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Nucleic Acids Research Apr 2024MeCP2 is a general regulator of transcription involved in the repression/activation of genes depending on the local epigenetic context. It acts as a chromatin regulator...
MeCP2 is a general regulator of transcription involved in the repression/activation of genes depending on the local epigenetic context. It acts as a chromatin regulator and binds with exquisite specificity to gene promoters. The set of epigenetic marks recognized by MeCP2 has been already established (mainly, cytosine modifications in CpG and CpA), as well as many of the constituents of its interactome. We unveil a new set of interactions for MeCP2 with the four canonical nucleosomal histones. MeCP2 interacts with high affinity with H2A, H2B, H3 and H4. In addition, Rett syndrome associated mutations in MeCP2 and histone epigenetic marks modulate these interactions. Given the abundance and the structural/functional relevance of histones and their involvement in epigenetic regulation, this new set of interactions and its modulating elements provide a new addition to the 'alphabet' for this epigenetic reader.
Topics: Methyl-CpG-Binding Protein 2; Nucleosomes; Histones; Humans; Epigenesis, Genetic; Protein Binding; Rett Syndrome; Mutation; Animals
PubMed: 38321951
DOI: 10.1093/nar/gkae051 -
Epilepsia Open Apr 2024Evaluate the long-term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients...
OBJECTIVE
Evaluate the long-term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients without intellectual disability (ID).
METHODS
Long-term outcomes from a Norwegian VNS quality registry are reported in 105 patients with DEEs (Lennox-Gastaut syndrome [LGS] n = 62; Dravet n = 16; Rett n = 9; other syndromes n = 18) were compared with 212 epilepsy patients without ID, with median follow-up of 88 and 72 months, respectively. Total seizure reduction was evaluated at 6, 12, 24, 36, and 60 months. Effect on different seizure types was evaluated at baseline and last observation carried forward (LOCF).
RESULTS
Median monthly seizure frequency at LOCF was reduced by 42.2% (p < 0.001) in patients with DEE and by 55.8% (p < 0.001) in patients without ID. In DEE patients, ≥50% seizure reduction at 6 and 24 months were 17.1% and 37.1%, respectively, and 33.5% and 48.6% for patients without ID. Seizure reduction ≥75% at 60 months occurred in 14.3% of DEE patients and 23.1% of patients without ID. Highest median reduction was for atonic seizures, most notably 64.6% for LGS patients. A better effect was seen at 2 years among DEE patients with unchanged medication compared with those with changed medication (54.5% vs. 35.6% responders, p = 0.078). More DEE patients were reported to have greater improvement in ictal or postictal severity (43.8% vs. 28.3%, p = 0.006) and alertness (62.9% vs. 31.6%, p < 0.001) than patients without ID. For both groups, use of the magnet reduced seizure severity. Hoarseness was the most common adverse effect in both groups. In addition, DEE patients were frequently reported to have sleep disturbance, general discomfort, or abdominal problems.
SIGNIFICANCE
Our data indicate that VNS is very effective for atonic seizures. Patients without ID had best overall seizure reduction, however, patients with DEE had higher retention rates probably due to other positive effects.
PLAIN LANGUAGE SUMMARY
DEE refers to a group of patients with severe epilepsy and intellectual disability. Many of these patients have restricted lifestyles with frequent seizures. VNS is a treatment option for patients who do not respond well to medicines, either because of insufficient effect or serious adverse effects. Our study shows that VNS is well tolerated in this patient group and leads to a reduction in all seizure types, most notably for seizures leading to fall. Many patients experience other positive effects like shorter and milder seizures, as well as improvement in alertness.
Topics: Humans; Vagus Nerve Stimulation; Intellectual Disability; Treatment Outcome; Epilepsy; Seizures; Lennox Gastaut Syndrome
PubMed: 38318727
DOI: 10.1002/epi4.12908 -
Frontiers in Pharmacology 2023Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with...
Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2 years and older. Here, we present the development of trofinetide from bench research to clinical studies and emphasize how the collaboration between academia, the pharmaceutical industry, and patient advocacy led to the recent approval. The bench-to-bedside development of trofinetide underscores the value of collaboration between these groups in the development and approval of treatments for rare diseases.
PubMed: 38318312
DOI: 10.3389/fphar.2023.1341746 -
Clinical Therapeutics Mar 2024Trofinetide is the first drug to be approved by the US Food and Drug Administration for use in the treatment of patients with Rett syndrome, a multisystem disorder...
