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"Kabuki"
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Kabuki syndrome: international consensus diagnostic criteria
BackgroundKabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A. Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal.MethodsAn international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed.ResultsThe authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented.ConclusionAs targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.
Journal Article
Creating Kabuki Plays
This volume makes available for the first time a complete translation in English of a key text for our understanding of Kabuki, viz. Kezairoku, Sakusha Shikihô (Valuable Notes on Playwriting, A Playwrights’ Methodology, written 1801), being the only extant treatise fully devoted to the subject of Kabuki playwriting. At the hand of this vital text, the author addresses the history, methodology, and practitioners of Kabuki playwriting of the Edo Period (1603-1867.) The reader will find a critical examination of Kezairoku, and discussions regarding the connections between the Kabuki and literary worlds of Edo Japan, and between playwriting and the oral arts. The availability of the entire Kezairoku in English, together with a full contextualization of its teachings and meanings, offers a volume of great significance to both Japan and theatre scholars.
eBook
Immune thrombocytopenia in Kabuki syndrome, a comparison with non-Kabuki cases in the UK paediatric ITP registry
Background
This study aims to compare the clinical presentation of Immune Thrombocytopenia (ITP) in children with Kabuki syndrome (KS) to those with sporadic ITP in the UK Paediatric ITP Registry. The Margot et al. analysis of a Kabuki database identified that children with KS had higher rates of chronic ITP and of other haematological abnormalities. This study aims to identify if children with KS do exhibit these features compared to the sporadic ITP population using data from the UK Paediatric ITP Registry between January 2006 and February 2020.
Results
Of 2013 ITP patients, five had a confirmed diagnosis of KS, representing a 0.25% prevalence (95% CI = 0.031 – 0.47%). The relative prevalence of ITP in KS was estimated at 79 (95% CI = 10–149,
p
< 0.0001). Clinical presentations were similar between KS and non-KS children, with non-significant differences in severity of bleeding and platelet counts. One KS patient exhibited chronic ITP and another presented with symptoms not exclusively attributable to thrombocytopenia.
Conclusions
Our findings suggest that the clinical presentation and course of ITP in children with KS are comparable to those of general ITP patients. Despite the elevated risk of ITP in KS, the manifestations of the condition do not differ significantly.
Journal Article
Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms
Background
Kabuki syndrome (KS), is a infrequent inherited malformation syndrome caused by mutations in a H3 lysine 4 methylase (
KMT2D
) or an X-linked histone H3 lysine 27 demethylase (UTX/
KDM6A
). The characteristics in patients with KS have not yet been well recognized.
Data sources
We used databases including PubMed and Google Scholar to search for publications about the clinical features and the etiology of Kabuki syndrome. The most relevant articles to the scope of this review were chosen for analysis.
Results
Clinical diagnosis of KS is challenging in initial period, because many clinical characteristics become apparent only in subsequent years. Recently, the genetic and functional interaction between KS-associated genes and their products have been elucidated. New clinical findings were reported including nervous system and intellectual performance, endocrine-related disorders and immune deficiency and autoimmune disease. Cancer risks of Kabuki syndrome was reviewed. Meanwhile, we discussed the Kabuki-like syndrome. Digital clinical genetic service, such as dysmorphology database can improve availability and provide high-quality diagnostic services. Given the significant clinical relevance of KS-associated genes and epigenetic modifications crosstalk, efforts in the research for new mechanisms are thus of maximum interest.
Conclusions
Kabuki syndrome has a strong clinical and biological heterogeneity. The main pathogenesis of Kabuki syndrome is the imbalance between switch-on and -off of the chromatin. The direction of drug research may be to regulate the normal opening of chromatin. Small molecule inhibitors of histone deacetylases maybe helpful in treatment of mental retardation and reduce cancer risk in KS.
Journal Article
KMT2C/D COMPASS complex-associated diseases KCDCOM-ADs: an emerging class of congenital regulopathies
The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [
KMT2D
] and 2 [
KDM6A
]), Rubinstein-Taybi syndrome (type 1 [
CBP
] and 2 [
EP300
]), and Kleefstra syndrome type 2 (
KMT2C
). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.
Journal Article
A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in Kabuki syndrome
Kabuki syndrome (KS) is associated with hyperinsulinemic hypoglycemia (HH) in 0.3–4% of patients, thus exceeding the prevalence in the general population. HH association is stronger for KS type 2 (KDM6A-KS, OMIM #300867) than KS type 1 (KMT2D-KS, OMIM #147920). Both the disease-associated genes, KMD6A and KMT2D, modulate the chromatin dynamic. As such, KS is considered to be the best characterized pediatric chromatinopathy. However, the exact pathogenetic mechanisms leading to HH in this syndrome remain still unclear.
We selected on the electronic database PubMed all articles describing or hypothesizing the mechanisms underlying the dysregulated insulin secretion in KS.
The impact on the gene expression due to the KDM6A or KMT2D function loss may lead to a deregulated pancreatic β-cell differentiation during embryogenesis. Moreover, both KMT2D gene and KDM6A gene are implicated in promoting the transcription of essential pancreatic β-cell genes and in regulating the metabolic pathways instrumental for insulin release. Somatic KMT2D or KDM6A mutations have also been described in several tumor types, including insulinoma, and have been associated with metabolic pathways promoting pancreatic cell proliferation.
The impact of pathogenic variants in KDM6A and KDM2D genes on β-cell insulin release remains to be fully clarified. Understanding this phenomenon may provide valuable insight into the physiological mechanisms of insulin release and into the pathological cascade causing hyperinsulinism in KS. The identification of these molecular targets may open new therapeutic opportunities based on epigenetic modifiers.
Journal Article