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Frontiers in Public Health 2024The main aim of the present study was to examine whether the use of a low-tech tool, called click4all, inserted into cognitive and motor training can increase social... (Observational Study)
Observational Study Randomized Controlled Trial
INTRODUCTION
The main aim of the present study was to examine whether the use of a low-tech tool, called click4all, inserted into cognitive and motor training can increase social interaction of patients with Rett Syndrome (RTT) with classmates in a school setting.
METHODS
Twenty-seven participants with RTT were randomly assigned to two groups: the experimental group received treatment with click4all, and the control group received traditional treatment without click4all. Parameters were measured before treatment (T1), 6 months after treatment (T2), 6 months after the second treatment phase (T3) and at the end of the third treatment phase (T4).
RESULTS
The results demonstrated an increase in levels of social interaction among classmates and patients with RTT in the experimental group, over time, compared to the control group, 95% CI [5.20-15.30]. Classmates also showed a higher level of knowledge related to participants of the experimental group, and this increased over time, 95% CI [24.98-63.52]. The level of knowledge related to the control group was stable over time and lower than the experimental group.
DISCUSSION
This study demonstrated that the use of a low-tech tool can increase social interactions of patients with RTT in a school setting. This is important, as patients with RTT are often restricted in an isolation condition.
Topics: Humans; Rett Syndrome; Female; Social Interaction; Child; Adolescent; Male; Schools
PubMed: 38645452
DOI: 10.3389/fpubh.2024.1353099 -
Frontiers in Genetics 2024Rett syndrome (RTT, MIM #312750) is a rare genetic disorder that leads to developmental regression and severe disability and is caused by pathogenic variants in the...
Rett syndrome (RTT, MIM #312750) is a rare genetic disorder that leads to developmental regression and severe disability and is caused by pathogenic variants in the gene. The diagnosis of RTT is based on clinical features and, depending on resources and access, on molecular confirmation. There is scarce information on molecular diagnosis from patients in Latin America, mostly due to limited availability and coverage of genomic testing. This pilot study aimed to implement genomic testing and characterize clinical and molecular findings in a group of Chilean patients with a clinical diagnosis of RTT. Twenty-eight patients with suspected RTT underwent characterization of phenotypic manifestations and molecular testing using Clinical Exome Solution CES_V2 by SOPHiA Genetics. Data was analyzed using the commercial bioinformatics platform, SOPHiA DDM. A virtual panel of 34 genes, including and other genes that are in the differential diagnosis of RTT, was used to prioritize initial analyses, followed by evaluation of the complete exome sequence data. Twelve patients (42.8% of participants) had variants in , of which 11 (39.2%) were interpreted as pathogenic/likely pathogenic (P/LP), thus confirming the diagnosis of RTT in them. Eight additional patients (28.5%) harbored ten variants in nine other genes. Four of these variants were interpreted as P/LP (14.2%) ( and ) resulting in alternative neurodevelopmental diagnoses, and six were considered of uncertain significance. No evident candidate variant was found for eight patients. This study allowed to reach a diagnosis in half of the participants. The diagnosis of RTT was confirmed in over a third of them, while others were found to have alternative neurodevelopmental disorders. Further evaluation is needed to identify the cause in those with negative or uncertain results. This information is useful for the patients, families, and clinicians to guide clinical management, even more so since the development of novel therapies for RTT. We also show the feasibility of implementing a step-wide approach to genomic testing in a setting with limited resources.
PubMed: 38566815
DOI: 10.3389/fgene.2024.1278198 -
BioRxiv : the Preprint Server For... Mar 2024A longstanding challenge in gene therapy is expressing a dosage-sensitive gene within a tight therapeutic window. For example, loss of function causes Rett syndrome,...
A longstanding challenge in gene therapy is expressing a dosage-sensitive gene within a tight therapeutic window. For example, loss of function causes Rett syndrome, while its duplication causes duplication syndrome. Viral gene delivery methods generate variable numbers of gene copies in individual cells, creating a need for gene dosage-invariant expression systems. Here, we introduce a compact miRNA-based, incoherent feed-forward loop circuit that achieves precise control of expression in cells and brains, and improves outcomes in an AAV-based mouse model of Rett syndrome gene therapy. Single molecule analysis of endogenous and ectopic mRNA revealed precise, sustained expression across a broad range of gene dosages. Delivered systemically in a brain-targeting AAV capsid, the circuit strongly suppressed Rett behavioral symptoms for over 24 weeks, outperforming an unregulated gene therapy. These results demonstrate that synthetic miRNA-based regulatory circuits can enable precise in vivo expression to improve the safety and efficacy of gene therapy.
PubMed: 38559034
DOI: 10.1101/2024.03.13.584179 -
Scientific Reports Mar 2024CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and...
CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. Patients with CDD frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in individuals with CDD (n = 17) and their healthy relatives (n = 17). Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. In particular, at genus level, CDD microbial communities were characterized by an increase in the relative abundance of Clostridium_AQ, Eggerthella, Streptococcus, and Erysipelatoclostridium, and by a decrease in Eubacterium, Dorea, Odoribacter, Intestinomonas, and Gemmiger, pointing toward a dysbiotic profile. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features and ambulation capacity. Enrichment in Lachnoclostridium and Enterobacteriaceae was observed in the microbiota of patients with more severe GI symptoms, while Clostridiaceae, Peptostreptococcaceae, Coriobacteriaceae, Erysipelotrichaceae, Christensenellaceae, and Ruminococcaceae were enriched in patients experiencing daily epileptic seizures. Our findings suggest a potential connection between CDD, microbiota and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in subjects with CDD. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of patients with CDD.
Topics: Humans; Gastrointestinal Microbiome; Spasms, Infantile; Epileptic Syndromes; Rett Syndrome; Seizures; Protein Serine-Threonine Kinases
PubMed: 38548767
DOI: 10.1038/s41598-024-56989-0 -
Genes Feb 2024Systematic data on endocrinopathies in Rett syndrome (RTT) patients remain limited and inconclusive. The aim of this retrospective observational two-center study was to... (Observational Study)
Observational Study
Systematic data on endocrinopathies in Rett syndrome (RTT) patients remain limited and inconclusive. The aim of this retrospective observational two-center study was to assess the prevalence of endocrinopathies in a pediatric population of RTT patients. A total of 51 Caucasian patients (47 girls, 4 boys) with a genetically confirmed diagnosis of RTT were enrolled (mean age 9.65 ± 5.9 years). The patients were referred from the Rett Center of two Italian Hospitals for endocrinological evaluation. All the study population underwent clinical and auxological assessments and hormonal workups. mutations were detected in 38 cases (74.5%), deletions in 11 (21.6%), and mutations in 2 (3.9%). Overall, 40 patients were treated with anti-seizure medications. The most frequent endocrinological finding was short stature (47%), followed by menstrual cycle abnormalities (46.2%), weight disorders (45.1%), low bone mineral density (19.6%), hyperprolactinemia (13.7%) and thyroid disorders (9.8%). In the entire study population, endocrinopathies were significantly more frequent in patients with mutations ( = 0.0005), and epilepsy was more frequent in deletions ( = 0.02). In conclusion, our data highlighted that endocrinopathies are not rare in RTT, especially in patients with deletions. Therefore, in the context of a multidisciplinary approach, endocrinological evaluation should be recommended for RTT patients.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Male; Endocrine System Diseases; Mutation; Prevalence; Protein Serine-Threonine Kinases; Retrospective Studies; Rett Syndrome
PubMed: 38540345
DOI: 10.3390/genes15030287 -
Cellular and Molecular Life Sciences :... Mar 2024N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central...
N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.
Topics: Child; Humans; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Epilepsy; Mutation, Missense; Phenotype
PubMed: 38538865
DOI: 10.1007/s00018-023-05069-z -
Asian Journal of Surgery Mar 2024
PubMed: 38538395
DOI: 10.1016/j.asjsur.2024.03.059 -
BMC Pediatrics Mar 2024Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and stereotypic hand movements. Given the limited treatment options for Rett syndrome, there is a dire need for effective interventions.
OBJECTIVE
To evaluate the safety and efficacy of trofinetide in Randomized Controlled Trials (RCTs) that report on Rett syndrome patients.
METHODS
We identified 109 articles from four databases (Scopus, PubMed, Web of Science, and Cochrane CENTRAL). After removing the duplicates, we narrowed them down to 59 articles for further assessment. We included RCTs that evaluated the efficacy and safety of trofinetide in patients with Rett syndrome. Three studies were eligible for inclusion. Two independent reviewers evaluated the identified studies' titles, abstracts, and full texts, extracting pertinent data. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) 2.0 tool. We then conducted a meta-analysis using the fixed effects model in the case of insignificant heterogeneity; otherwise, we used the random effects model. Based on the nature of the outcome, we analyzed the mean difference or the odds ratio. Analysis was conducted using RevMan version 5.3.
RESULTS
Among the analyzed outcomes in 181 patients in the trofinetide group and 134 patients in the placebo group, significant improvement in Rett Syndrome Behavior Questionnaire (RSBQ) scores was observed at 200 mg dosage (overall mean difference: -3.53, p = 0.001). Clinical Global Impression-Improvement (CGI-I) scores improved considerably at 200 mg dosage (overall mean difference: -0.34, p < 0.0001). No substantial changes were observed in Motor Behavioral Assessment (MBA) or Top 3 Caregiver Concerns. We evaluated Treatment Emergent Adverse Events (TEAEs) across the various dosages and noted significant associations with diarrhea (200 mg), vomiting (200 mg), and irritability (200 mg). However, we did not find a significant association between any of the dosages and the incidence of decreased appetite.
