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Journal of Autism and Developmental... May 2024Rett syndrome (RTT) is a rare multi-systemic disorder primarily linked to mutations in MECP2 gene. This study aims to describe the prevalence of orthopedic conditions in...
PURPOSE
Rett syndrome (RTT) is a rare multi-systemic disorder primarily linked to mutations in MECP2 gene. This study aims to describe the prevalence of orthopedic conditions in RTT patients, and examine their intricate interplay with functional capabilities, and MECP2 variant subtypes.
METHODS
Conducted as a cross-sectional retrospective observational study, the research encompassed 55 patients meeting clinical RTT criteria and holding MECP2 mutations. A review of clinical records was performed to gather demographic data, mutation subtypes, orthopedic conditions, management strategies, and assessments of function.
RESULTS
Mean age of the participants was 10.22 ± 4.64 years (range, 2.9-19.41). Prevalence rates of orthopedic conditions were as follows: kyphoscoliosis 63.6%, hip displacement 14.6%, knee problems 40%, and foot deformities 75.5%. Significant relationship emerged between spinal (p < 0.01) and knee deformities (p < 0.01) with reduced motor function across various domains. Hip displacement significantly affected sitting ability (p = 0.002), and foot deformities impacted standing and walking capabilities (p = 0.049). Mutation clusters analysis revealed significant correlations with spinal (p = 0.022) and knee deformities (p = 0.002). Linear models highlighted the critical importance of mutation clusters, spine deformities, age, and hip management concerning functional variables.
CONCLUSIONS
In this study, foot deformities were the most frequent orthopedic manifestation, followed by spinal, knee, and hip deformities; and unveiled their relationships with functional status and groups of mutations in RTT patients.
LEVEL OF EVIDENCE
Level IV, Case series.
PubMed: 38795288
DOI: 10.1007/s10803-024-06399-y -
Genes May 2024Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene (). Most...
Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene (). Most often, the disease causing the allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI), resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known genotype effects and an age-dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity, allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on genotype with a correlation between XCI and severity observed only in individuals with variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.
Topics: Rett Syndrome; X Chromosome Inactivation; Humans; Methyl-CpG-Binding Protein 2; Female; Child; Severity of Illness Index; Chromosomes, Human, X; Genotype; Child, Preschool; Adolescent; Adult; Male; Alleles; Young Adult
PubMed: 38790223
DOI: 10.3390/genes15050594 -
Disease Models & Mechanisms Jun 2024Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes,...
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.
Topics: Animals; Rett Syndrome; Dendritic Spines; Female; Phenotype; Receptor, trkB; Methyl-CpG-Binding Protein 2; Behavior, Animal; Ligands; Pyramidal Cells; Mice; Brain-Derived Neurotrophic Factor; Hippocampus; Heterozygote; Mice, Inbred C57BL; Disease Models, Animal; Benzamides
PubMed: 38785269
DOI: 10.1242/dmm.050612 -
American Journal of Medical Genetics.... May 2024Typical (or classic) Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by a period of regression, partial or complete loss of purposeful hand...
Typical (or classic) Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by a period of regression, partial or complete loss of purposeful hand movements, and acquired speech, impaired gait, and stereotyped hand movements. In over 95% of typical RTT, a pathogenic variant is found in the methyl-CPG binding protein 2 gene (MECP2). Here, we describe a young woman with clinically diagnosed typical RTT syndrome who lacked a genetic diagnosis despite 20 years of investigation and multiple rounds of sequencing the MECP2 gene. Recently, additional genetic testing using next-generation sequencing was completed, which revealed a partial insertion of the BCL11A gene within exon 4 of MECP2, resulting in a small deletion in MECP2, causing likely disruption of MeCP2 function due to a frameshift. This case demonstrates the ever-changing limitations of genetic testing, as well as the importance of continual pursuit of a diagnosis as technologies improve and are more widely utilized.
PubMed: 38775384
DOI: 10.1002/ajmg.a.63725 -
Neurological Sciences : Official... May 2024Rett syndrome (RTT) is an uncommon inherited neurodevelopmental disorder that affects brain development, mostly in females. It results from mutation in MECP2 gene in the... (Review)
Review
BACKGROUND
Rett syndrome (RTT) is an uncommon inherited neurodevelopmental disorder that affects brain development, mostly in females. It results from mutation in MECP2 gene in the long arm (q) of the X chromosome.
