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Journal articles on the topic 'CDKL deficiency disorder'

Author: Grafiati

Published: 14 March 2023

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1

Mukhin, K. Yu, O. A. Pylaeva, M. Yu Bobylova, and V. A. Chadaev. "Genetic epilepsy caused by CDKL5 gene mutations as an example of epileptic encephalopathy and developmental encephalopathy: literature review and own observations." Russian Journal of Child Neurology 16, no. 1-2 (July 30, 2021): 10–41. http://dx.doi.org/10.17650/2073-8803-2021-16-1-2-10-41.

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The disease caused by mutations in the CDKL5 gene (encoding cyclin-dependent kinase 5, CDK5) belongs to the group of early (infantile) epileptic encephalopathies caused by alterations in the genome. Currently, the disease is called “developmental encephalopathy and epileptic encephalopathy type 2”. This disorder is a complex combination of symptoms that develop due to deficiency or absence of the CDKL5 gene product, which is serine/threonine kinase. The CDKL5 gene is located on X chromosome; the disease has an X-linked dominant inheritance pattern. This literature review summarizes relevant studies analyzing the disease caused by CDKL5 gene mutations, including its genetic and epidemiological aspects, clinical manifestations, characteristics of epilepsy, principles of diagnosis, and therapeutic approaches. We present a case series of several patients with genetic disorders involving the CDKL5 gene.

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2

Demarest, Scott, Elia M. Pestana-Knight, Heather E. Olson, Jenny Downs, Eric D. Marsh, Walter E. Kaufmann, Carol-Anne Partridge, et al. "Severity Assessment in CDKL5 Deficiency Disorder." Pediatric Neurology 97 (August 2019): 38–42. http://dx.doi.org/10.1016/j.pediatrneurol.2019.03.017.

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3

Kadam, Shilpa D., Brennan J. Sullivan, Archita Goyal, Mary E. Blue, and Constance Smith-Hicks. "Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic." International Journal of Molecular Sciences 20, no. 20 (October 15, 2019): 5098. http://dx.doi.org/10.3390/ijms20205098.

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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.

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4

Jakimiec, Martyna, Justyna Paprocka, and Robert Śmigiel. "CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy." Brain Sciences 10, no. 2 (February 17, 2020): 107. http://dx.doi.org/10.3390/brainsci10020107.

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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.

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5

Brock, Dylan, Andrea Fidell, Jacob Thomas, Elizabeth Juarez-Colunga, Tim A. Benke, and Scott Demarest. "Cerebral Visual Impairment in CDKL5 Deficiency Disorder Correlates With Developmental Achievement." Journal of Child Neurology 36, no. 11 (September 22, 2021): 974–80. http://dx.doi.org/10.1177/08830738211019284.

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Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder is a rare neurodevelopmental disorder characterized by infantile-onset refractory epilepsy, profound developmental delays, and cerebral visual impairment. Although there is evidence that the presence of cerebral visual impairment in CDKL5 deficiency disorder is common, the potential impact of cerebral visual impairment severity on developmental attainment has not been explored directly. Focusing on a cohort of 46 children with CDKL5 deficiency disorder, examination features indicative of cerebral visual impairment were quantified and compared to developmental achievement. The derived cerebral visual impairment severity score was inversely correlated with developmental attainment, bolstering the supposition that cerebral visual impairment severity may provide a useful early biomarker of disease severity and prognosis. This study demonstrates the utility of a cerebral visual impairment score to better capture the range of cerebral visual impairment severity in the CDKL5 deficiency disorder population and further elucidates the interaction between cerebral visual impairment and developmental outcomes.

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6

Jhang, Cian-Ling, Hom-Yi Lee, Jin-Chung Chen, and Wenlin Liao. "Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder." Human Molecular Genetics 29, no. 14 (June 26, 2020): 2408–19. http://dx.doi.org/10.1093/hmg/ddaa122.

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Abstract Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.

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7

Barbiero, Isabella, Roberta De Rosa, and Charlotte Kilstrup-Nielsen. "Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?" International Journal of Molecular Sciences 20, no. 17 (August 21, 2019): 4075. http://dx.doi.org/10.3390/ijms20174075.

