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 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 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 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 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 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.

scholarly journals Rett syndrome: Novel correlations linking >96% genotype, disease severity, and seizures

2020 ◽  
pp. 1-11
Author(s):  
Lourdes M. Rodriguez ◽  
Alan K. Percy ◽  
Gary R. Cutter
Keyword(s):  
Disease Severity ◽  
Rett Syndrome ◽  
Seizure Frequency ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Severity ◽  
Seizure Type ◽  
The Novel ◽  
Generalized Seizures ◽  
Novel Association

BACKGROUND: Rett Syndrome (RTT), an incurable neurodevelopmental disorder associated in >96% with the X-linked gene, MECP2 includes seizures, among its most difficult issues, impacting many features and increasing morbidity and mortality. Linking these seizures with clinical severity in RTT is critical for estimating risk and guiding therapy. OBJECTIVE: Our primary purpose was to identify associations between type and frequency of seizures, disease severity, and specific MECP2 mutations to address the hypothesis that seizure frequency correlates with specific mutations and directly impacts clinical severity. METHODS: Mutation, seizure type and frequency, and clinical severity assessed by the Clinical Severity Scale (CSS) were extracted from the 5211 Natural History Study of Rett Syndrome and Related Disorders [1]. This involved observations from 222 Persons with classic or variant RTT and MECP2 mutation positive non-Rett diagnoses. Descriptive analyses were assessed utilizing SPSS software. Mutations include R106W, R133C, R168X, R294X, R306C, other point mutations, and early truncations. RESULTS: Greater frequency of generalized seizures and seizures of any type were associated with R106W mutations; R168X mutations had the highest disease severity, and R133C mutations had the lowest disease severity. CONCLUSION: Important correlations exist across several common MECP2 mutations, including the novel association between generalized seizure frequency and mild CSS.

scholarly journals Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome

2021 ◽  
Vol 22 (8) ◽  
pp. 4240
Author(s):  
Cinzia Signorini ◽  
Silvia Leoncini ◽  
Thierry Durand ◽  
Jean-Marie Galano ◽  
Alexandre Guy ◽  
...  
Keyword(s):  
Disease Progression ◽  
Gene Mutation ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Biological Significance ◽  
Clinical Severity ◽  
Stage Ii ◽  
Disease Stage ◽  
Mecp2 Gene ◽  
Mecp2 Mutation

Neuroprostanes, a family of non-enzymatic metabolites of the docosahexaenoic acid, have been suggested as potential biomarkers for neurological diseases. Objective biological markers are strongly needed in Rett syndrome (RTT), which is a progressive X-linked neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene with a predominant multisystemic phenotype. The aim of the study is to assess a possible association between MECP2 mutations or RTT disease progression and plasma levels of 4(RS)-4-F4t-neuroprostane (4-F4t-NeuroP) and 10(RS)-10-F4t-neuroprostane (10-F4t-NeuroP) in typical RTT patients with proven MECP2 gene mutation. Clinical severity and disease progression were assessed using the Rett clinical severity scale (RCSS) in n = 77 RTT patients. The 4-F4t-NeuroP and 10-F4t-NeuroP molecules were totally synthesized and used to identify the contents of the plasma of the patients. Neuroprostane levels were related to MECP2 mutation category (i.e., early truncating, gene deletion, late truncating, and missense), specific hotspot mutations (i.e., R106W, R133C, R168X, R255X, R270X, R294X, R306C, and T158M), and disease stage (II through IV). Circulating 4-F4t-NeuroP and 10-F4t-NeuroP were significantly related to (i) the type of MECP2 mutations where higher levels were associated to gene deletions (p ≤ 0.001); (ii) severity of common hotspot MECP2 mutation (large deletions, R168X, R255X, and R270X); (iii) disease stage, where higher concentrations were observed at stage II (p ≤ 0.002); and (iv) deficiency in walking (p ≤ 0.0003). This study indicates the biological significance of 4-F4t-NeuroP and 10-F4t-NeuroP as promising molecules to mark the disease progression and potentially gauge genotype–phenotype associations in RTT.

