The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy
Stephanie Fehr,Meredith Wilson,Meredith Wilson,Jennepher Downs,Jennepher Downs,Simon G. Williams,Alessandra Murgia,Stefano Sartori,Marilena Vecchi,Gladys Ho,Gladys Ho,Roberta Polli,Stavroula Psoni,Xinhua Bao,Nicholas de Klerk,Helen Leonard,John Christodoulou,John Christodoulou +17 more
TLDR
The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies, and should be considered separate to RTT, rather than another variant.Abstract:
The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.read more
Citations
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Identification of an elaborate complex mediating postsynaptic inhibition.
Akiyoshi Uezu,Daniel J. Kanak,Tyler Wa Bradshaw,Erik J. Soderblom,Christina M. Catavero,Alain C. Burette,Richard J. Weinberg,Scott H. Soderling +7 more
TL;DR: Clustered regularly interspaced short palindromic repeats depletion of one of these previously uncharacterized proteins led to decreased postsynaptic inhibitory sites, reduced the frequency of miniature inhibitory currents, and increased excitability in the hippocampus.
Journal ArticleDOI
Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis
Natalie Trump,Amy McTague,Helen Brittain,Apostolos Papandreou,Apostolos Papandreou,Esther Meyer,Esther Meyer,Adeline Ngoh,Adeline Ngoh,Rodger Palmer,Deborah Morrogh,Christopher Boustred,Jane A. Hurst,Lucy Jenkins,Manju A Kurian,Manju A Kurian,Richard H Scott +16 more
TL;DR: The data demonstrate the considerable utility of a gene panel approach in the diagnosis of patients with early-onset epilepsy and severe developmental delay disorders and provide further insights into the phenotypic spectrum and genotype–phenotype correlations for a number of the causative genes.
Journal ArticleDOI
Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.
I-Ting Judy Wang,Megan Allen,Darren Goffin,Xinjian Zhu,Andrew H. Fairless,Edward S. Brodkin,Steve J. Siegel,Eric D. Marsh,Julie A. Blendy,Zhaolan Zhou +9 more
TL;DR: It is demonstrated that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory, and a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders is established.
Journal ArticleDOI
Quantitative phosphoproteomic analysis of the molecular substrates of sleep need.
Zhiqiang Wang,Jing Ma,Chika Miyoshi,Yuxin Li,Makito Sato,Yukino Ogawa,Tingting Lou,Chengyuan Ma,Xue Gao,Chi-Yu Lee,Tomoyuki Fujiyama,Xiaojie Yang,Shuang Zhou,Noriko Hotta-Hirashima,Daniela Klewe-Nebenius,Aya Ikkyu,Miyo Kakizaki,Satomi Kanno,Liqin Cao,Satoru Takahashi,Junmin Peng,Yonghao Yu,Hiromasa Funato,Hiromasa Funato,Masashi Yanagisawa,Masashi Yanagisawa,Qinghua Liu +26 more
TL;DR: In this paper, the authors investigated the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and sleepy mouse models of increased sleep need.
Journal ArticleDOI
Mapping Pathological Phenotypes in a Mouse Model of CDKL5 Disorder
Elena Amendola,Yang Zhan,Camilla Mattucci,Enrico Castroflorio,Eleonora Calcagno,Claudia Fuchs,Giuseppina Lonetti,Davide Silingardi,Alexei L. Vyssotski,Dominika Farley,Elisabetta Ciani,Tommaso Pizzorusso,Maurizio Giustetto,Cornelius Gross +13 more
TL;DR: Physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder identifies physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKl5 disorder.
References
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Journal ArticleDOI
Rett syndrome: Revised diagnostic criteria and nomenclature
Jeffrey L. Neul,Walter E. Kaufmann,Daniel G. Glaze,John Christodoulou,Angus John Clarke,Nadia Bahi-Buisson,Helen Leonard,Mark E.S. Bailey,N. Carolyn Schanen,Michele Zappella,Alessandra Renieri,Peter Huppke,Alan K. Percy +12 more
TL;DR: The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials.
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WHO Motor Development Study: Windows of achievement for six gross motor development milestones
TL;DR: The methods for generating windows of achievement for six gross motor developmental milestones are reviewed and the actual windows with commonly used motor development scales are compared to compare with those of previous studies.
Journal ArticleDOI
Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation
Linda S. Weaving,John Christodoulou,John Christodoulou,Sarah L. Williamson,Sarah L. Williamson,Kathie L. Friend,Olivia L. D. McKenzie,Hayley Archer,Julie Evans,Angus John Clarke,Gregory J. Pelka,Gregory J. Pelka,Gregory J. Pelka,Patrick P.L. Tam,Catherine M. Watson,Hooshang Lahooti,Carolyn Ellaway,Carolyn Ellaway,Bruce Bennetts,Bruce Bennetts,Helen Leonard,Jozef Gecz,Jozef Gecz +22 more
TL;DR: CDKL5 is confirmed as another locus associated with epilepsy and X-linked mental retardation and suggested that mutations in CDKL 5 can lead to a clinical phenotype that overlaps RTT, however, it remains to be determined whether CDkL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.
Journal ArticleDOI
Mutations in the X-Linked Cyclin-Dependent Kinase–Like 5 (CDKL5/STK9) Gene Are Associated with Severe Neurodevelopmental Retardation
Jiong Tao,Hilde Van Esch,M. Hagedorn-Greiwe,Kirsten Hoffmann,Bettina Moser,Martine Raynaud,Jürgen Sperner,Jean-Pierre Fryns,Eberhard Schwinger,Jozef Gecz,Hans-Hilger Ropers,Vera M. Kalscheuer +11 more
TL;DR: It is reported that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome.
Journal ArticleDOI
Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation
Vera M. Kalscheuer,Jiong Tao,A. Donnelly,Georgina Hollway,Eberhard Schwinger,S. Kübart,Corinna Menzel,Maria Hoeltzenbein,Niels Tommerup,Helen J. Eyre,Michael G. Harbord,Eric Haan,Grant R. Sutherland,Hans-Hilger Ropers,Jozef Gecz +14 more
TL;DR: A study of two severely affected female patients with apparently de novo balanced X;autosome translocations, both disrupting the serine-threonine kinase 9 (STK9) gene, shows that STK9 is subject to X-inactivation in normal female somatic cells and is functionally absent in the two patients, because of preferential inactivation of the normal X.
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