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CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy caused by mutations in the X-linked CDKL5 gene that encodes a serine/threonine kinase. CDD is characterised by the early onset of seizures and impaired cognitive and motor skills. Loss of CDKL5 in vitro and in vivo affects neuronal morphology at early and late stages of maturation, suggesting a link between CDKL5 and the neuronal cytoskeleton. Recently, various microtubule (MT)-binding proteins have been identified as interactors of CDKL5, indicating that its roles converge on regulating MT functioning. MTs are dynamic structures that are important for neuronal morphology, migration and polarity. The delicate control of MT dynamics is fundamental for proper neuronal functions, as evidenced by the fact that aberrant MT dynamics are involved in various neurological disorders. In this review, we highlight the link between CDKL5 and MTs, discussing how CDKL5 deficiency may lead to deranged neuronal functions through aberrant MT dynamics. Finally, we discuss whether the regulation of MT dynamics through microtubule-targeting agents may represent a novel strategy for future pharmacological approaches in the CDD field.

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8

La Montanara, Paolo, Arnau Hervera, Lucas L. Baltussen, Thomas H. Hutson, Ilaria Palmisano, Francesco De Virgiliis, Guiping Kong, et al. "Cyclin-dependent–like kinase 5 is required for pain signaling in human sensory neurons and mouse models." Science Translational Medicine 12, no. 551 (July 8, 2020): eaax4846. http://dx.doi.org/10.1126/scitranslmed.aax4846.

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Cyclin-dependent–like kinase 5 (CDKL5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)–derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of CDKL5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)–dependent signaling, which are disrupted in both CDKL5 mutant murine DRG and human iPS–derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

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9

Jagtap, Smita, Jessica M. Thanos, Ting Fu, Jennifer Wang, Jasmin Lalonde, Thomas O. Dial, Ariel Feiglin, et al. "Aberrant mitochondrial function in patient-derived neural cells from CDKL5 deficiency disorder and Rett syndrome." Human Molecular Genetics 28, no. 21 (September 13, 2019): 3625–36. http://dx.doi.org/10.1093/hmg/ddz208.

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Abstract The X-linked neurodevelopmental diseases CDKL5 deficiency disorder (CDD) and Rett syndrome (RTT) are associated with intellectual disability, infantile spasms and seizures. Although mitochondrial dysfunction has been suggested in RTT, less is understood about mitochondrial function in CDD. A comparison of bioenergetics and mitochondrial function between isogenic wild-type and mutant neural progenitor cell (NPC) lines revealed increased oxygen consumption in CDD mutant lines, which is associated with altered mitochondrial function and structure. Transcriptomic analysis revealed differential expression of genes related to mitochondrial and REDOX function in NPCs expressing the mutant CDKL5. Furthermore, a similar increase in oxygen consumption specific to RTT patient–derived isogenic mutant NPCs was observed, though the pattern of mitochondrial functional alterations was distinct from CDKL5 mutant–expressing NPCs. We propose that aberrant neural bioenergetics is a common feature between CDD and RTT disorders. The observed changes in oxidative stress and mitochondrial function may facilitate the development of therapeutic agents for CDD and related disorders.

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10

Gill, Deepak. "A potential new treatment for CDKL5 deficiency disorder." Lancet Neurology 21, no. 5 (May 2022): 394–95. http://dx.doi.org/10.1016/s1474-4422(22)00127-2.

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11

Rodak, Małgorzata, Mariola Jonderko, Patrycja Rozwadowska, Magdalena Machnikowska-Sokołowska, and Justyna Paprocka. "CDKL5 Deficiency Disorder (CDD)—Rare Presentation in Male." Children 9, no. 12 (November 24, 2022): 1806. http://dx.doi.org/10.3390/children9121806.

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CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the X-linked cyclin-dependent kinase 5 (CDKL5) gene. This rare disorder occurs more frequently in females than in males. The incidence is estimated to be approximately 1: 40,000–60,000 live births. So far, 50 cases have been described in boys. The clinical course in males tends to be more severe and is often associated with death in the first or second decade of life. The authors present an unreported 2.5-year-old male patient with drug-resistant epilepsy who was diagnosed with a de novo mutation in the CDKL5 gene. First seizures developed in the fifth week of life and have progressed steadily since then. The child’s psychomotor development was strongly delayed, and generalized hypotonia was noticed since birth. Brain MRI showed areas of incomplete myelination, posterior narrowing of the corpus callosum, a pineal cyst of up to 3 mm, and open islet lids. Intensive antiseizure medications (ASMs), a ketogenic diet, and steroid therapy were not successful. Short-term improvement was achieved with the implantation of a vagal nerve stimulator (VNS). Due to the progressive course of the disease, the boy requires frequent modification of ASMs.