OBJECTIVE
Trofinetide is a recently developed drug that has a neuroprotective effect on neurons, and it is our aim in this meta-analysis to evaluate its efficacy and safety in treating Rett syndrome patients.
METHODS
We searched 5 databases (PubMed, Scopus, Embase, Web of Science, and Cochrane Library databases) to identify randomized controlled trials (RCTs) comparing Trofinetide and placebo in patients with Rett syndrome until August 13, 2023.Our primary outcomes were the Clinical Global Impression-Improvement (CGI) and the Rett syndrome Behavior Questionnaire (RSBQ). We used Risk of Bias Assessment tool-2 (ROB2) to assess the methodological quality of the included randomized controlled trials.
RESULTS
Three RCTs with a total of 325 patients were included with a follow-up duration ranging from one month to three months. 186 patients received the intervention drug (Trofinetide) and 138 received the placebo. Trofinetide was found to reduce CGI and RSBQ significantly more than placebo (MD = -0.35, 95% CI [-0.52 to -0.18], P 0.0001), (MD = -3.40, 95% CI [-3.69 to -3.12], P 0.00001) respectively. Most adverse events did not show any statistical difference between Trofinetide and the placebo.
CONCLUSION
Trofinetide offers promise as a potential effective and safe therapeutic opportunity for a population without many available treatments, with improvements seen on both CGI and RSBQ assessments and no severe adverse effects reported.
PubMed: 38771525
DOI: 10.1007/s10072-024-07584-8 -
The European Journal of Neuroscience May 2024MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by the gain of dose of at least the genes MECP2 and IRAK1 and is characterised by...
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by the gain of dose of at least the genes MECP2 and IRAK1 and is characterised by intellectual disability (ID), developmental delay, hypotonia, epilepsy and recurrent infections. It mainly affects males, and females can be affected or asymptomatic carriers. Rett syndrome (RTT) is mainly triggered by loss of function mutations in MECP2 and is a well described syndrome that presents ID, epilepsy, lack of purposeful hand use and impaired speech, among others. As a result of implementing omics technology, altered biological pathways in human RTT samples have been reported, but such molecular characterisation has not been performed in patients with MDS. We gathered human skin fibroblasts from 17 patients with MDS, 10 MECP2 duplication carrier mothers and 21 patients with RTT, and performed multi-omics (RNAseq and proteomics) analysis. Here, we provide a thorough description and compare the shared and specific dysregulated biological processes between the cohorts. We also highlight the genes TMOD2, SRGAP1, COPS2, CNPY2, IGF2BP1, MOB2, VASP, FZD7, ECSIT and KIF3B as biomarker and therapeutic target candidates due to their implication in neuronal functions. Defining the RNA and protein profiles has shown that our four cohorts are less alike than expected by their shared phenotypes.
PubMed: 38746988
DOI: 10.1111/ejn.16389 -
European Journal of Paediatric... May 2024This study evaluated the receptive vocabulary of girls diagnosed with Rett Syndrome (RS) by employing eye-tracking technology and examined how these objective measures...
OBJECTIVE
This study evaluated the receptive vocabulary of girls diagnosed with Rett Syndrome (RS) by employing eye-tracking technology and examined how these objective measures compared with parents' perceptions of their daughters' language abilities.
METHOD
Fourteen girls with RS and eleven typically developing peers participated. Instruments included the Kerr Scale, a parental questionnaire on communication skills, the Peabody Picture Vocabulary Test - PPVT-4, and eye-tracking equipment. The PPVT-4's initial 12 cards, each displaying four images, were presented on screen for 5 s for the child's initial inspection. Subsequently, the same card was shown for 5 s with instructions to identify the picture matching the word, repeated three times in a randomized order.
RESULTS
Eye-tracking assessments revealed that girls with RS with less severe symptoms, performed below typically developing peers with aged 3-4 years. The number of eye fixations emerged as a reliable metric for assessing their performance. A positive correlation was found between parental reports of their daughters' vocabulary knowledge and their ability to identify the correct stimulus, suggesting comprehension and active engagement in the testing process.
CONCLUSION
This study presents a pioneering approach by combining parental perceptions with eye-tracking measures to assess receptive vocabulary in girls diagnosed with Rett Syndrome. Despite showing lower performance levels compared to significantly younger peers, the findings suggest that these individuals use less effectively eye contact as a mode of communication.
