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Neurotherapeutics : the Journal of the... Jun 2024The neurodevelopmental disorder Pitt Hopkins syndrome (PTHS) causes clinical symptoms similar to Rett syndrome (RTT) patients. However, RTT is caused by MECP2 mutations...
The neurodevelopmental disorder Pitt Hopkins syndrome (PTHS) causes clinical symptoms similar to Rett syndrome (RTT) patients. However, RTT is caused by MECP2 mutations whereas mutations in the TCF4 gene lead to PTHS. The mechanistic commonalities underling these two disorders are unknown, but their shared symptomology suggest that convergent pathway-level disruption likely exists. We reprogrammed patient skin derived fibroblasts into induced neuronal progenitor cells. Interestingly, we discovered that MeCP2 levels were decreased in PTHS patient iNPCs relative to healthy controls and that both iNPCs and iAstrocytes displayed defects in function and differentiation in a mutation-specific manner. When Tcf4 mice were genetically crossed with mice overexpressing MeCP2, molecular and phenotypic defects were significantly ameliorated, underlining and important role of MeCP2 in PTHS pathology. Importantly, post-natal intracerebroventricular gene replacement therapy with adeno-associated viral vector serotype 9 (AAV9)-expressing MeCP2 (AAV9.P546.MeCP2) significantly improved iNPC and iAstrocyte function and effectively ameliorated histological and behavioral defects in Tcf4 mice. Combined, our data suggest a previously unknown role of MeCP2 in PTHS pathology and common pathways that might be affected in multiple neurodevelopmental disorders. Our work highlights potential novel therapeutic targets for PTHS, including upregulation of MeCP2 expression or its downstream targets or, potentially, MeCP2-based gene therapy.
PubMed: 38876822
DOI: 10.1016/j.neurot.2024.e00376 -
Expert Review of Gastroenterology &... Jun 2024Although gastrointestinal (GI) comorbidities are experienced by over 90% of individuals with Rett syndrome (RTT), a neurodevelopmental disorder associated with mutations...
INTRODUCTION
Although gastrointestinal (GI) comorbidities are experienced by over 90% of individuals with Rett syndrome (RTT), a neurodevelopmental disorder associated with mutations in the MECP2 gene, many neurologists and pediatricians do not rank the management of these comorbidities among the most important treatment goals for RTT. Trofinetide, the first approved pharmacologic treatment for RTT, confers improvements in RTT symptoms but is associated with adverse GI events, primarily diarrhea and vomiting. Treatment strategies for GI comorbidities and drug-associated symptoms in RTT represent an unmet clinical need.
AREAS COVERED
This perspective covers GI comorbidities experienced by those with RTT, either with or without trofinetide treatment. PubMed literature searches were undertaken on treatment recommendations for the following conditions: constipation, diarrhea, vomiting, aspiration, dysphagia, gastroesophageal reflux, nausea, gastroparesis, gastritis, and abdominal bloating.
EXPERT OPINION
The authors recommend a proactive approach to management of symptomatic GI comorbidities and drug-associated symptoms in RTT to enhance drug tolerance and improve the quality of life of affected individuals. Management strategies for common GI comorbidities associated with RTT are reviewed based on authors' clinical experience and augmented by recommendations from the literature.
PubMed: 38869952
DOI: 10.1080/17474124.2024.2368014 -
European Spine Journal : Official... Jun 2024Surgical correction of neuromuscular scoliosis is often a challenging and extensive procedure. Due to this complexity and the high disease burden that these patients... (Review)
Review
PURPOSE
Surgical correction of neuromuscular scoliosis is often a challenging and extensive procedure. Due to this complexity and the high disease burden that these patients carry, per and post-operative complications are not uncommon. The purpose of this study was to systematically review and describe the pooled rates of postoperative complications and analyze risk factors for complications in neuromuscular scoliosis surgery described in the literature in the last ten years.
METHODS
A systematic review of the English literature across multiple databases was conducted using search criteria (neuromuscular scoliosis AND complications) and using PRISMA guidelines (Jan 2012-July 2022). Studies with less than 30 patients and follow-up of < 2 years were excluded. Data extraction and meta-analysis were performed using random mode effect. Statistical analysis was conducted using OpenMeta software. Meta-regression analysis was used to detect risk factors (surgical approach, intraoperative time, intraoperative blood loss, preoperative Cobb angle and patient diagnosis) associated with each complication group. Confidence interval (CI) was set at 95%.