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12

Peikes, Tyler, Jessica N. Hartley, Aizeddin A. Mhanni, Cheryl R. Greenberg, and Juan Pablo Appendino. "Reflex Seizures in a Patient with CDKL5 Deficiency Disorder." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 46, no. 04 (April 29, 2019): 482–85. http://dx.doi.org/10.1017/cjn.2019.29.

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13

Morkous, Sameh S. "Quality Of Life in Individuals with CDKL5 Deficiency Disorder." Pediatric Neurology Briefs 36 (December 30, 2022): 5. http://dx.doi.org/10.15844/pedneurbriefs-36-5.

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14

Patnaik, Abhisarika, Eleonora Spiombi, Angelisa Frasca, Nicoletta Landsberger, Marta Zagrebelsky, and Martin Korte. "Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner." International Journal of Molecular Sciences 21, no. 9 (April 27, 2020): 3079. http://dx.doi.org/10.3390/ijms21093079.

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The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

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15

De Rosa, Roberta De, Serena Valastro, Clara Cambria, Isabella Barbiero, Carolina Puricelli, Marco Tramarin, Silvia Randi, Massimiliano Bianchi, Flavia Antonucci, and Charlotte Kilstrup-Nielsen. "Loss of CDKL5 Causes Synaptic GABAergic Defects That Can Be Restored with the Neuroactive Steroid Pregnenolone-Methyl-Ether." International Journal of Molecular Sciences 24, no. 1 (December 21, 2022): 68. http://dx.doi.org/10.3390/ijms24010068.

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CDKL5 deficiency disorder (CDD) is an X-linked neurodevelopmental disorder characterised by early-onset drug-resistant epilepsy and impaired cognitive and motor skills. CDD is caused by mutations in cyclin-dependent kinase-like 5 (CDKL5), which plays a well-known role in regulating excitatory neurotransmission, while its effect on neuronal inhibition has been poorly investigated. We explored the potential role of CDKL5 in the inhibitory compartment in Cdkl5-KO male mice and primary hippocampal neurons and found that CDKL5 interacts with gephyrin and collybistin, two crucial organisers of the inhibitory postsynaptic sites. Through molecular and electrophysiological approaches, we demonstrated that CDKL5 loss causes a reduced number of gephyrin puncta and surface exposed γ2 subunit-containing GABAA receptors, impacting the frequency of miniature inhibitory postsynaptic currents, which we ascribe to a postsynaptic function of CDKL5. In line with previous data showing that CDKL5 loss impacts microtubule (MT) dynamics, we showed that treatment with pregnenolone-methyl-ether (PME), which promotes MT dynamics, rescues the above defects. The impact of CDKL5 deficiency on inhibitory neurotransmission might explain the presence of drug-resistant epilepsy and cognitive defects in CDD patients. Moreover, our results may pave the way for drug-based therapies that could bypass the need for CDKL5 and provide effective therapeutic strategies for CDD patients.

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16

Katayama, Syouichi, Noriyuki Sueyoshi, Tetsuya Inazu, and Isamu Kameshita. "Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder." Neural Plasticity 2020 (June 5, 2020): 1–14. http://dx.doi.org/10.1155/2020/6970190.

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Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.

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17

Lupori, Leonardo, Giulia Sagona, Claudia Fuchs, Raffaele Mazziotti, Antonia Stefanov, Elena Putignano, Debora Napoli, Enrica Strettoi, Elisabetta Ciani, and Tommaso Pizzorusso. "Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder." Human Molecular Genetics 28, no. 17 (April 24, 2019): 2851–61. http://dx.doi.org/10.1093/hmg/ddz102.

