Clinical manifestation of CDKL5 deficiency disorder and identified mutations in a cohort of Slovak patients.

CDKL5 deficiency disorder (CDD) is an independent clinical entity associated with early-onset encephalopathy, which is often considered the type of epileptic encephalopathy with CDKL5 mutation also found in children diagnosed with early-onset seizure (Hanefeld) type of Rett syndrome, epileptic spasms, West syndrome, Lennox-Gastaut syndrome, or autism. Since early seizure onset is a prominent feature, in this study, a cohort of 54 unrelated patients consisting of 26 males and 28 females was selected for CDKL5 screening, with seizures presented before 12 months of age being the only clinical criterion. Five patients were found to have pathogenic or likely pathogenic variants in CDKL5 while 1 was found to have a variant of uncertain significance (p.L522V). Although CDKL5 variants are more frequently identified in female patients, we identified three male and three female patients (11.1 %, 6/54) in this study. Missense variant with unknown inheritance (p.L522V), de novo missense variant (p.E60 K), two de novo splicing (IVS15 + 1G > A, IVS16 + 2 T > A), and one de novo nonsense variant p.W125* were identified using Sanger sequencing. Whole exome analysis approach revealed de novo frameshift variant c.1247_1248delAG in a mosaic form in one of the males. Patient clinical features are reviewed and compared to those previously described in related literature. Variable clinical features were presented in CDKL5 positive patients characterised in this study. In addition to more common features, such as early epileptic seizures, severe intellectual disability, and gross motor impairment, inappropriate laughing/screaming spells and hypotonia appeared at the age of 1 year in all patients, regardless of the type of CDKL5 mutation or sex. All three CDKL5 positive males from our cohort were initially diagnosed with West syndrome, which suggests that the CDKL5 gene mutations are a significant cause of West syndrome phenotype, and also indicate the overlapping characteristics of these two clinical entities.