Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) has epilepsy as a cardinal feature. Here we report two new female patients and review six previously published patients, one male and five females, with features of CDD but who never developed epilepsy. In contrast with the classical and severe CDD phenotype, they presented with milder gross motor delays, autism spectrum disorder, and no visual cortical impairment. Prolonged video electroencephalography was normal in adult cases but showed interictal frontal-temporal bilateral spikes and sharp waves in sleep in the three-year-old girl. Causative CDKL5 variants included two likely gene damaging (nonsense and frameshift) and six missense variants, being de novo or maternally inherited from asymptomatic females with skewed X-chromosome inactivation (two missense variants). Our data indicate that a milder form of CDD without epilepsy can occur in some cases without clear correlation with specific variants in the CDKL5 gene.
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| http://dx.doi.org/10.1016/j.pediatrneurol.2023.04.015 | DOI Listing |
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Sci Rep
December 2024
Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate (Milan), 20054, Italy.
The CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental disorder characterized by early-onset epilepsy, intellectual disability, motor and visual dysfunctions. The causative gene is CDKL5, which codes for a kinase required for brain development. There is no cure for CDD patients; treatments are symptomatic and focus mainly on seizure control.
View Article and Find Full Text PDFMeasuring the Burden of Epilepsy Hospitalizations in CDKL5 Deficiency Disorder.
Pediatr Neurol
November 2024
The Kids Research Institute Australia, The University of Western Australia, Northern Entrance, Western Australia, Australia. Electronic address:
Background: Information on the hospital service use among individuals with CDKL5 Deficiency Disorder, an ultrarare developmental epileptic encephalopathy, is limited, evidence of which could assist with service planning. Therefore, using baseline and longitudinal data on 379 genetically verified individuals in the International CDKL5 Disorder Database, we aimed to investigate rates of seizure-related and other hospitalizations and associated length of stay in this cohort.
Methods: Outcome variables were lifetime count of family-reported hospitalizations and average length of stay both for seizure- (management and/or investigative) and non-seizure-related causes.
Natural language processing and expert follow-up establishes tachycardia association with CDKL5 deficiency disorder.
Genet Med Open
November 2023
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Purpose: CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy with multisystemic comorbidities. Cardiovascular involvement in CDD was shown in animal models but is yet poorly described in CDD cohorts.
Methods: We identified 38 individuals with genetically confirmed CDD through the Cleveland Clinic CDD specialty clinic and matched 190 individuals with non-genetic epilepsy to them as a comparison group.
Article Synopsis
- CDKL5 deficiency disorder (CDD) is a rare condition caused by genetic variants in the CDKL5 gene that lead to issues with neuronal development and function, particularly impacting epilepsy.
- Research using patient-derived induced pluripotent stem cells aimed to understand how these variants affect neurons, showing that while some aspects like neurite length appeared similar to controls, organoid-derived neurons exhibited increased network activity and excitability.
- The findings suggest that differences in neuronal behavior and gene expression are specific to excitatory cortical neurons, highlighting the potential for developing targeted therapies for CDD by exploring the molecular mechanisms behind early neuronal hyperexcitability.
Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.
J Neurodev Disord
November 2024
Department of Biomedical and Neuromotor Science, University of Bologna, Piazza Di Porta San Donato 2, 40126, Bologna, Italy.
Background: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice.
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