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Abstract CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder characterized by a severe global developmental delay and early-onset seizures. Notably, patients show distinctive visual abnormalities often clinically diagnosed as cortical visual impairment. However, the involvement of cerebral cortical dysfunctions in the origin of the symptoms is poorly understood. CDD mouse models also display visual deficits, and cortical visual responses can be used as a robust biomarker in CDKL5 mutant mice. A deeper understanding of the circuits underlying the described visual deficits is essential for directing preclinical research and translational approaches. Here, we addressed this question in two ways: first, we performed an in-depth morphological analysis of the visual pathway, from the retina to the primary visual cortex (V1), of CDKL5 null mice. We found that the lack of CDKL5 produced no alteration in the organization of retinal circuits. Conversely, CDKL5 mutants showed reduced density and altered morphology of spines and decreased excitatory synapse marker PSD95 in the dorsal lateral geniculate nucleus and in V1. An increase in the inhibitory marker VGAT was selectively present in V1. Second, using a conditional CDKL5 knockout model, we showed that selective cortical deletion of CDKL5 from excitatory cells is sufficient to produce abnormalities of visual cortical responses, demonstrating that the normal function of cortical circuits is dependent on CDKL5. Intriguingly, these deficits were associated with morphological alterations of V1 excitatory and inhibitory synaptic contacts. In summary, this work proposes cortical circuit structure and function as a critically important target for studying CDD.

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18

Hector, Ralph D., Vera M. Kalscheuer, Friederike Hennig, Helen Leonard, Jenny Downs, Angus Clarke, Tim A. Benke, et al. "CDKL5 variants." Neurology Genetics 3, no. 6 (December 2017): e200. http://dx.doi.org/10.1212/nxg.0000000000000200.

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Objective:To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene.Methods:We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity.Results:The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency.Conclusions:These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain.

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19

Tassinari, Marianna, Nicola Mottolese, Giuseppe Galvani, Domenico Ferrara, Laura Gennaccaro, Manuela Loi, Giorgio Medici, et al. "Luteolin Treatment Ameliorates Brain Development and Behavioral Performance in a Mouse Model of CDKL5 Deficiency Disorder." International Journal of Molecular Sciences 23, no. 15 (August 5, 2022): 8719. http://dx.doi.org/10.3390/ijms23158719.

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CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene, is characterized by early-onset epilepsy, intellectual disability, and autistic features. Although pharmacotherapy has shown promise in the CDD mouse model, safe and effective clinical treatments are still far off. Recently, we found increased microglial activation in the brain of a mouse model of CDD, the Cdkl5 KO mouse, suggesting that a neuroinflammatory state, known to be involved in brain maturation and neuronal dysfunctions, may contribute to the pathophysiology of CDD. The present study aims to evaluate the possible beneficial effect of treatment with luteolin, a natural flavonoid known to have anti-inflammatory and neuroprotective activities, on brain development and behavior in a heterozygous Cdkl5 (+/−) female mouse, the mouse model of CDD that best resembles the genetic clinical condition. We found that inhibition of neuroinflammation by chronic luteolin treatment ameliorates motor stereotypies, hyperactive profile and memory ability in Cdkl5 +/− mice. Luteolin treatment also increases hippocampal neurogenesis and improves dendritic spine maturation and dendritic arborization of hippocampal and cortical neurons. These findings show that microglia overactivation exerts a harmful action in the Cdkl5 +/− brain, suggesting that treatments aimed at counteracting the neuroinflammatory process should be considered as a promising adjuvant therapy for CDD.

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Leonard, Helen, Mohammed Junaid, Kingsley Wong, Alex A. Aimetti, Elia Pestana Knight, and Jenny Downs. "Influences on the trajectory and subsequent outcomes in CDKL5 deficiency disorder." Epilepsia 63, no. 2 (November 27, 2021): 352–63. http://dx.doi.org/10.1111/epi.17125.

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21

MacKay, Conor I., David Bick, Jeremy W. Prokop, Ivan Muñoz, John Rouse, Jenny Downs, and Helen Leonard. "Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?" American Journal of Medical Genetics Part A 182, no. 5 (February 8, 2020): 1217–22. http://dx.doi.org/10.1002/ajmg.a.61504.

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22

Hong, William, Isabel Haviland, Elia Pestana-Knight, Judith L. Weisenberg, Scott Demarest, Eric D. Marsh, and Heather E. Olson. "CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment." CNS Drugs 36, no. 6 (May 28, 2022): 591–604. http://dx.doi.org/10.1007/s40263-022-00921-5.

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Benke, Tim A., and Peter C. Kind. "Proof-of-concept for a gene replacement approach to CDKL5 deficiency disorder." Brain 143, no. 3 (March 1, 2020): 716–18. http://dx.doi.org/10.1093/brain/awaa055.

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Demarest, Scott T., Heather E. Olson, Angela Moss, Elia Pestana‐Knight, Xiaoming Zhang, Sumit Parikh, Lindsay C. Swanson, et al. "CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development." Epilepsia 60, no. 8 (July 16, 2019): 1733–42. http://dx.doi.org/10.1111/epi.16285.

