scholarly journals Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1)

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Giorgio Pini ◽  
Laura Congiu ◽  
Alberto Benincasa ◽  
Pietro DiMarco ◽  
Stefania Bigoni ◽  
...  
Keyword(s):  
Clinical Study ◽  
Cognitive Ability ◽  
Rett Syndrome ◽  
Brain Activity ◽  
Neurodevelopmental Disorder ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Cognitive Testing ◽  
Clinical Severity ◽  
Recombinant Human Insulin

Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p=0.0106) and RSS (p=0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum.

scholarly journals Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

2020 ◽  
Vol 10 (8) ◽  
pp. 515 ◽  
Author(s):  
Conor Keogh ◽  
Giorgio Pini ◽  
Ilaria Gemo ◽  
Walter E. Kaufmann ◽  
Daniela Tropea
Keyword(s):  
Clinical Response ◽  
Rett Syndrome ◽  
Network Formation ◽  
Neurodevelopmental Disorder ◽  
Clinical Manifestations ◽  
Statistical Modelling ◽  
Preliminary Evidence ◽  
Response To Treatment ◽  
Clinical Assessments ◽  
Network Measures

Rett Syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the gene MeCP2, which is involved in the development and function of cortical networks. The clinical presentation of RTT is generally severe and includes developmental regression and marked neurologic impairment. Insulin-Like growth factor 1 (IGF1) ameliorates RTT-relevant phenotypes in animal models and improves some clinical manifestations in early human trials. However, it remains unclear whether IGF1 treatment has an impact on cortical electrophysiology in line with MeCP2’s role in network formation, and whether these electrophysiological changes are related to clinical response. We performed clinical assessments and resting-state electroencephalogram (EEG) recordings in eighteen patients with classic RTT, nine of whom were treated with IGF1. Among the treated patients, we distinguished those who showed improvements after treatment (responders) from those who did not show any changes (nonresponders). Clinical assessments were carried out for all individuals with RTT at baseline and 12 months after treatment. Network measures were derived using statistical modelling techniques based on interelectrode coherence measures. We found significant interaction between treatment groups and timepoints, indicating an effect of IGF1 on network measures. We also found a significant effect of responder status and timepoint, indicating that these changes in network measures are associated with clinical response to treatment. Further, we found baseline variability in network characteristics, and a machine learning model using these measures applied to pretreatment data predicted treatment response with 100% accuracy (100% sensitivity and 100% specificity) in this small patient group. These results highlight the importance of network pathology in RTT, as well as providing preliminary evidence for the potential of network measures as tools for the characterisation of disease subtypes and as biomarkers for clinical trials.

scholarly journals Cytokine Dysregulation inMECP2- andCDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, andω-3 PUFAs

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Silvia Leoncini ◽  
Claudio De Felice ◽  
Cinzia Signorini ◽  
Gloria Zollo ◽  
Alessio Cortelazzo ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Redox Homeostasis ◽  
Clinical Severity ◽  
Cyclin Dependent Kinase ◽  
Omega 3 ◽  
Inflammatory Status ◽  
Cytokine Levels ◽  
Before And After ◽  
Cytokine Dysregulation

An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated inMECP2- (MECP2-RTT) (n=16) andCDKL5-Rett syndrome (CDKL5-RTT) (n=8), before and afterω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. InMECP2-RTT, a Th2-shifted balance was evidenced, whereas inCDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. InMECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced inCDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

scholarly journals Rett syndrome: a sex-biased neurodevelopmental disorder

2017 ◽  
Vol 39 (1) ◽  
pp. 30-33 ◽  
Author(s):  
Eyleen Goh
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorders ◽  
Expression Profiles ◽  
Neurodevelopmental Disorder ◽  
Gene Expression Profiles ◽  
Autism Spectrum ◽  
Related Disorder ◽  
Genetic Sequences ◽  
Biochemical Profiles ◽  
Males And Females

