There is variability in the attainment of developmental milestones in the CDKL5 disorder

Abstract

BackgroundIndividuals with the CDKL5 disorder have been described as having severely impaired development. A few individuals have been reported having attained more milestones including walking and running. Our aim was to investigate variation in attainment of developmental milestones and associations with underlying genotype.MethodsData was sourced from the International CDKL5 Disorder Database, and individuals were included if they had a pathogenic or probably pathogenic CDKL5 mutation and information on early development. Kaplan-Meier time-to-event analyses investigated the occurrence of developmental milestones. Mutations were grouped by their structural/functional consequence, and Cox regression was used to investigate the relationship between genotype and milestone attainment.ResultsThe study included 109 females and 18 males. By 5 years of age, only 75% of the females had attained independent sitting and 25% independent walking whilst a quarter of the males could sit independently by 1 year 3 months. Only one boy could walk independently. No clear relationship between mutation group and milestone attainment was present, although females with a late truncating mutation attained the most milestones.ConclusionAttainment of developmental milestones is severely impaired in the CDKL5 disorder, with the majority who did attain skills attaining them at a late age. It appears as though males are more severely impaired than the females. Larger studies are needed to further investigate the role of genotype on clinical variability.

Impacts of caring for a child with the CDKL5 disorder on parental wellbeing and family quality of life

“…Hence, every mutation was categorised into one of five groups according to the subsequent protein function: No functional protein; Missense/in-frame mutations within kinase domain; Truncations between aa172 and aa781; Truncations after aa781; and mutations that could not be grouped [8]. …”

“…Genotype-phenotype relationships have been difficult to study because of the paucity of recurrent mutations and the generally small case series. Our recent study ( n  = 127) which examined early development in this disorder categorised mutation types into four groups according to the effect on protein function and found that compared with those with no functional protein, those with a truncating mutation after amino acid (aa) 781 were more likely to acquire motor and communication skills [8]. …”

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

“…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.…”

A novel C‐terminal truncated mutation in hCDKL5 protein causing a severe West syndrome: Comparison with previous truncated mutations and genotype/phenotype correlation

“…The CDKL5 protein C‐terminal region (amino acids 298‐1030) includes two putative nuclear localization signals NLS1 and NLS2 at positions (312‐315 aa) and (784‐789 aa) respectively, a nuclear export site (NES) at position (836‐845 aa). However, the hCDKL5_5 isoform contains the same domains as hCDKL5_1 to hCDKL5_4 isoforms but with an additional signal peptidase I serine active site (971‐978aa) (Hector et al, 2016; Fehr et al, 2015).…”