CONCLUSION
Trofinetide demonstrated potential in improving RSBQ and CGI-I scores at 200 mg dosage. Although no substantial changes were found in MBA and top 3 caregiver concerns. Adverse events were linked to specific dosages.
Topics: Female; Humans; Rett Syndrome; Randomized Controlled Trials as Topic; Glutamates; Diarrhea
PubMed: 38521908
DOI: 10.1186/s12887-024-04526-3 -
Frontiers in Neuroscience 2024Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent...
Functional contribution of the intestinal microbiome in autism spectrum disorder, attention deficit hyperactivity disorder, and Rett syndrome: a systematic review of pediatric and adult studies.
INTRODUCTION
Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent studies have shown the presence of gut microbiota alterations in neurodevelopmental disorders. Here we performed a systematic review of alterations of the intestinal microbiota composition and function in pediatric and adult patients affected by autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Rett syndrome (RETT).
METHODS
We searched selected keywords in the online databases of PubMed, Cochrane, and OVID (January 1980 to December 2021) with secondary review of references of eligible articles. Two reviewers independently performed critical appraisals on the included articles using the Critical Appraisal Skills Program for each study design.
RESULTS
Our systematic review identified 18, 7, and 3 original articles describing intestinal microbiota profiles in ASD, ADHD, and RETT, respectively. Decreased Firmicutes and increased Bacteroidetes were observed in the gut microbiota of individuals affected by ASD and ADHD. Proinflammatory cytokines, short-chain fatty acids and neurotransmitter levels were altered in ASD and RETT. Constipation and visceral pain were related to changes in the gut microbiota in patients affected by ASD and RETT. Hyperactivity and impulsivity were negatively correlated with (phylum Firmicutes) and positively correlated with sp. (phylum Bacteroidetes) in ADHD subjects. Five studies explored microbiota-or diet-targeted interventions in ASD and ADHD. Probiotic treatments with sp. and fecal microbiota transplantation from healthy donors reduced constipation and ameliorated ASD symptoms in affected children. Perinatal administration of sp. prevented the onset of Asperger and ADHD symptoms in adolescence. Micronutrient supplementation improved disease symptomatology in ADHD without causing significant changes in microbiota communities' composition.
DISCUSSION
Several discrepancies were found among the included studies, primarily due to sample size, variations in dietary practices, and a high prevalence of functional gastrointestinal symptoms. Further studies employing longitudinal study designs, larger sample sizes and multi-omics technologies are warranted to identify the functional contribution of the intestinal microbiota in developmental trajectories of the human brain and neurobehavior.
SYSTEMATIC REVIEW REGISTRATION
https://clinicaltrials.gov/, CRD42020158734.
PubMed: 38516317
DOI: 10.3389/fnins.2024.1341656 -
Frontiers in Genome Editing 2024Rett syndrome is an acquired progressive neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene which encodes a pleiotropic protein that functions...
Rett syndrome is an acquired progressive neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene which encodes a pleiotropic protein that functions as a global transcriptional regulator and a chromatin modifier. Rett syndrome predominantly affects heterozygous females while affected male hemizygotes rarely survive. Gene therapy of Rett syndrome has proven challenging due to a requirement for stringent regulation of expression with either over- or under-expression being toxic. Ectopic expression of MECP2 in conjunction with regulatory miRNA target sequences has achieved some success, but the durability of this approach remains unknown. Here we evaluated a nuclease-free homologous recombination (HR)-based genome editing strategy to correct mutations in the MECP2 gene. The stem cell-derived AAVHSCs have previously been shown to mediate seamless and precise HR-based genome editing. We tested the ability of HR-based genome editing to correct pathogenic mutations in Exons 3 and 4 of the MECP2 gene and restore the wild type sequence while preserving all native genomic regulatory elements associated with MECP2 expression, thus potentially addressing a significant issue in gene therapy for Rett syndrome. Moreover, since the mutations are edited directly at the level of the genome, the corrections are expected to be durable with progeny cells inheriting the edited gene. The AAVHSC MECP2 editing vector was designed to be fully homologous to the target MECP2 region and to insert a promoterless Venus reporter at the end of Exon 4. Evaluation of AAVHSC editing in a panel of Rett cell lines bearing mutations in Exons 3 and 4 demonstrated successful correction and rescue of expression of the edited MECP2 gene. Sequence analysis of edited Rett cells revealed successful and accurate correction of mutations in both Exons 3 and 4 and permitted mapping of HR crossover events. Successful correction was observed only when the mutations were flanked at both the 5' and 3' ends by crossover events, but not when both crossovers occurred either exclusively upstream or downstream of the mutation. Importantly, we concluded that pathogenic mutations were successfully corrected in every Rett line analyzed, demonstrating the therapeutic potential of HR-based genome editing.
PubMed: 38495533
DOI: 10.3389/fgeed.2024.1346781