Decades of research on neurodevelopmental disorders have focused on genetics. Although there has been significant progress, the aetiology of many neurodevelopmental disorders still remains unknown. Deciphering genetic sequences of the whole genome can identify disease-causing mutations in individuals. However, the same genetic sequences do not necessarily result in similar gene expression profiles, or the consequential biochemical profiles in every cell and in all individuals. In particular, studies have shown that differential biochemical profiles in males and females, possibly play a role in neurodevelopmental disorders being biased towards a different gender. Interestingly, autism spectrum disorder (ASD) is biased towards boys although it is not an X-linked disorder, whereas Rett syndrome, an ASD-related disorder where the disease-causing gene is located on the X-chromosome, is found almost exclusively in girls.

scholarly journals The relationship of Rett syndrome and MECP2 disorders to autism

2012 ◽  
Vol 14 (3) ◽  
pp. 253-262 ◽  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Protein Product ◽  
The Many ◽  
Clinical Conditions ◽  
Relationship Of ◽  
The Relationship ◽  
Clinical Problems ◽  
Insight Into

Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.

scholarly journals Atypical Social Rank Recognition in Autism Spectrum Disorder

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shino Ogawa ◽  
Mayuko Iriguchi ◽  
Young-A Lee ◽  
Sakiko Yoshikawa ◽  
Yukiori Goto
Keyword(s):  
Autism Spectrum Disorder ◽  
Neurodevelopmental Disorder ◽  
Social Rank ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Neural Systems ◽  
Normal Children ◽  
Robust Recognition ◽  
Group Members

Abstract Social animals, including humans, structure social groups where social hierarchy exists. Recognizing social rank of other group members is a crucial ability to subsist in such environments. Here we show preliminary evidence with a relatively small number of samples that children with autism spectrum disorder, a neurodevelopmental disorder involving social dysfunction, exhibit atypical, and more robust recognition of social rank than normal children, which may be developed to compensate deficits of the neural systems processing social information.

The Effect of Prenatal Valproate Exposure in Serotonin Transporter Knockout Rats On Anxiety and Cognition: A Gene*Environment Interaction Model of Autism Spectrum Disorder

2021 ◽  
Author(s):  
◽  
Caren L. August
Keyword(s):  
Autism Spectrum Disorder ◽  
Cognitive Ability ◽  
Serotonin Transporter ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Starting Point

<p>Autism Spectrum Disorder is a complex neurodevelopmental disorder which is often associated with increased anxiety and deficits in cognitive ability. The present research investigated a potential gene*environment interaction between two factors previously implicated in ASD in a rat model; prenatal exposure to valproate (VPA) and genetic reduction of the serotonin transporter (SERT). Wildtype and heterozygous SERT knockout rats prenatally exposed to VPA or saline on gestational day12.5 (G12.5) were assessed on measures of anxiety: elevated plus-maze and novelty suppressed-feeding and cognitive ability: prepulse inhibition and latent inhibition. A significant main effect was found for VPA exposure in all paradigms, showing increased anxiety-typical behaviour and abnormal cognitive ability. However, no significant effect of genotype or interaction was observed. Results from the present study do not confirm gene*environment interaction between prenatal VPA and heterozygous SERT knockout but this may be due to several factors that are discussed within the thesis. In any case, this study represents a starting point for further studies investigating other combinations of genetic and environmental factors as models of ASD pathogenesis.</p>

Clinical, Molecular, and Computational Analysis in Patients With a Novel Double Mutation and a New Synonymous Variant in MeCP2: Report of the First Missense Mutation Within the AT-hook1 Cluster in Rett Syndrome

2017 ◽  
Vol 32 (8) ◽  
pp. 694-703 ◽  
Author(s):  
Marwa Kharrat ◽  
Yosra Kamoun ◽  
Fatma Kamoun ◽  
Emna Ellouze ◽  
Marwa Maalej ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Rett Syndrome ◽  
Phenotypic Variability ◽  
Neurodevelopmental Disorder ◽  
Clinical Severity ◽  
Bioinformatics Analyses ◽  
Double Mutation ◽  
Synonymous Variant ◽  
In Cis ◽  
The Relationship