PubMed: 38729045
DOI: 10.1016/j.ejpn.2024.05.001 -
Developmental Neuroscience May 2024Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). After gene transfer in... (Review)
Review
BACKGROUND
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). After gene transfer in mice, exogenous MeCP2 expression must be regulated to avoid dose-dependent toxicity.
SUMMARY
The preclinical gene therapy literature for treating RTT illustrates a duly diligent progression that begins with proof-of-concept studies and advances toward the development of safer, regulated MECP2 viral genome designs. This design progression was partly achieved through international collaborative studies. In 2023, clinicians administered investigational gene therapies for RTT to patients a decade after the first preclinical gene therapy publications for RTT (clinical trial numbers NCT05606614 and NCT05898620). As clinicians take on a more prominent role in MECP2 gene therapy research, preclinical researchers may continue to test more nuanced hypotheses regarding the safety, efficacy, and mechanism of MECP2 gene transfer.
KEY MESSAGE
This review summarizes the history of preclinical MECP2 gene transfer for treating RTT and acknowledges major contributions among colleagues in the field. The first clinical injections are a shared milestone.
PubMed: 38723617
DOI: 10.1159/000539267 -
Pediatric Pulmonology May 2024Despite the publication of the 2020 guidelines on how to manage Rett Syndrome (RS), some fundamental topics are still open, in particular respiratory problems.
BACKGROUND
Despite the publication of the 2020 guidelines on how to manage Rett Syndrome (RS), some fundamental topics are still open, in particular respiratory problems.
OBJECTIVE
Identification and reinforcement of current recommendations concerning the management of respiratory issues in RS patients.
MATERIALS AND METHODS
Using a Delphi approach, the leading group reviewed the literature and formulated 14 statements. A multidisciplinary panel of 29 experts were invited to score, for each statement, their agreement on a 1-5 scale. The cut-off level for consensus was 75%, obtained through multiple rounds.
RESULTS
The panel agreed that in all RS types, respiratory issues should be faced at an early stage, regardless of epilepsy onset. It is recommended to perform periodically sleep studies in all Congenital Rett Syndrome, and in selected cases with other RS types. Noninvasive ventilation should be considered in all RS subjects with sleep respiratory disorders and in those with hypotonia associated with hypercapnia. Chest physiotherapy should be performed in all RS patients with difficult management of the accumulation of respiratory secretions, using airway clearance techniques and devices (PEP-mask, AMBU bag, or cough machine), more appropriate and tolerated by the patients. The panel recommended individualized programs for the management of scoliosis, and to consider performing gastrostomy in patients at increased risk of ab ingestis pneumonia.
CONCLUSIONS
This consensus could support everyday clinical practice on respiratory issues in RS patients, complementary to existing recommendations by regulatory agencies and guidelines.
PubMed: 38721909
DOI: 10.1002/ppul.27030 -
Annals of Neurology Jul 2024This study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders...
OBJECTIVE
This study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders and to assess the potential for these features to act as objective measures of cortical function for Rett syndrome (RTT).
METHODS
EEG amplitude and power features were derived from the resting EEG of 60 females with RTT (median age = 10.7 years) and 26 neurotypical females (median age = 10.6 years). Analyses focus on group differences and within the RTT group, associations between the EEG parameters and clinical severity. For a subset of participants (n = 20), follow-up data were available for assessing the reproducibility of the results and the stability in the parameters over 1 year.
RESULTS
Compared to neurotypical participants, participants with RTT had greater amplitude variability and greater low-frequency activity as reflected by greater delta power, more negative 1/f slope, and lower theta/delta, alpha/delta, beta/delta, alpha/theta, and beta/theta ratios. Greater delta power, more negative 1/f slope, and lower power ratios were associated with greater severity. Analyses of year 1 data replicated the associations between 1/f slope and power ratios and clinical severity and demonstrated good within-subject consistency in these measures.
INTERPRETATION
Overall, group comparisons reflected a greater predominance of lower versus higher frequency activity in participants with RTT, which is consistent with prior clinical interpretations of resting EEG in this population. The observed associations between the EEG power measures and clinical assessments and the repeatability of these measures underscore the potential for EEG to provide an objective measure of cortical function and clinical severity for RTT. ANN NEUROL 2024;96:175-186.
Topics: Humans; Female; Electroencephalography; Child; Adolescent; Severity of Illness Index; Rett Syndrome; Young Adult; Adult; Brain Waves; Reproducibility of Results
PubMed: 38721759
DOI: 10.1002/ana.26948