scholarly journals Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc) IgM Antibody Fraction

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Anna Maria Papini ◽  
Francesca Nuti ◽  
Feliciana Real-Fernandez ◽  
Giada Rossi ◽  
Caterina Tiberi ◽  
...  
Keyword(s):  
Immune System ◽  
Rett Syndrome ◽  
Pervasive Developmental Disorders ◽  
Developmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Antibody Recognition ◽  
Forkhead Box ◽  
Significant Difference

Rett syndrome (RTT), a neurodevelopmental disorder affecting exclusively (99%) female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) and, more rarely, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1). In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM) in RTT patients (n=53) and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (n=82) and healthy age-matched controls (n=29). To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc), a syntheticN-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc) assay (P=0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology.

scholarly journals Subclinical Inflammatory Status in Rett Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Alessio Cortelazzo ◽  
Claudio De Felice ◽  
Roberto Guerranti ◽  
Cinzia Signorini ◽  
Silvia Leoncini ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Rett Syndrome ◽  
De Novo ◽  
Clinical Chemistry ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Protein Levels ◽  
Large Deletions ◽  
Inflammatory Status

Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused byde novoloss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., “pseudo-autistic”) RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four majorMECP2gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h,P<0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P=0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n=6spots) or negative (n=9spots), and to a lesser extent as proteins involved in the immune system (n=2spots), with some proteins having overlapping functions on metabolism (n=7spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by theMECP2gene mutation.

scholarly journals Sphingolipid Metabolism Perturbations in Rett Syndrome

Metabolites ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 221 ◽  
Author(s):  
Cappuccio ◽  
Donti ◽  
Pinelli ◽  
Bernardo ◽  
Bravaccio ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Metabolic Profiling ◽  
Neurodevelopmental Disorder ◽  
Sphingolipid Metabolism ◽  
Tandem Mass ◽  
Mecp2 Gene ◽  
Loss Of Function ◽  
Disease Pathogenesis ◽  
Blood Samples ◽  
Disease Biomarkers

Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying MECP2 mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers.

scholarly journals Inflammatory Lung Disease in Rett Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Claudio De Felice ◽  
Marcello Rossi ◽  
Silvia Leoncini ◽  
Glauco Chisci ◽  
Cinzia Signorini ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Upper Airway ◽  
Redox Status ◽  
Null Mouse ◽  
Gene Encoding ◽  
Respiratory Dysfunction ◽  
Lung Histology ◽  
Reduced And Oxidized Glutathione ◽  
Major Target

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n= 228) and to examine lung histology in aMecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228) of patients versus ~18% of healthy controls, with “high” (39.8%) and “low” (34.8%) patterns dominating over “mixed” (19.6%) and “simple mismatch” (5.9%) types. Increased plasma levels of non-protein-bound iron (NPBI), F2-isoprostanes (F2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examinedMecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.

scholarly journals Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mirko Luoni ◽  
Serena Giannelli ◽  
Marzia Tina Indrigo ◽  
Antonio Niro ◽  
Luca Massimino ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Protein Translation ◽  
Mutant Mice ◽  
Gene Encoding ◽  
Strong Immune Response ◽  
Intravenous Injections ◽  
Protein Levels ◽  
Mecp2 Protein ◽  
The Brain

Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.

scholarly journals Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gabrielle L. Sell ◽  
Wendy Xin ◽  
Emily K. Cook ◽  
Mark A. Zbinden ◽  
Thomas B. Schaffer ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Developmental Disorders ◽  
Motor Coordination ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Behavioral Deficits ◽  
Altered Expression ◽  
Exciting Potential

AbstractIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

scholarly journals Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Syouichi Katayama ◽  
Noriyuki Sueyoshi ◽  
Tetsuya Inazu ◽  
Isamu Kameshita
Keyword(s):  
Catalytic Activity ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Cyclin Dependent Kinase ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Transcriptional Mapping ◽  
Target Molecules ◽  
New Treatment ◽  
The Relationship

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.

scholarly journals Evidence based case report: Pyridoxine supplementation in children with pervasive developmental disorders

2014 ◽  
Vol 54 (3) ◽  
pp. 186
Author(s):  
Sekarpramita Darmaputri ◽  
Tjhin Wiguna
Keyword(s):  
Serotonin Receptors ◽  
Pervasive Developmental Disorders ◽  
Developmental Disorders ◽  
Developmental Disorder ◽  
Social Withdrawal ◽  
Neurodevelopmental Disorder ◽  
Psychotropic Medications ◽  
The Other ◽  
Evidence Based ◽  
Atypical Autism