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Di Nardo, Alessia, Alina Rühmkorf, Patricia Award, Ashton Brennecke, Michela Fagiolini, and Mustafa Sahin. "Phenotypic characterization of Cdkl5-knockdown neurons establishes elongated cilia as a functional assay for CDKL5 Deficiency Disorder." Neuroscience Research 176 (March 2022): 73–78. http://dx.doi.org/10.1016/j.neures.2021.10.001.

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Loi, Manuela, Laura Gennaccaro, Claudia Fuchs, Stefania Trazzi, Giorgio Medici, Giuseppe Galvani, Nicola Mottolese, et al. "Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of CDKL5 Deficiency Disorder." International Journal of Molecular Sciences 22, no. 11 (May 31, 2021): 5950. http://dx.doi.org/10.3390/ijms22115950.

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Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3β or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3β/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3β and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3β/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients.

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Siri, Barbara, Costanza Varesio, Elena Freri, Francesca Darra, Simone Gana, Davide Mei, Francesco Porta, et al. "CDKL5 deficiency disorder in males: Five new variants and review of the literature." European Journal of Paediatric Neurology 33 (July 2021): 9–20. http://dx.doi.org/10.1016/j.ejpn.2021.04.007.

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Van Bergen, Nicole J., Sean Massey, Tegan Stait, Molly Ellery, Boris Reljić, Luke E. Formosa, Anita Quigley, et al. "Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder." Neurobiology of Disease 155 (July 2021): 105370. http://dx.doi.org/10.1016/j.nbd.2021.105370.

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Appendino, Juan Pablo. "Hypermotor-tonic-spasms seizure sequence related to CDKL5 deficiency disorder: a typical case." Epileptic Disorders 24, no. 6 (December 1, 2022): 1–2. http://dx.doi.org/10.1684/epd.2022.1480.

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30

MacKay, Conor I., Kingsley Wong, Scott T. Demarest, Tim A. Benke, Jenny Downs, and Helen Leonard. "Exploring genotype‐phenotype relationships in the CDKL5 deficiency disorder using an international dataset." Clinical Genetics 99, no. 1 (October 20, 2020): 157–65. http://dx.doi.org/10.1111/cge.13862.

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31

Dale, Tristan, Jenny Downs, Heather Olson, Ann Marie Bergin, Stephanie Smith, and Helen Leonard. "Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder." Epilepsy Research 151 (March 2019): 31–39. http://dx.doi.org/10.1016/j.eplepsyres.2019.02.001.

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Elagib, Kamaleldin E., Ivailo S. Mihaylov, Lorrie L. Delehanty, Grant C. Bullock, Kevin D. Ouma, Jill F. Caronia, Sara L. Gonias, and Adam N. Goldfarb. "Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation." Blood 112, no. 13 (December 15, 2008): 4884–94. http://dx.doi.org/10.1182/blood-2008-03-145722.

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Abstract The transcription factor GATA-1 participates in programming the differentiation of multiple hematopoietic lineages. In megakaryopoiesis, loss of GATA-1 function produces complex developmental abnormalities and underlies the pathogenesis of megakaryocytic leukemia in Down syndrome. Its distinct functions in megakaryocyte and erythroid maturation remain incompletely understood. In this study, we identified functional and physical interaction of GATA-1 with components of the positive transcriptional elongation factor P-TEFb, a complex containing cyclin T1 and the cyclin-dependent kinase 9 (Cdk9). Megakaryocytic induction was associated with dynamic changes in endogenous P-TEFb composition, including recruitment of GATA-1 and dissociation of HEXIM1, a Cdk9 inhibitor. shRNA knockdowns and pharmacologic inhibition both confirmed contribution of Cdk9 activity to megakaryocytic differentiation. In mice with megakaryocytic GATA-1 deficiency, Cdk9 inhibition produced a fulminant but reversible megakaryoblastic disorder reminiscent of the transient myeloproliferative disorder of Down syndrome. P-TEFb has previously been implicated in promoting elongation of paused RNA polymerase II and in programming hypertrophic differentiation of cardiomyocytes. Our results offer evidence for P-TEFb cross-talk with GATA-1 in megakaryocytic differentiation, a program with parallels to cardiomyocyte hypertrophy.