Serotonin Dysfunction in Pathological Gamblers: Increased Prolactin Response to Oral m-CPP Versus Placebo

CNS Spectrums ◽  
2006 ◽  
Vol 11 (12) ◽  
pp. 956-965 ◽  
Author(s):  
Stefano Pallanti ◽  
Silvia Bernardi ◽  
Leonardo Quercioli ◽  
Concetta DeCaria ◽  
Eric Hollander
Keyword(s):  
Clinical Severity ◽  
Acute Administration ◽  
Double Blind ◽  
Pathological Gamblers ◽  
Healthy Control ◽  
Cortisol Responses ◽  
Gambling Severity ◽  
Prolactin Response ◽  
The Relationship

ABSTRACTObjectiveAcute administration of the partial serotonin (5-HT) agonist meta-chlorophenylpi-perazine (m-CPP), that is used also as a street drug, has been reported to induce a “high” and craving response in various impulsive and sub-stance addiction disorders.IntroductionTo clarify altered 5-HT metabolism in pathological gamblers and to explore the specific role of serotonergic system in non substance addictions, we assessed behavioral (“high” and “craving”) and neuroendocrine (prolactin and cortisol) responses to an oral single dose of m-CPP and placebo in pathological gamblers and matched controls. Moreover, the relationship between neuroendocrine outcome and clinical severity has been assessed.MethodTwenty-six pathological gamblers and 26 healthy control subjects enter a double-blind, placebo-controlled-crossed administration of orally dose m-CPP 0.5 mg/kg. Outcome measures included prolactin and cortisol levels, gambling severity, mood, craving and “high” scales.ResultsPathological gamblers had significantly increased prolactin response compared to controls at 180 minutes and at 210 minutes post–administration. Greater pathological gamblers severity correlated with increased neuroendocrine responsiveness to m-CCP, suggesting greater 5-HT dysregulation. Pathological gambling patients had a significantly increased “high” sensation after m-CPP administration compared with control.ConclusionThese results provide additional evidence for 5-HT disturbance in pathological gamblers and they support the hypotheses that the role of the 5-HT dysfunction related to the experience of “high” might represent the path-way that leads to dyscontrolled behavior in patho-logical gamblers. Furthermore, the “high” feeling induced by m-CPP in pathological subjects may represent a marker of vulnerability to both behav-ioral and substance addictions.

Ty1 in vitro integration: effects of mutations in cis and in trans

1994 ◽  
Vol 14 (9) ◽  
pp. 5731-5740
Author(s):  
L T Braiterman ◽  
J D Boeke
Keyword(s):  
Missense Mutation ◽  
Frameshift Mutations ◽  
Amino Terminal ◽  
Dna Molecule ◽  
Conserved Domain ◽  
In Trans ◽  
In Cis ◽  
Obvious Similarity ◽  
Insertion Mutations

Mutations within the TYB gene of Ty1 encoding integrase (IN) as well as alterations in its substrate, a linear DNA molecule, were examined for their effects on in vitro IN activity, using a recently developed physical assay. Five different codon-insertion mutations, two frameshift mutations, and one missense mutation, previously identified as transposition-deficient mutations, were tested. Virus-like particles, the source of IN, from two different protease mutants and a reverse transcriptase mutant exhibited near-normal to normal IN activity. Two frameshift mutations mapping within the phylogenetically variable C-terminal domain of IN resulted in significant in vitro IN activity. In contrast, three mutations within the amino-terminal conserved domain of IN completely abolished IN activity. When the substrate termini were mutated, we found that substrates with as few as 4 bp of Ty1 termini were capable of efficiently generating integration products. Surprisingly, certain substrates that lacked obvious similarity to Ty1 termini were also readily integrated into both linear and circular targets, whereas others were not used as substrates at all. Termini rich in adenosine residues were among the more active substrates; however, certain substrates lacking terminal adenosine residues can form small quantities of integration products, including complete integration reactions.

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