RESULTS
Twenty-two studies met the inclusion criteria involving 2155 patients. The level of evidence among studies were III (9) and IV (13). The most common primary diagnosis was cerebral palsy (43%) followed by Duchenne muscle dystrophy (20%), myelomeningocele (7.4%), spinal muscle atrophy (7.1%), Rett syndrome (< 2%) and combined other pathologies (20.2%). The pooled incidence rate of wound complications was the highest, amongst all complications, at 13.3% (CI 10.838 to 16.861); closely followed by respiratory complications (11.8%;CI 5.7 to 19.7). Implant failure occurred in 7.1% cases (CI 6.418 to 11.465), gastrointestinal complications was 5.2%; CI 2.4 to 8), pseudarthrosis in (4.6%;CI 2.2 to 6.9) and neurological deficit in 2.9% (CI 1.989 to 6.086). The pooled rate of revision surgery was (9.6%; CI 6.2 to 12.9). Heterogeneity was assessed using I test which results were moderately heterogeneous. Meta-regression analysis revealed that the diagnosis of myelomeningocele or Duchenne muscle dystrophy or spinal muscle atrophy were strongly associated with wound and respiratory complications (p = 0.007 and p = 0.005, respectively).
CONCLUSION
Wound-related (13.3%) and respiratory complications (11.8%) remain the most common complications among studies after corrective surgery for neuromuscular scoliosis. Both are significantly associated with Duchenne muscle dystrophy, spinal muscle atrophy and myelomeningocele.
PubMed: 38869648
DOI: 10.1007/s00586-024-08338-y -
Autism : the International Journal of... Jun 2024Sleep problems are common and impactful among individuals with Rett syndrome (RTT) and their caregivers. We examined the sleep patterns of 29 RTT patients and their...
Sleep problems are common and impactful among individuals with Rett syndrome (RTT) and their caregivers. We examined the sleep patterns of 29 RTT patients and their primary caregivers using various assessment tools. The study found that a majority of the patients experienced sleep disturbances, with younger patients showing more sleep difficulties. Caregivers also reported poor sleep quality. The findings emphasize the need to address sleep problems in RTT management, as improving sleep quality can positively impact the well-being of individuals with RTT and their caregivers.
PubMed: 38853381
DOI: 10.1177/13623613241254620 -
American Journal of Medical Genetics.... Jun 2024Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by...
Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by a variety of mechanisms which include large deletions (70%-75%), maternal uniparental disomy (UPD) (20%-30%), and imprinting defects (2%-5%) or balanced translocations. Individuals often have a characteristic behavior disorder with mild intellectual disability, infantile hypotonia associated with poor sucking, short stature, and obesity. PWS is characterized by hypothalamic-pituitary axis dysfunction with growth hormone (GH) deficiency, hypogonadism, and several other hormonal deficiencies resulting in short stature, centrally driven excessive appetite (hyperphagia), central obesity, cryptorchidism, and decreased lean body mass. In this study, we determined and sought differences in the incidence of thyroid abnormalities among the common genetic subtypes in a cohort of 52 subjects with PWS because there was limited literature available. We also sought the effects of growth hormone (GH) treatment on the thyroid profile. Fifty-two subjects with a genetically confirmed diagnosis of PWS were included in this study at the University of California, Irvine. Blood samples for baseline thyroxine stimulating hormone (TSH) and free thyroxine (fT4) levels were obtained in the morning after an overnight fast for 8-12 h. Statistical analyses were performed with SPSS (SPSS Inc., 21.0). Mean values were analyzed by one-way ANOVA, and student's t-test and statistical significance were set at p < 0.05. The subjects included 26 males and 26 females with an age range of 3-38 years. There were 29 subjects with chromosome 15q11-q13 deletions and 23 with UPD; 28 were GH treated currently or in the past, and 24 never received GH. There was no significant difference in age or body mass index (BMI) (kg/m2) between GH-treated versus non-GH-treated groups. BMI was higher in the deletion group compared to the UPD group (p = 0.05). We identified two individuals who were clinically diagnosed and treated for hypothyroidism, one of whom was on GH supplements. We identified two additional individuals with subclinical hypothyroidism who were not on GH treatment, giving a frequency of 7.6% (4/52) in this cohort of patients. We did not find significant differences in thyroid function (TSH) in the deletion versus UPD groups. We found significant differences in thyroid function, however, between GH-treated and non-GH-treated groups. The mean TSH was lower (2.25 ± 1.17 uIU/M, range 0.03-4.92 uIU/M versus 2.80 ± 1.44 uIU/M, range 0.55-5.33 uIU/M respectively, p = 0.046), and the free T4 levels were significantly higher (1.13 ± 0.70 and 1.03 ± 0.11 ng/dL, respectively, p = 0.05) in the GH-treated individuals compared to non-GH-treated individuals. In this cohort of subjects with PWS, we identified two previously diagnosed individuals with hypothyroidism and two individuals with subclinical hypothyroidism (4/52, 7.6%), three of whom were not receiving GH treatment. We did not find any significant differences in thyroid function between molecular subtypes; however, we found that euthyroid status (lower TSH levels and higher free T4 levels) was significantly higher in individuals who were treated with GH compared to the untreated group. We recommend that individuals with PWS should be screened regularly for thyroid deficiency and start treatment early with GH in view of the potentially lower incidence of thyroid deficiency.