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Bao, Junxiang, Guangbi Li, Xinxu Yuan, Pin-Lan Li, and Erich Gulbins. "Contribution of p62 to Phenotype Transition of Coronary Arterial Myocytes with Defective Autophagy." Cellular Physiology and Biochemistry 41, no. 2 (2017): 555–68. http://dx.doi.org/10.1159/000457877.

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Background: Autophagy disorder contributes to dedifferentiation of arterial smooth muscle cells, but the mechanisms are poorly understood. Here, we sought to investigate the role of scaffolding adaptor p62/SQSTM1 (p62) in phenotype switching of mouse coronary arterial myocytes (CAMs) induced by CD38 gene deficiency or lysosomal dysfunction which blocks autophagic flux in the cells. Methods: Protein expression was measured by western blot analysis and immunofluorescent staining. Cell cycle and proliferation rate were analyzed by flow cytometry and MTS assay respectively. mRNA abundance was tested by qRT-PCR. Results: CD38 gene deficiency or bafilomycin A1 (baf), a selective lysosomal inhibitor treatment increased proliferation rate and vimentin expression in CAMs which was prevented by p62 gene silencing. Cell percentage in G<Sub>2</Sub>/M and G<Sub>0</Sub>/G<Sub>1</Sub> phase was decreased and increased by CD38 deficiency or baf treatment, respectively which was accompanied by accrual of cyclin-dependent kinase 1 (CDK1) protein. Although free ubiquitin content was increased, the colocalization of it to CDK1 was markedly decreased in CD38-/- or baf treated CAMs. Furthermore, the changes in both cell cycle and CDK1 ubiquitinylation could be restored by p62 gene silencing. Conclusion: The results suggest in CD38-/- or baf treated CAMs, p62 accumulation promotes phenotype transition and proliferation by accelerating cell cycle progress through G<Sub>2</Sub>/M which might relate to the compromised ubiquitinylation and degradation of CDK1.

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Frasca, Angelisa, Efterpi Pavlidou, Matteo Bizzotto, Yunan Gao, Dario Balestra, Mirko Pinotti, Hans Atli Dahl, Nicholas D. Mazarakis, Nicoletta Landsberger, and Maria Kinali. "Not Just Loss-of-Function Variations." Neurology Genetics 8, no. 2 (March 9, 2022): e666. http://dx.doi.org/10.1212/nxg.0000000000000666.

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Background and ObjectivesCDKL5 deficiency disorder (CDD) is a neurodevelopmental encephalopathy characterized by early-onset epilepsy and impaired psychomotor development. Variations in the X-linked CDKL5 gene coding for a kinase cause CDD. Molecular genetics has proved that almost all pathogenic missense substitutions localize in the N-terminal catalytic domain, therefore underlining the importance for brain development and functioning of the kinase activity. CDKL5 also features a long C-terminal domain that acts as negative regulator of the enzymatic activity and modulates its subcellular distribution. CDD is generally attributed to loss-of-function variations, whereas the clinical consequences of increased CDKL5 activity remain uncertain. We have identified a female patient characterized by mild epilepsy and neurologic symptoms, harboring a novel c.2873C>G nucleotide substitution, leading to the missense variant p.(Thr958Arg). To increase our comprehension of genetic variants in CDKL5-associated neurologic disorders, we have characterized the molecular consequences of the identified substitution.MethodsMRI and video EEG telemetry were used to describe brain activity and capture seizure. The Bayley III test was used to evaluate the patient development. Reverse transcriptase PCR was used to analyze whether the identified nucleotide variant affects messenger RNA stability and/or splicing. The X chromosome inactivation pattern was analyzed determining the DNA methylation status of the androgen receptor (AR) gene and by sequencing of expressed alleles. Western blotting was used to investigate whether the novel Thr958Arg substitution affects the stability and/or enzymatic activity of CDKL5. Immunofluorescence was used to define whether CDKL5 subcellular distribution is affected by the Thr958Arg substitution.ResultsOur data suggested that the proband tends toward a skewed X chromosome inactivation pattern in favor of the novel variant. The molecular investigation revealed that the p.(Thr958Arg) substitution leads to a significant increase in the autophosphorylation of both the TEY motif and residue Tyr171 of CDKL5, as well as in the phosphorylation of the target protein MAP1S, indicating an hyperactivation of CDKL5. This occurs without evidently affecting the kinase subcellular distribution.DiscussionOur data provide a strong indication that the c.2873C>G nucleotide substitution represents an hypermorphic pathogenic variation of CDKL5, therefore highlighting the importance of a tight control of CDKL5 activity in the brain.

