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 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 Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder

2021 ◽  
Vol 7 (2) ◽  
pp. e579
Author(s):  
Kenneth A. Myers ◽  
Carla Marini ◽  
Gemma L. Carvill ◽  
Amy McTague ◽  
Julie Panetta ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Sleep Disturbance ◽  
Behavioral Problems ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Epileptic Encephalopathy ◽  
Seizure Type ◽  
Convulsive Status Epilepticus ◽  
Phenotypic Spectrum ◽  
Hot Weather

ObjectiveTo describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia.MethodsWe performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures.ResultsTwenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days–13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance.ConclusionsMBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.

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 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 Rare alternative second line injectable drug resistance markers identified by gene-wise genome wide association in M. tuberculosis with unexplained resistance

2021 ◽  
Author(s):  
Derek Vanian Conkle-Gutierrez ◽  
Calvin Kim ◽  
Sarah M Ramirez-Busby ◽  
Samuel J Modlin ◽  
Mikael Mansjö ◽  
...  
Keyword(s):  
Statistical Power ◽  
Point Mutations ◽  
Kanamycin Resistance ◽  
The Novel ◽  
Second Line ◽  
Mechanisms Of Resistance ◽  
Phenotypic Resistance ◽  
Genomic Markers ◽  
Novel Association ◽  
Promoter Mutations

Point mutations in the rrs gene and eis promoter are known to confer resistance to second-line injectable drugs (SLIDs) amikacin (AMK), capreomycin (CAP), and kanamycin (KAN). While mutations in these canonical genes confer a majority of SLID-resistance, alternative mechanisms of resistance are not uncommon and threaten effective treatment decisions when using conventional molecular diagnostics. In total, 1184 clinical M. tuberculosis isolates from 7 countries were studied for genomic markers associated with phenotypic resistance. The markers rrs:A1401G and rrs:G1484T were associated with resistance to all three SLIDs, and three known markers in the eis promoter (eis:G-10A, eis:C-12T, and eis:C-14T) were similarly associated with kanamycin resistance (KAN-R). Among 325, 324, 270 AMK-R, CAP-R, and KAN-R isolates, 264 (81.2%), 250 (77.2%), and 249 (92.3%) harbored canonical mutations, respectively. Thirteen isolates harbored more than one canonical mutation. Canonical mutations did not account for 111 of the phenotypically resistant isolates. A gene-wise method identified three genes and promoters with mutations that, on aggregate, associated with unexplained resistance to at least one SLID. Our analysis associated whiB7 promoter mutations with KAN resistance, supporting clinical relevance for the previously demonstrated role of whiB7 overexpression in KAN resistance. We also provide evidence for the novel association of ppe51 (a gene previously associated with various antimicrobial compounds) with AMK resistance, and for the novel association of thrB with AMK and CAP resistance. The use of gene-wise association can provide additional insight, and therefore is recommended for identification of rare mechanisms of resistance when individual mutations carry insufficient statistical power.

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.

Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with bone disease severity in Rett syndrome

2019 ◽  
Author(s):  
Carla Caffarelli ◽  
Tomai Pitinca Maria Dea ◽  
Valentina Francolini ◽  
Roberto Canitano ◽  
felice Claudio De ◽  
...  
Keyword(s):  
Disease Severity ◽  
Rett Syndrome ◽  
Bone Disease ◽  
Binding Protein ◽  
Mecp2 Mutation ◽  
Mutation Type

scholarly journals HPV Strain Predicts Severity of Juvenile-Onset Recurrent Respiratory Papillomatosis with Implications for Disease Screening

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2556
Author(s):  
Mary C. Bedard ◽  
Alessandro de Alarcon ◽  
Yann-Fuu Kou ◽  
David Lee ◽  
Alexandra Sestito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Severity ◽  
Disease Onset ◽  
Tissue Bank ◽  
Benign Neoplasm ◽  
Recurrent Respiratory Papillomatosis ◽  
Clinical Severity ◽  
Viral Gene ◽  
Juvenile Onset ◽  
Severity Scores

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is the most common benign neoplasm of the larynx in children, presenting with significant variation in clinical course and potential for progression to malignancy. Since JoRRP is driven by human papillomavirus (HPV), we evaluated viral factors in a prospective cohort to identify predictive factors of disease severity. Twenty children with JoRRP undergoing routine debridement of papillomas were recruited and followed for ≥1 year. Demographical features, clinical severity scores, and surgeries over time were tabulated. Biopsies were used to establish a tissue bank and primary cell cultures for HPV6 vs. HPV11 genotyping and evaluation of viral gene expression. We found that patients with HPV11+ disease had an earlier age at disease onset, higher frequency of surgeries, increased number of lifetime surgeries, and were more likely to progress to malignancy. However, the amplitude of viral E6/E7 gene expression did not account for increased disease severity in HPV11+ patients. Determination of HPV strain is not routinely performed in the standard of care for JoRRP patients; we demonstrate the utility and feasibility of HPV genotyping using RNA-ISH for screening of HPV11+ disease as a biomarker for disease severity and progression in JoRRP patients.

scholarly journals The Abstruse Side of Type I Interferon Immunotherapy for COVID-19 Cases with Comorbidities

2021 ◽  
Vol 1 (1) ◽  
pp. 49-59
Author(s):  
Selvakumar Subbian
Keyword(s):  
Infectious Diseases ◽  
Disease Severity ◽  
Type I Interferon ◽  
Host Factors ◽  
Type I ◽  
The Novel ◽  
Inflammatory Drugs ◽  
Precautionary Measures ◽  
Inducible Genes

The Coronavirus Disease-2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed 1.2 million people globally since December 2019. Although the host factors underpinning COVID-19 pathology are not fully understood, type I interferon (IFN-I) response is considered crucial for SARS-CoV-2 pathogenesis. Perturbations in IFN-I signaling and associated interferon-inducible genes (ISG) are among the primary disease severity indicators in COVID-19. Consequently, IFN-I therapy, either alone or in- combination with existing antiviral or anti-inflammatory drugs, is tested in many ongoing clinical trials to reduce COVID-19 mortality. Since signaling by the IFN-I family of molecules regulates host immune response to other infectious and non-infectious diseases, any imbalance in this family of cytokines would impact the clinical outcome of COVID-19, as well as other co-existing diseases. Therefore, it is imperative to evaluate the beneficial-versus-detrimental effects of IFN-I immunotherapy for COVID-19 patients with divergent disease severity and other co-existing conditions. This review article summarizes the role of IFN-I signaling in infectious and non-infectious diseases of humans. It highlights the precautionary measures to be considered before administering IFN-I to COVID-19 patients having other co-existing disorders. Finally, suggestions are proposed to improve IFN-I immunotherapy to COVID-19.

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