Rett syndrome is an X-linked neurodevelopmental disorder, primarily caused by MECP2 mutations. In this study, clinical, molecular and bioinformatics analyses were performed in Rett patients to understand the relationship between MECP2 mutation type and the clinical severity. Two double MeCP2 mutations were detected: a novel one (p.G185 V in cis with p.R255X) in P1 and a known one (p.P179 S in cis with p.R255X) in P2. Besides, a novel synonymous mutation (c.807C>T; p.G269G), which could affect mRNA splicing, was identified in P3. The results from clinical severity analysis have shown that P1 was more severely affected than P2 with CSS being 35 and 14, respectively. Therefore, the phenotypic variability in P1 and P2 could be explained by the potential pathogenic effect of the RTT-causing missense mutation p.G185 V in the AT-hook1. In conclusion, clinical, molecular, and in silico investigations in the studied patients have been proven to be substantial for the genotype-phenotype correlation.

scholarly journals A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials

2020 ◽  
Vol 125 (6) ◽  
pp. 493-509
Author(s):  
Melissa Raspa ◽  
Carla M. Bann ◽  
Angela Gwaltney ◽  
Timothy A. Benke ◽  
Cary Fu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Rett Syndrome ◽  
Motor Behavior ◽  
Factor Model ◽  
Five Factor Model ◽  
Neurodevelopmental Disorder ◽  
Behavioral Assessment ◽  
Motor Dysfunction ◽  
Assessment Scale ◽  
Clinical Severity

Abstract Rett syndrome (RTT) is a neurodevelopmental disorder that primarily affects females. Recent work indicates the potential for disease modifying therapies. However, there remains a need to develop outcome measures for use in clinical trials. Using data from a natural history study (n = 1,075), we examined the factor structure, internal consistency, and validity of the clinician-reported Motor Behavior Assessment scale (MBA). The analysis resulted in a five-factor model: (1) motor dysfunction, (2) functional skills, (3) social skills, (4) aberrant behavior, and (5) respiratory behaviors. Item Response Theory (IRT) analyses demonstrated that all items had acceptable discrimination. The revised MBA subscales showed a positive relationship with parent reported items, age, and a commonly used measure of clinical severity in RTT, and mutation type. Further work is needed to evaluate this measure longitudinally and to add items related to the RTT phenotype.

Oscillations or Synchrony? Disruption of Neural Synchrony despite Enhanced Gamma Oscillations in a Model of Disrupted Perceptual Coherence

2015 ◽  
Vol 27 (12) ◽  
pp. 2416-2426 ◽  
Author(s):  
João Castelhano ◽  
Inês Bernardino ◽  
José Rebola ◽  
Eugenio Rodriguez ◽  
Miguel Castelo-Branco
Keyword(s):  
Brain Activity ◽  
Neurodevelopmental Disorder ◽  
Gamma Oscillations ◽  
Autism Spectrum ◽  
Human Model ◽  
Central Coherence ◽  
Oscillatory Activity ◽  
Neural Synchrony ◽  
Coherent Integration ◽  
Holistic Perception

It has been hypothesized that neural synchrony underlies perceptual coherence. The hypothesis of loss of central perceptual coherence has been proposed to be at the origin of abnormal cognition in autism spectrum disorders and Williams syndrome, a neurodevelopmental disorder linked with autism, and a clearcut model for impaired central coherence. We took advantage of this model of impaired holistic processing to test the hypothesis that loss of neural synchrony plays a separable role in visual integration using EEG and a set of experimental tasks requiring coherent integration of local elements leading to 3-D face perception. A profound reorganization of brain activity was identified. Neural synchrony was reduced across stimulus conditions, and this was associated with increased amplitude modulation at 25–45 Hz. This combination of a dramatic loss of synchrony despite increased oscillatory activity is strong evidence that synchrony underlies central coherence. This is the first time, to our knowledge, that dissociation between amplitude and synchrony is reported in a human model of impaired perceptual coherence, suggesting that loss of phase coherence is more directly related to disruption of holistic perception.

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization

2015 ◽  
Vol 396 (11) ◽  
pp. 1233-1240 ◽  
Author(s):  
Lucia Ciccoli ◽  
Claudio De Felice ◽  
Silvia Leoncini ◽  
Cinzia Signorini ◽  
Alessio Cortelazzo ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Morphological Changes ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Current Evidence ◽  
Loss Of Function ◽  
Beneficial Effects ◽  
Spectrum Disorders

Abstract In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a ‘model’ condition for autism spectrum disorders.

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