PubMed: 38837660
DOI: 10.1002/ajmg.a.63724 -
Journal of Neurodevelopmental Disorders Jun 2024In the search for objective tools to quantify neural function in Rett Syndrome (RTT), which are crucial in the evaluation of therapeutic efficacy in clinical trials,...
BACKGROUND
In the search for objective tools to quantify neural function in Rett Syndrome (RTT), which are crucial in the evaluation of therapeutic efficacy in clinical trials, recordings of sensory-perceptual functioning using event-related potential (ERP) approaches have emerged as potentially powerful tools. Considerable work points to highly anomalous auditory evoked potentials (AEPs) in RTT. However, an assumption of the typical signal-averaging method used to derive these measures is "stationarity" of the underlying responses - i.e. neural responses to each input are highly stereotyped. An alternate possibility is that responses to repeated stimuli are highly variable in RTT. If so, this will significantly impact the validity of assumptions about underlying neural dysfunction, and likely lead to overestimation of underlying neuropathology. To assess this possibility, analyses at the single-trial level assessing signal-to-noise ratios (SNR), inter-trial variability (ITV) and inter-trial phase coherence (ITPC) are necessary.
METHODS
AEPs were recorded to simple 100 Hz tones from 18 RTT and 27 age-matched controls (Ages: 6-22 years). We applied standard AEP averaging, as well as measures of neuronal reliability at the single-trial level (i.e. SNR, ITV, ITPC). To separate signal-carrying components from non-neural noise sources, we also applied a denoising source separation (DSS) algorithm and then repeated the reliability measures.
RESULTS
Substantially increased ITV, lower SNRs, and reduced ITPC were observed in auditory responses of RTT participants, supporting a "neural unreliability" account. Application of the DSS technique made it clear that non-neural noise sources contribute to overestimation of the extent of processing deficits in RTT. Post-DSS, ITV measures were substantially reduced, so much so that pre-DSS ITV differences between RTT and TD populations were no longer detected. In the case of SNR and ITPC, DSS substantially improved these estimates in the RTT population, but robust differences between RTT and TD were still fully evident.
CONCLUSIONS
To accurately represent the degree of neural dysfunction in RTT using the ERP technique, a consideration of response reliability at the single-trial level is highly advised. Non-neural sources of noise lead to overestimation of the degree of pathological processing in RTT, and denoising source separation techniques during signal processing substantially ameliorate this issue.
Topics: Humans; Rett Syndrome; Adolescent; Female; Evoked Potentials, Auditory; Child; Young Adult; Electroencephalography; Auditory Perception; Reproducibility of Results; Acoustic Stimulation; Male; Signal-To-Noise Ratio; Adult
PubMed: 38831410
DOI: 10.1186/s11689-024-09544-x -
Archives of Biochemistry and Biophysics Jul 2024To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered a broad-spectrum pathology, instead of... (Review)
Review
To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered a broad-spectrum pathology, instead of just a neurodevelopmental disease, due to the multitude of peripheral co-morbidities and the compromised metabolic pathways, affecting the patients. The altered molecular processes include an impaired mitochondrial function, a perturbed redox homeostasis, a chronic subclinical inflammation and an improper cholesterol metabolism. The persistent subclinical inflammatory condition was first defined ten years ago, as a previously unrecognized feature of RTT, playing a role in the pathology progress and modulation of phenotypical severity. In light of this, the present work aims at reviewing the current knowledge on the chronic inflammatory status and the altered immune/inflammatory functions in RTT, as well as investigating the emerging mechanisms underlying this condition with a special focus on the latest findings about inflammasome system, autoimmunity responses and intestinal micro- and mycobiota. On these bases, although further research is needed, future therapeutic strategies able to re-establish an adequate immune/inflammatory response could represent potential approaches for RTT patients.
