector et al, 2016).…”

“…However, this concept is difficult to prove in human patients as XCI is frequently measured from peripheral blood samples and it is difficult to determine whether the same XCI ratio is also present in the brain. Nevertheless, it is clear that boys carrying mutations in CDKL5 , though much rare, show more severe epileptic encephalopathy than girls (Fehr et al, 2016), probably because of the expression of CDKL5 mutation in every cell in males, but in half of the cells in females.…”

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

“…CDD is one of the more common genetic causes of epilepsy in early childhood . Patients with CDD are reported to have very early onset of epilepsy (median of 6 weeks) and severe developmental delay, with many patients unable to achieve independent walking or speech . However, CDD also affects several other neurologic domains, with evidence of disrupted sleep, gastrointestinal problems, dysautonomia, and cortical visual impairment (CVI) .…”

“…7 Patients with CDD are reported to have very early onset of epilepsy (median of 6 weeks 8 ) and severe developmental delay, with many patients unable to achieve independent walking or speech. 9,10 However, CDD also affects several other neurologic domains, with evidence of disrupted sleep, 11 gastrointestinal problems, 12 dysautonomia, 4 and cortical visual impairment (CVI). 4 CVI is also seen in rodent models of CDKL5 13 and has been demonstrated to be an important comorbidity and potentially a marker of clinical improvement in other epileptic encephalopathies.…”