Abstract
Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies.
Highlights
In the following review we compare the overlapping and contrasting features in Rett syndrome (RTT) and cyclin-dependent kinase-like 5 (CDKL5) disorder (CDD) in clinic, as well as their respective rodent models
Most of the studies presented here have used Mecp2-null male mice or rats as their phenotype mirrors the severity of RTT albeit that RTT is not typically lethal as is observed in most KO models, and the developmental onset of symptoms is later than is observed in RTT
Fewer studies have examined Mecp2-heterozygous models, which matches the genotype of girls with RTT, as the phenotypic features develop much later and are less severe than is experienced in patients with RTT
Summary
In the following review we compare the overlapping and contrasting features in Rett syndrome (RTT) and CDKL5 disorder (CDD) in clinic, as well as their respective rodent models. As we seek to translate preclinical discoveries to the clinic, a forthcoming challenge will be successfully evaluating preclinical studies to pursue for their translational utility. We reflect upon lessons learned from recent clinical trials while reviewing the progress in preclinical research. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, epilepsy, circuit homeostasis, sleep impairment, and the insights gained from pre-clinical and clinical studies
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