Topics: Rett Syndrome; Humans; Inflammation; Inflammasomes; Methyl-CpG-Binding Protein 2; Animals; Gastrointestinal Microbiome
PubMed: 38815782
DOI: 10.1016/j.abb.2024.110046 -
Clinical and Experimental Pediatrics May 2024Global developmental delay (GDD) and intellectual disability (ID) are relatively common neurodevelopmental disorders that significantly impact affected children, their...
Global developmental delay (GDD) and intellectual disability (ID) are relatively common neurodevelopmental disorders that significantly impact affected children, their families, and society. The etiology of GDD/ID is notably diverse, encompassing both genetic and acquired factors. Although the precise cause of most GDD/ID cases remains unclear, an estimated half of all cases can be attributed to genetic factors. Thus, a detailed medical history and comprehensive physical examination remain pivotal for guiding diagnostic investigations into the underlying causes of GDD/ID. Advancements in genetic testing have supplanted traditional methods such as karyotyping and fluorescence in situ hybridization with chromosomal microarrays, which are now the primary genetic tests for children with idiopathic GDD/ID. Moreover, the evaluation of Fragile X and Rett syndrome should be an integral component of initial diagnostic assessments. In recent years, whole-exome sequencing and whole-genome sequencing have emerged as important diagnostic tools for evaluating children with GDD/ID and have substantially enhanced the diagnostic yield rates. Gene therapy has emerged as a promising avenue and is poised to become a cornerstone in addressing various genetic developmental and epilepsy disorders. Early intervention facilitated by a proficient multidisciplinary team can markedly enhance the prognosis and outcomes of GDD/ID, particularly when parents or caregivers are actively engaged in the interventional process. This review discusses risk factors and common underlying causes, explores recent evidence and recommendations for genetic evaluation, and offers management strategies for children with GDD/ID.
PubMed: 38810986
DOI: 10.3345/cep.2023.01697 -
BioRxiv : the Preprint Server For... May 2024Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett...
Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time, and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of mutant females, indicating wild-type-expressing cells normalizing transcriptional homeostasis. These results improve understanding of RTT progression and treatment.
PubMed: 38798575
DOI: 10.1101/2024.05.16.594595 -
Research in Developmental Disabilities Jul 2024Functional connectivity is scarcely studied in Rett syndrome (RTT). Explorations revealed associations between RTT's clinical, genetic profiles, and coherence measures,...
BACKGROUND
Functional connectivity is scarcely studied in Rett syndrome (RTT). Explorations revealed associations between RTT's clinical, genetic profiles, and coherence measures, highlighting an unexplored frontier in understanding RTT's neural mechanisms and cognitive processes.
AIMS
To evaluate the effects of diverse cognitive stimulations-learning-focused versus gaming-oriented-on electroencephalography brain connectivity in RTT. The comparison with resting states aimed to uncover potential biomarkers and insights into the neural processes associated with RTT.
METHODS AND PROCEDURES
The study included 15 girls diagnosed with RTT. Throughout sessions lasting about 25 min, participants alternated between active and passive tasks, using an eyetracker device while their brain activity was recorded with a 20-channel EEG. Results revealed significant alterations during cognitive tasks, notably in delta, alpha and beta bands. Both tasks induced spectral pattern changes and connectivity shifts, hinting at enhanced neural processing. Hemispheric asymmetry decreased during tasks, suggesting more balanced neural processing. Linear and nonlinear connectivity alterations were observed in active tasks compared to resting state, while passive tasks showed no significant changes.
CONCLUSIONS AND IMPLICATIONS
Results underscores the potential of cognitive stimulation for heightened cognitive abilities, promoting enhanced brain connectivity and information flow in Rett syndrome. These findings offer valuable markers for evaluating cognitive interventions and suggest gaming-related activities as effective tools for improving learning outcomes.
Topics: Humans; Rett Syndrome; Female; Electroencephalography; Child; Cognition; Adolescent; Video Games; Brain; Learning; Young Adult
PubMed: 38795554
DOI: 10.1016/j.ridd.2024.104751