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Yennawar, Madhumita, Rachel S. White, and Frances E. Jensen. "AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder." Journal of Neuroscience 39, no. 24 (April 5, 2019): 4814–28. http://dx.doi.org/10.1523/jneurosci.2041-18.2019.

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Pizzo, R., A. Lamarca, M. Sassoè-Pognetto, and M. Giustetto. "Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder." Neuroscience 445 (October 2020): 130–43. http://dx.doi.org/10.1016/j.neuroscience.2019.08.033.

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Lim, Zhan, Kingsley Wong, Jenny Downs, Keely Bebbington, Scott Demarest, and Helen Leonard. "Vagus nerve stimulation for the treatment of refractory epilepsy in the CDKL5 Deficiency Disorder." Epilepsy Research 146 (October 2018): 36–40. http://dx.doi.org/10.1016/j.eplepsyres.2018.07.013.

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Saldaris, Jacinta M., Peter Jacoby, Helen Leonard, Tim A. Benke, Scott Demarest, Eric D. Marsh, and Jenny Downs. "Psychometric properties of QI-Disability in CDKL5 Deficiency Disorder: Establishing readiness for clinical trials." Epilepsy & Behavior 139 (February 2023): 109069. http://dx.doi.org/10.1016/j.yebeh.2022.109069.

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Yoshimura, Yuri, Atsushi Morii, Yuuki Fujino, Marina Nagase, Arisa Kitano, Shiho Ueno, Kyoka Takeuchi, Riko Yamashita, and Tetsuya Inazu. "Comprehensive In Silico Functional Prediction Analysis of CDKL5 by Single Amino Acid Substitution in the Catalytic Domain." International Journal of Molecular Sciences 23, no. 20 (October 14, 2022): 12281. http://dx.doi.org/10.3390/ijms232012281.

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Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase whose pathological mutations cause CDKL5 deficiency disorder. Most missense mutations are concentrated in the catalytic domain. Therefore, anticipating whether mutations in this region affect CDKL5 function is informative for clinical diagnosis. This study comprehensively predicted the pathogenicity of all 5700 missense substitutions in the catalytic domain of CDKL5 using in silico analysis and evaluating their accuracy. Each missense substitution was evaluated as “pathogenic” or “benign”. In silico tools PolyPhen-2 HumDiv mode/HumVar mode, PROVEAN, and SIFT were selected individually or in combination with one another to determine their performance using 36 previously reported mutations as a reference. Substitutions predicted as pathogenic were over 88.0% accurate using each of the three tools. The best performance score (accuracy, 97.2%; sensitivity, 100%; specificity, 66.7%; and Matthew’s correlation coefficient (MCC), 0.804) was achieved by combining PolyPhen-2 HumDiv, PolyPhen-2 HumVar, and PROVEAN. This provided comprehensive information that could accurately predict the pathogenicity of the disease, which might be used as an aid for clinical diagnosis.

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Devinsky, Orrin, LaToya King, Judith Bluvstein, and Daniel Friedman. "Ataluren for drug‐resistant epilepsy in nonsense variant‐mediated Dravet syndrome and CDKL5 deficiency disorder." Annals of Clinical and Translational Neurology 8, no. 3 (February 4, 2021): 639–44. http://dx.doi.org/10.1002/acn3.51306.

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Dale, Tristan, Jenny Downs, Kingsley Wong, and Helen Leonard. "The perceived effects of cannabis products in the management of seizures in CDKL5 Deficiency Disorder." Epilepsy & Behavior 122 (September 2021): 108152. http://dx.doi.org/10.1016/j.yebeh.2021.108152.

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Kluckova, Daniela, Miriam Kolnikova, Veronika Medova, Csaba Bognar, Tomas Foltan, Lucia Svecova, Andrej Gnip, Ludevit Kadasi, Andrea Soltysova, and Andrej Ficek. "Clinical manifestation of CDKL5 deficiency disorder and identified mutations in a cohort of Slovak patients." Epilepsy Research 176 (October 2021): 106699. http://dx.doi.org/10.1016/j.eplepsyres.2021.106699.

