AI Article Synopsis
- - The study focused on CDKL5 deficiency disorder (CDD) in a mouse model, which showed that seizures occur in female mice with specific genetic mutations, but not in male knockout mice or homozygous females, aiming to link genetic variants to clinical outcomes in CDD patients.
- - It included 11 patients (6 females and 5 males), using digital PCR for genetic diagnosis and assessing their clinical features through standardized scoring methods while comparing the severity between patients with different genetic backgrounds, specifically hemizygous versus mosaic or heterozygous variants.
- - Results indicated that all patients experienced seizures irrespective of their genetic type, but those with cellular mosaicism had less severe accompanying conditions like feeding and visual impairments. This suggests
Article Abstract
Objective: In a study using a mouse model of CDKL5 deficiency disorder (CDD), seizures are specific to female mice heterozygous for Cdkl5 mutations and not observed in hemizygous knockout males or homozygous knockout females. The aim of this study was to examine whether the clinical phenotype of patients with CDD can be impacted by the type of genetic variant.
Methods: Eleven CDD patients (six females and five males) were included in this study. The molecular diagnosis of hemizygous male patients was performed using digital PCR and their clinical phenotypes were compared with those of patients with mosaic or heterozygous CDKL5 variants. The severity of clinical phenotypes was graded by using CDKL5 Developmental Score and the adapted version of the CDKL5 Clinical Severity Assessment. The effect of cellular mosaicism on the severity of CDD was studied by comparing the clinical characteristics and comorbidities between individuals with hemizygous and mosaic or heterozygous CDKL5 variants.
Results: One of the five male patients was mosaic for the CDKL5 variant. All patients developed seizures irrespective of their genetic status of the pathogenic variant. However, cellular mosaicism of CDKL5 deficiency was associated with lesser severity of other comorbidities such as feeding, respiratory, and visual functional impairments.
Significance: This study provided evidence that cellular mosaicism of CDKL5 deficiency was not necessarily required for developing epilepsy. CDD patients not only exhibited clinical features of epilepsy but also exhibited the developmental consequences arising directly from the effect of the CDKL5 pathogenic variant.
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| http://dx.doi.org/10.1016/j.jns.2022.120498 | DOI Listing |
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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.
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