Pervasive developmental disorders (PDD)is defined as a neurodevelopmental disorder,c haract erized by social withdrawal,communication deficits, and repetitivebehaviors. PDD include autistic disorder, Rett'ssyndrome, childhood disintegrative disorder, Asperger' ssyndrome, and pervasive developmental disorder nototherwise specified or atypical autism.1 Update ofepidemiological studies published between 1966 and2006 show reports of estimated prevalence for autismhas varied between 3 .31 and 86 children per 10,000, 2and predominantly occurs in males than females(male:female ratio = 4: 1) .3There is a hypothesis that behavioral problemsin children with pervasive developmental disorderare highly associated with the neurotransmitterimbalances. Therefore, psychotropic medications (eg.atypical antipsychotics, selective serotonin reuptakeinhibitors, and psychostimulants), which work ondopamine and serotonin receptors, are the FDAapprovedmedications for PDD.4 On the other hands,the use of novel, unconventional, and/or off- labeltreatments associated with the n eurotransmitterspathway for children with POD is increasing andmore common.

scholarly journals In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment

2019 ◽  
Vol 20 (22) ◽  
pp. 5593 ◽  
Author(s):  
Muhamad Fahmi ◽  
Gen Yasui ◽  
Kaito Seki ◽  
Syouichi Katayama ◽  
Takako Kaneko-Kawano ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Structural Characteristics ◽  
Neurodevelopmental Disorder ◽  
Cyclin Dependent Kinase ◽  
Disordered Structure ◽  
Molecular Features ◽  
Forkhead Box ◽  
In Silico Study ◽  
Repressor Complex ◽  
Phylogenetic Profiling

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order–disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT.

scholarly journals JNK signaling provides a novel therapeutic target for Rett syndrome

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Clara Alice Musi ◽  
Anna Maria Castaldo ◽  
Anna Elisa Valsecchi ◽  
Sara Cimini ◽  
Noemi Morello ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Clinical Symptoms ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Jnk Signaling ◽  
Functional Changes ◽  
Jnk Activation ◽  
Stress Pathway

Abstract Background Rett syndrome (RTT) is a monogenic X-linked neurodevelopmental disorder characterized by loss-of-function mutations in the MECP2 gene, which lead to structural and functional changes in synapse communication, and impairments of neural activity at the basis of cognitive deficits that progress from an early age. While the restoration of MECP2 in animal models has been shown to rescue some RTT symptoms, gene therapy intervention presents potential side effects, and with gene- and RNA-editing approaches still far from clinical application, strategies focusing on signaling pathways downstream of MeCP2 may provide alternatives for the development of more effective therapies in vivo. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) stress pathway in the pathogenesis of RTT using different animal and cell models and evaluate JNK inhibition as a potential therapeutic approach. Results We discovered that the c-Jun N-terminal kinase (JNK) stress pathway is activated in Mecp2-knockout, Mecp2-heterozygous mice, and in human MECP2-mutated iPSC neurons. The specific JNK inhibitor, D-JNKI1, promotes recovery of body weight and locomotor impairments in two mouse models of RTT and rescues their dendritic spine alterations. Mecp2-knockout presents intermittent crises of apnea/hypopnea, one of the most invalidating RTT pathological symptoms, and D-JNKI1 powerfully reduces this breathing dysfunction. Importantly, we discovered that also neurons derived from hiPSC-MECP2 mut show JNK activation, high-phosphorylated c-Jun levels, and cell death, which is not observed in the isogenic control wt allele hiPSCs. Treatment with D-JNKI1 inhibits neuronal death induced by MECP2 mutation in hiPSCs mut neurons. Conclusions As a summary, we found altered JNK signaling in models of RTT and suggest that D-JNKI1 treatment prevents clinical symptoms, with coherent results at the cellular, molecular, and functional levels. This is the first proof of concept that JNK plays a key role in RTT and its specific inhibition offers a new and potential therapeutic tool to tackle RTT.

scholarly journals Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

2019 ◽  
Author(s):  
Gabrielle L. Sell ◽  
Wendy Xin ◽  
Emily K. Cook ◽  
Mark A. Zbinden ◽  
Thomas B. Schaffer ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Angelman Syndrome ◽  
Developmental Disorders ◽  
Motor Coordination ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Altered Expression ◽  
Exciting Potential

ABSTRACTIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in >1-2% of patients with autism spectrum disorders – a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 is a direct substrate of UBE3A ubiquitin ligase activity. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

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