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Tangarorang, Jodilee, Helen Leonard, Amy Epstein, and Jenny Downs. "A framework for understanding quality of life domains in individuals with the CDKL5 deficiency disorder." American Journal of Medical Genetics Part A 179, no. 2 (December 18, 2018): 249–56. http://dx.doi.org/10.1002/ajmg.a.61012.

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Fuchs, Claudia, Laura Gennaccaro, Elisa Ren, Giuseppe Galvani, Stefania Trazzi, Giorgio Medici, Manuela Loi, et al. "Pharmacotherapy with sertraline rescues brain development and behavior in a mouse model of CDKL5 deficiency disorder." Neuropharmacology 167 (May 2020): 107746. http://dx.doi.org/10.1016/j.neuropharm.2019.107746.

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Leonard, Helen, Mohammed Junaid, Kingsley Wong, Scott Demarest, and Jenny Downs. "Exploring quality of life in individuals with a severe developmental and epileptic encephalopathy, CDKL5 Deficiency Disorder." Epilepsy Research 169 (January 2021): 106521. http://dx.doi.org/10.1016/j.eplepsyres.2020.106521.

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Aledo-Serrano, Ángel, Patricia Gómez-Iglesias, Rafael Toledano, Juan Jose Garcia-Peñas, Irene Garcia-Morales, Carla Anciones, Victor Soto-Insuga, Timothy A. Benke, Isabel del Pino, and Antonio Gil-Nagel. "Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort." Epilepsy & Behavior 118 (May 2021): 107946. http://dx.doi.org/10.1016/j.yebeh.2021.107946.

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Talamo, M. C., M. Pellas, C. Urbinati, L. Cosentino, and B. De Filippis. "P.236 Inhibition of p21-activated kinase rescues disrupted phenotype in a mouse model of CDKL5 deficiency disorder." European Neuropsychopharmacology 31 (February 2020): S45—S46. http://dx.doi.org/10.1016/j.euroneuro.2019.12.062.

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Ademuwagun, Ibitayo Abigail, Gbolahan Oladipupo Oduselu, Solomon Oladapo Rotimi, and Ezekiel Adebiyi. "Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders." Bioinformatics and Biology Insights 17 (January 2023): 117793222311582. http://dx.doi.org/10.1177/11779322231158254.

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Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.

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Gorbenko Del Blanco, Darya, Laura C. G. de Graaff, Dirk Posthouwer, Theo J. Visser, and Anita C. S. Hokken-Koelega. "Isolated GH deficiency: mutation screening and copy number analysis of HMGA2 and CDK6 genes." European Journal of Endocrinology 165, no. 4 (October 2011): 537–44. http://dx.doi.org/10.1530/eje-11-0478.

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ObjectiveIn most patients, the genetic cause of isolated GH deficiency (IGHD) is unknown. By identifying several genes associated with height variability within the normal population, three separate genome-wide association studies provided new candidate genes for human growth disorders. We selected two of them for genetic screening of our IGHD population.AimWe aimed to determine whether high-mobility group A2 (HMGA2) and cyclin-dependent protein kinase 6 (CDK6) are involved in the pathogenicity of IGHD.MethodsWe directly sequenced coding regions and exon–intron boundaries of the genesHMGA2andCDK6in 105 Caucasian IGHD patients from the Dutch HYPOPIT study. In addition, we developed a new probe set of multiplex ligation-dependent probe amplification for both genes in order to detect copy number variations.ResultsIn one patient with classical IGHD phenotype, we identified a new heterozygous 20 bp deletion in the intronic region ofHMGA2(c.250-29_-9del), which was absent in the databases and healthy controls. Together, with recently published data concerning the 12q14 microdeletion syndrome, where patients with anHMGA2haploinsufficiency had proportionate short stature, this study provides further support of the important role for HMGA2 in growth. InCDK6, we found only known polymorphisms.ConclusionsThis study provides the first report of a deletion in theHMGA2gene that might be related to IGHD. We suggest that this gene is investigated as a second screening in patients with a classical IGHD phenotype in which mutations in classical candidate genes have been excluded.

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Terzic, Barbara, Yue Cui, Andrew C. Edmondson, Sheng Tang, Nicolas Sarmiento, Daria Zaitseva, Eric D. Marsh, Douglas A. Coulter, and Zhaolan Zhou. "X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder." Neurobiology of Disease 148 (January 2021): 105176. http://dx.doi.org/10.1016/j.nbd.2020.105176.

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