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https://www.readbyqxmd.com/read/29778428/status-dystonicus-due-to-missense-variant-in-arx-diagnosis-and-management
#1
Kathleen M Gorman, Heather Cary, Laura Gaffney, Eva Forman, Dympna Waldron, Fowzy Al-Delami, Bryan J Lynch, Mary D King, Nicholas M Allen
Movement disorders are increasingly identified in infantile encephalopathies due to single gene disorders (e.g. SCN2A, CDKL5, ARX). The associated movement disorder can be challenging to recognise and treat. We report a 2 year-old boy with a background history of Ohtahara syndrome due to a missense variant in ARX (the aristaless-related homeobox gene) who subsequently developed status dystonicus. ARX is a transcription factor that plays a critical role in cortical neuronal development and is associated with a range of important neurodevelopmental disorders depending on the site of the pathogenic variant...
May 3, 2018: European Journal of Paediatric Neurology: EJPN
https://www.readbyqxmd.com/read/29760947/incorporating-epilepsy-genetics-into-clinical-practice-a-360%C3%A2-evaluation
#2
Stephanie Oates, Shan Tang, Richard Rosch, Rosalie Lear, Elaine F Hughes, Ruth E Williams, Line H G Larsen, Qin Hao, Hans Atli Dahl, Rikke S Møller, Deb K Pal
We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29752575/expression-pattern-of-cdkl5-during-zebrafish-early-development-implications-for-use-as-model-for-atypical-rett-syndrome
#3
Marta Vitorino, Nídia Cunha, Natércia Conceição, M Leonor Cancela
Atypical Rett syndrome is a child neurodevelopmental disorder induced by mutations in CDKL5 gene and characterized by a progressive regression in development with loss of purposeful use of the hands, slowed brain and head growth, problems with walking, seizures, and intellectual disability. At the moment, there is no cure for this pathology and little information is available concerning animal models capable of mimicking its phenotypes, thus the development of additional animal models should be of interest to gain more knowledge about the disease...
May 11, 2018: Molecular Biology Reports
https://www.readbyqxmd.com/read/29702698/comprehensive-behavioral-analysis-of-the-cdkl5-knockout-mice-revealed-significant-enhancement-in-anxiety-and-fear-related-behaviors-and-impairment-in-both-acquisition-and-long-term-retention-of-spatial-reference-memory
#4
Kosuke Okuda, Keizo Takao, Aya Watanabe, Tsuyoshi Miyakawa, Masashi Mizuguchi, Teruyuki Tanaka
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles...
2018: PloS One
https://www.readbyqxmd.com/read/29618004/the-antidepressant-tianeptine-reverts-synaptic-ampa-receptor-defects-caused-by-deficiency-of-cdkl5
#5
Marco Tramarin, Laura Rusconi, Lara Pizzamiglio, Isabella Barbiero, Diana Peroni, Linda Scaramuzza, Tim Guilliams, David Cavalla, Flavia Antonucci, Charlotte Kilstrup-Nielsen
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a complex neurological disorder, characterised by infantile seizures, impairment of cognitive and motor skills, and autistic features. Loss of Cdkl5 in mice affects dendritic spine maturation and dynamics but the underlying molecular mechanisms are still far from fully understood. Here we show that Cdkl5 deficiency in primary hippocampal neurons leads to deranged expression of the alpha-amino-3-hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPA-R)...
March 30, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29603837/treatment-with-the-gsk3-beta-inhibitor-tideglusib-improves-hippocampal-development-and-memory-performance-in-juvenile-but-not-adult-cdkl5-knockout-mice
#6
Claudia Fuchs, Norma Fustini, Stefania Trazzi, Laura Gennaccaro, Roberto Rimondini, Elisabetta Ciani
Cyclin-dependent kinase-like 5 (CDKL5) disorder is a severe neurodevelopmental disorder characterized by early-onset epileptic seizures, severe developmental delay, and intellectual disability. To date, no effective pharmacological treatments are available to improve the neurological phenotype that is due to mutations in the CDKL5 gene. Murine models of CDKL5 disorder have recently been generated, making the preclinical testing of pharmacological interventions possible. Using a Cdkl5 knockout (KO) mouse model, we recently demonstrated that deficiency of Cdkl5 causes defects in postnatal hippocampal development and hippocampus-dependent learning and memory...
March 30, 2018: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29588952/gene-panel-analysis-for-nonsyndromic-cryptogenic-neonatal-infantile-epileptic-encephalopathy
#7
Cheuk-Wing Fung, Anna Ka-Yee Kwong, Virginia Chun-Nei Wong
Objective: Epileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic-based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high-throughput next-generation sequencing (NGS) was used to investigate the genetic causes of non-syndromic cryptogenic neonatal/infantile EE (NIEE)...
