CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

Abstract

CDKL5 deficiency disorder (CDD) is a complex of clinical symptoms resulting from the presence of non-functional CDKL5 protein, i.e., serine-threonine kinase (previously referred to as STK9), or its complete absence. The clinical picture is characterized by epileptic seizures (that start within the first three months of life and most often do not respond to pharmacological treatment), epileptic encephalopathy secondary to seizures, and retardation of psychomotor development, which are often observed already in the first months of life. Due to the fact that CDKL5 is located on the X chromosome, the prevalence of CDD among women is four times higher than in men. However, the course is usually more severe among male patients. Recently, many clinical centers have analyzed this condition and provided knowledge on the function of CDKL5 protein, the natural history of the disease, therapeutic options, and their effectiveness and prognosis. The International CDKL5 Disorder Database was established in 2012, which focuses its activity on expanding knowledge related to this condition and disseminating such knowledge to the families of patients.

Complete loss of CASK causes severe ataxia through cerebellar degeneration in human and mouse

“…Mutational analysis of orthologous genes in murine models also produces phenotypes which are clearly post-developmental, presenting only in adulthood 78 . Incidentally, just like CASK mutations, CDKL5 and MeCP2 mutations in males are associated with epileptic encephalopathy 2, 3 . These data raise the possibility that even in disorders such as Rett syndrome (MeCP2 mutation) and CDKL5 deficiency, the pathology may be neurodegenerative, as originally suggested by Andreas Rett 5 , but the clinical course may not be progressive in females due to the mosaic expression of the normal gene under heterozygous conditions.…”

Novel pre-clinical model for CDKL5 Deficiency Disorder

“…So far, more than 265 variants have been reported in CDKL5, with mutations distributed all along the length of the protein [15]. Approximately 27% of these are considered pathogenic with many of these located in the catalytic domain [15].…”

“…To determine the spatial expression of cdkl5, we performed in situ hybridization and found that cdkl5 is expressed in the brain from 1 dpf, in the muscle at 2 dpf, in the otic vesicles, eyes and heart from 2 dpf, in the kidneys from 3 dpf and in the developing spinal cord from 4 dpf (Supplementary Figure 1b). The brain, spinal cord, eyes, muscle, and kidneys represent tissues that are affected in patients carrying CDKL5 mutations [15] indicating that zebrafish may be a suitable model to study CDD pathogenesis.…”

“…The copyright holder for this preprint this version posted April 9, 2021. ; https://doi.org/10.1101/2021.04.07.438335 doi: bioRxiv preprint than 265 variants have been identified in CDKL5, with approximately 70 of these considered pathogenic [15]. Many mutations are located within the catalytic domain, and those disrupting catalytic activity lead to a complete loss of kinase function [4,15]. Due to the rarity of the disorder (1 in 60,000 live births) very little is known about long term prognosis, however, many patients die by early adulthood.…”

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

“…CDKL5 belongs to the serine-threonine kinase family and is widely distributed in the human body. The highest expression levels are in the peri- and postnatal stages of the nervous system, suggesting an important role in the process of brain development [ 23 ]. Recent studies demonstrated that CDKL5 regulates axon outgrowth, dendritic morphogenesis and synapse formation [ 24 ].…”