Molecular and Synaptic Bases of CDKL5 Disorder

Yingguo, Zhu; Xiong, Zhi‐Qi

doi:10.1002/dneu.22639

Cited by 70 publications

(59 citation statements)

References 79 publications

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“…[24][25][26][27] The CDKL5 protein has roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis and synapse development and function in the adult brain. 28 CDKL5 has multiple transcripts due to alternative splicing in mice and humans. The primary brain isoform is hCDKL5_1.…”

Section: Cdkl5 Protein and Molecular Biologymentioning

confidence: 99%

“…Molecular studies in rodent models have identified several pathways are altered in CDD, including the AKT/mTOR, AKT/GSK-3b and BDNF-Rac1 signaling pathways and the NGL-1-PSD95 interaction. 24,25,27,28,40,41 However, these rodent models demonstrate a behavioral phenotype but lack spontaneous seizure activity. [41][42][43] Dendritic outgrowth and spine development are inconsistently altered in cellular CDD models.…”

Section: Cdkl5 Protein and Molecular Biologymentioning

confidence: 99%

See 1 more Smart Citation

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review

Olson¹,

Demarest²,

Pestana-Knight³

et al. 2019

Pediatric Neurology

179

224

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Section: Cdkl5 Protein and Molecular Biologymentioning

confidence: 99%

Section: Cdkl5 Protein and Molecular Biologymentioning

confidence: 99%

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review

Olson¹,

Demarest²,

Pestana-Knight³

et al. 2019

Pediatric Neurology

179

224

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“…CDKL5 protein is widely expressed in the brain and plays important roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development [7,8]. Typical clinical characters of CDKL5-related disorders (CDD) include infantile-onset refractory epilepsy, hypotonia, developmental delay, intellectual disability, and visual impairment [2][3][4]9].…”

Section: Discussionmentioning

confidence: 99%

“…So far more than 100 pathogenic mutations have been reported. The clinical severity is associated with the location and type of mutations; for example, missense mutations located in the catalytic domain of CDKL5 could exhibit more severe phenotypes compared to patients carrying other CDKL5 mutations [8], but the exact genotype-phenotype correlation still remains obscure. In our patients, the three mutations are all de novo, as no mutations were found in their parents, and there were no reports previously.…”

Section: Discussionmentioning

confidence: 99%

Novel CDKL5 mutations were found in patients in China: retrospective investigation in cases of CDKL5-related disorders

Yan

et al. 2020

Ital J Pediatr

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Objective: CDKL5-related disorders (CDD) is an epileptic encephalopathy resulted of gene mutations of CDKL5. This study aimed to explore the development process of CDD and to expand its mutation spectrum. Methods: Clinic datawas collected about three infantile epileptic encephalopathy cases diagnosed at Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine. Next generation sequencing technology was used to find three de novo mutations of CDKL5. We searched published literatures about CDKL5 in pubmed and made an analysis about our clinic data and the related literatures. Results: The three patients were all girls. Their average onset age of seizures was around 2 months, and all of them have intractable epileptic seizures, severe intellectual disability, and hypotension. Among them, two presented infantile spasm and high arrhythmia in EEG, and the other manifested clonic seizure and broad epileptiform discharge in EEG. Extracerebral space widening in cranial MRIs was demonstrated in two cases. Visual evoked potential was abnormal in two cases. Seizures were resistant to all kinds of antiepileptic drugs (AEDs). Gene tests showed three de novo mutations of CDKL5: one was a truncated mutation (c.2254A > T,P.R752X, stop279), which was pathogenic according to the ACMG guide, the other two were missense mutations (c.377G > T,p.Cys126Phe) and a frameshift mutation (c.362-362insG(p.Ala122GlyfsTer7), which were likely pathogenic according to the ACMG. Conclusions: All three de novo mutations are first reported. Based on the combined related literature and the manifestations observed, we diagnosed the three children as CDKL5-related disorders, and concluded that the de novo CDKL5 mutations are the reason for their epilepsy.

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“…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 ]. The first identified EIEE-causing gene was ARX , encoding the transcription factor Aristaless-Related Homeobox [ 25 ].…”

Section: Developmental and Epileptic Encephalopathy (Dee)mentioning

confidence: 99%

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

Takai

Yamaguchi

Yoshida

et al. 2020

IJMS

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Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The Drosophila model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with Drosophila models for EIEE and discuss the future development of their practical use.

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Molecular and Synaptic Bases of CDKL5 Disorder

Cited by 70 publications

References 79 publications

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review

Novel CDKL5 mutations were found in patients in China: retrospective investigation in cases of CDKL5-related disorders

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

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