June 2017: Epilepsia Open
https://www.readbyqxmd.com/read/29510241/a-male-case-with-cdkl5-associated-encephalopathy-manifesting-transient-methylmalonic-acidemia
#8
Satoshi Akamine, Yoshito Ishizaki, Yasunari Sakai, Hiroyuki Torisu, Ryoko Fukai, Noriko Miyake, Kazuhiro Ohkubo, Hiroshi Koga, Masafumi Sanefuji, Ayumi Sakata, Masahiko Kimura, Seiji Yamaguchi, Osamu Sakamoto, Toshiro Hara, Hirotomo Saitsu, Naomichi Matsumoto, Shouichi Ohga
Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive. We herein report a 16-year-old boy, who suffered from intractable seizures 20 days after birth. Serial electroencephalograms detected recurrent focal epileptiform discharges from age 4 months, which evolved to hypsarrhythmia later in infancy. Mass-spectrometric analyses revealed increase in urinary excretion of methylmalonic acid without perturbed concentrations of propionic acid, homocystein and methionine...
March 3, 2018: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29474534/cdkl5-protein-substitution-therapy-rescues-neurological-phenotypes-of-a-mouse-model-of-cdkl5-disorder
#9
Stefania Trazzi, Marianna De Franceschi, Claudia Fuchs, Stefano Bastianini, Rocchina Viggiano, Leonardo Lupori, Raffaele Mazziotti, Giorgio Medici, Viviana Lo Martire, Elisa Ren, Roberto Rimondini, Giovanna Zoccoli, Renata Bartesaghi, Tommaso Pizzorusso, Elisabetta Ciani
Cyclin-dependent kinase like-5 (CDKL5) disorder is a rare neurodevelopmental disease caused by mutations in the CDKL5 gene. The consequent misexpression of the CDKL5 protein in the nervous system leads to a severe phenotype characterized by intellectual disability, motor impairment, visual deficits and early-onset epilepsy. No therapy is available for CDKL5 disorder. It has been reported that a protein transduction domain (TAT) is able to deliver macromolecules into cells and even into the brain when fused to a given protein...
May 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29455050/targeted-gene-panel-and-genotype-phenotype-correlation-in-children-with-developmental-and-epileptic-encephalopathy
#10
Ara Ko, Song Ee Youn, Se Hee Kim, Joon Soo Lee, Sangwoo Kim, Jong Rak Choi, Heung Dong Kim, Seung-Tae Lee, Hoon-Chul Kang
OBJECTIVE: We performed targeted gene-panel sequencing for children with developmental and epileptic encephalopathy (DEE) and evaluated the clinical implications of genotype-phenotype correlations. METHODS: We assessed 278 children with DEE using a customized gene panel that included 172 genes, and extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype. RESULTS: In 103 (37.1%) of the 278 patients with DEE, 35 different disease-causing monogenic mutations were identified...
March 2018: Epilepsy Research
https://www.readbyqxmd.com/read/29444904/mutation-in-an-alternative-transcript-of-cdkl5-in-a-boy-with-early-onset-seizures
#11
Dale L Bodian, John M Schreiber, Thierry Vilboux, Alina Khromykh, Natalie S Hauser
Infantile-onset epilepsies are a set of severe, heterogeneous disorders for which clinical genetic testing yields causative mutations in ~20-50% of affected individuals. We report the case of a boy presenting with intractable seizures at 2 weeks of age, for whom gene panel testing was unrevealing. Research-based whole genome sequencing of the proband and four unaffected family members identified a de novo mutation, NM_001323289.1:c.2828_2829delGA in CDKL5, a gene associated with X-linked early infantile epileptic encephalopathy 2...
February 14, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29420175/cdkl-family-kinases-have-evolved-distinct-structural-features-and-ciliary-function
#12
Peter Canning, Kwangjin Park, João Gonçalves, Chunmei Li, Conor J Howard, Timothy D Sharpe, Liam J Holt, Laurence Pelletier, Alex N Bullock, Michel R Leroux
Various kinases, including a cyclin-dependent kinase (CDK) family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling and development. Neurological disorders linked to CDK-Like (CDKL) proteins suggest that these underexplored kinases may have similar functions. Here, we present the crystal structures of human CDKL1, CDKL2, CDKL3, and CDKL5, revealing their evolutionary divergence from CDK and mitogen-activated protein kinases (MAPKs), including an unusual ?J helix important for CDKL2 and CDKL3 activity...
January 23, 2018: Cell Reports
https://www.readbyqxmd.com/read/29395664/rett-like-features-and-cortical-visual-impairment-in-a-japanese-patient-with-hecw2-mutation
#13
Haruhiko Nakamura, Mitsugu Uematsu, Yurika Numata-Uematsu, Yu Abe, Wakaba Endo, Atsuo Kikuchi, Yusuke Takezawa, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Tetsuya Niihori, Yoko Aoki, Kazuhiro Haginoya, Shigeo Kure
Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression...
May 2018: Brain & Development
https://www.readbyqxmd.com/read/29390993/efficient-strategy-for-the-molecular-diagnosis-of-intractable-early-onset-epilepsy-using-targeted-gene-sequencing
#14
John Hoon Rim, Se Hee Kim, In Sik Hwang, Soon Sung Kwon, Jieun Kim, Hyun Woo Kim, Min Jung Cho, Ara Ko, Song Ee Youn, Jihun Kim, Young Mock Lee, Hee Jung Chung, Joon Soo Lee, Heung Dong Kim, Jong Rak Choi, Seung-Tae Lee, Hoon-Chul Kang
BACKGROUND: We intended to evaluate diagnostic utility of a targeted gene sequencing by using next generation sequencing (NGS) panel in patients with intractable early-onset epilepsy (EOE) and find the efficient analytical step for increasing the diagnosis rate. METHODS: We assessed 74 patients with EOE whose seizures started before 3 years of age using a customized NGS panel that included 172 genes. Single nucleotide variants (SNVs) and exonic and chromosomal copy number variations (CNVs) were intensively examined with our customized pipeline and crosschecked with commercial or pre-built software...
February 1, 2018: BMC Medical Genomics
https://www.readbyqxmd.com/read/29345071/detecting-selection-signatures-on-the-x-chromosome-of-the-chinese-debao-pony
#15
X-X Liu, J-F Pan, Q-J Zhao, X-H He, Y-B Pu, J-L Han, Y-H Ma, L Jiang
The X chromosome shows a special interaction between demographic factors and genetic variation, and the analysis of X-linked genomic variation can therefore provide insights into the unique effects of demography and selection on the horse genome that cannot be readily detected by autosomal markers. Debao (DB) ponies have experienced intense selective pressure for the development of their small stature (<106 cm at adult height). To identify selective sweeps on the X chromosome of the DB pony, we performed a genome-wide scan of three Chinese horse breeds using an Equine SNP70 BeadChip...
February 2018: Journal of Animal Breeding and Genetics, Zeitschrift Für Tierzüchtung und Züchtungsbiologie
https://www.readbyqxmd.com/read/29322350/monogenic-disorders-that-mimic-the-phenotype-of-rett-syndrome
#16
Siddharth Srivastava, Sonal Desai, Julie Cohen, Constance Smith-Hicks, Kristin Barañano, Ali Fatemi, SakkuBai Naidu
Rett syndrome (RTT) is caused by mutations in methyl-CpG-binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. We performed a retrospective chart review on n = 319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup...
January 2018: Neurogenetics
https://www.readbyqxmd.com/read/29282321/a-mixed-modality-approach-towards-xi-reactivation-for-rett-syndrome-and-other-x-linked-disorders
#17
Lieselot L G Carrette, Chen-Yu Wang, Chunyao Wei, William Press, Weiyuan Ma, Raymond J Kelleher, Jeannie T Lee
The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset, including neurodevelopmental disorders, Rett syndrome (RTT), fragile X syndrome, and CDKL5 syndrome, also affects females. These disorders lack disease-specific treatment. Because female cells carry two X chromosomes, an emerging treatment strategy has been to reawaken the healthy allele on the inactive X (Xi). Here, we focus on methyl-CpG binding protein 2 (MECP2) restoration for RTT and combinatorially target factors in the interactome of Xist, the noncoding RNA responsible for X inactivation...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29261713/targeted-next-generation-sequencing-provides-novel-clues-for-associated-epilepsy-and-cardiac-conduction-disorder-sudep
#18
Monica Coll, Pasquale Striano, Carles Ferrer-Costa, Oscar Campuzano, Jesús Matés, Bernat Del Olmo, Anna Iglesias, Alexandra Pérez-Serra, Irene Mademont, Ferran Picó, Antonio Oliva, Ramon Brugada
Sudden unexpected death in epilepsy is an unpredicted condition in patients with a diagnosis of epilepsy, and autopsy does not conclusively identify cause of death. Although the pathophysiological mechanisms that underlie this entity remain unknown, the fact that epilepsy can affect cardiac function is not surprising. The genetic factors involving ion channels co-expressed in the heart and brain and other candidate genes have been previously described. In the present study, 20 epilepsy patients with personal or family history of heart rhythm disturbance/cardiac arrhythmias/sudden death were sequenced using a custom re-sequencing panel...
2017: PloS One
https://www.readbyqxmd.com/read/29241837/kinases-in-synaptic-development-and-neurological-diseases
#19
REVIEW
Lucas L Baltussen, Flavia Rosianu, Sila K Ultanir
Neuronal morphogenesis and synapse development is essential for building a functioning nervous system, and defects in these processes are associated with neurological disorders. Our understanding of molecular components and signalling events that contribute to neuronal development and pathogenesis is limited. Genes associated with neurodevelopmental and neurodegenerative diseases provide entry points for elucidating molecular events that contribute to these conditions. Several protein kinases, enzymes that regulate protein function by phosphorylating their substrates, are genetically linked to neurological disorders...
December 11, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29208534/loss-of-cdkl5-disrupts-respiratory-function-in-mice
#20
Kun-Ze Lee, Wenlin Liao
Cyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene encoding a serine-threonine kinase that is highly expressed in the central nervous system. Mutations in CDKL5 cause neurological and psychiatric symptoms, including early-onset seizures, motor dysfunction, autistic features and sleep breathing abnormalities in patients. It remains to be addressed whether loss of CDKL5 causes respiratory dysfunction in mice. Here, we examined the respiratory pattern of male Cdkl5-/y mice at 1-3 months of age during resting breathing and respiratory challenge (i...
January 2018: Respiratory Physiology & Neurobiology
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