PURPOSE
Trofinetide is the first drug to be approved by the US Food and Drug Administration for use in the treatment of patients with Rett syndrome, a multisystem disorder requiring multimodal therapies. Cytochrome P450 (CYP) 3A4 metabolizes >50% of therapeutic drugs and is the CYP isozyme most commonly expressed in the liver and intestines. In vitro studies suggest the concentration of trofinetide producing 50% inhibition (IC) of CYP3A4 is >15 mmol/L; that concentration was much greater than the target clinical concentration associated with the maximal intended therapeutic dose (12 g). Thus, trofinetide has a low potential for drug-drug interactions in the liver. However, there is potential for drug-drug interactions in the intestines given the oral route of administration and expected relatively high concentration in the gastrointestinal tract after dose administration.
METHODS
Using a validated physiologically based pharmacokinetic (PBPK) model, deterministic and stochastic simulations were used for assessing the PK properties related to exposure and bioavailability of midazolam (sensitive index substrate for CYP3A4) following an oral (15 mg) or intravenous (2 mg) dose, with and without single-dose and steady-state (12 g) coadministration of oral trofinetide.
FINDINGS
Following coadministration of intravenous midazolam and oral trofinetide, the PK properties of midazolam were unchanged. The trofinetide concentration in the gut wall was >15 mmol/L during the first 1.5 hours after dosing. With the coadministration of oral midazolam and trofinetide, the model predicted increases in fraction of dose reaching the portal vein, bioavailability, C, and AUC of 30%, 30%, 18%, and 30%, respectively.
IMPLICATIONS
In this study that used a PBPK modeling approach, it was shown that CYP3A4 enzyme activity in the liver was not affected by trofinetide coadministration, but trofinetide was predicted to be a weak inhibitor of intestinal CYP3A4 metabolism after oral administration at therapeutic doses.
Topics: Humans; Pharmaceutical Preparations; Cytochrome P-450 CYP3A; Midazolam; Drug Interactions; Models, Biological; Cytochrome P-450 CYP3A Inhibitors; Glutamates
PubMed: 38307724
DOI: 10.1016/j.clinthera.2023.12.007 -
Orphanet Journal of Rare Diseases Jan 2024Rett syndrome (RTT) is a rare neurodevelopmental condition associated with mutations in the gene coding for the methyl-CpG-binding protein 2 (MECP2). It is primarily...
BACKGROUND
Rett syndrome (RTT) is a rare neurodevelopmental condition associated with mutations in the gene coding for the methyl-CpG-binding protein 2 (MECP2). It is primarily observed in girls and affects individuals globally. The understanding of the neurobiology of RTT and patient management has been improved by studies that describe the demographic and clinical presentation of individuals with RTT. However, in Ireland, there is a scarcity of data regarding individuals with RTT, which impedes the ability to fully characterize the Irish RTT population. Together with the Rett Syndrome Association of Ireland (RSAI), we prepared a questionnaire to determine the characteristics of RTT individuals in Ireland. Twenty-five families have participated in the study to date, providing information about demographics, genetics, familial history, clinical features, and regression.
RESULTS
The results show that Irish individuals with RTT have comparable presentation with respect to individuals in other countries; however, they had a better response to anti-epileptic drugs, and fewer skeletal deformities were reported. Nonetheless, seizures, involuntary movements and regression were more frequently observed in Irish individuals. One of the main findings of this study is the limited genetic information available to individuals to support the clinical diagnosis of RTT.
CONCLUSIONS
Despite the limited sample size, this study is the first to characterize the RTT population in Ireland and highlights the importance of having a swift access to genetic testing to sharpen the characterization of the phenotype and increase the visibility of Irish individuals in the international RTT community.
Topics: Female; Humans; Rett Syndrome; Ireland; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Demography
PubMed: 38291497
DOI: 10.1186/s13023-024-03046-8 -
Pediatric Neurology Mar 2024This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye...
BACKGROUND
This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye gaze communication, gait abnormalities, and sleep issues. The research aims to identify social profiles in RTT and explore their correlation with sleep, sleep-disordered breathing (SDB), and daytime sleepiness.
METHODS
Standard overnight sleep macrostructure and respiratory parameters were assessed. Extracting 25 social-related items and one for daytime sleepiness from the Rett Syndrome Behavioral Questionnaire, factor analysis was applied to establish latent social profiles. These profiles were then correlated with sleep parameters. The nonparametric Mann-Whitney U test compared social profiles based on the presence of SDB (defined by an apnea-hypopnea index greater than one per hour) and daytime sleepiness.
RESULTS
The study involved 12 female subjects with confirmed RTT diagnoses and MECP2 mutations, aged 8.54 ± 5.30 years. The Rett Syndrome Behavioral Questionnaire revealed a total average score of 25.83 ± 12.34, indicating varying degrees of social impairments. Comprising 25 social-related items, factor analysis yielded four social profiles: "interactive motricity," "mood change," "anxiety/agitation," and "gazing." Longer sleep onset latency correlated with increased socio-behavioral impairments, particularly in interactive motricity reduction. Conversely, higher rapid eye movement sleep was associated with fewer interactive socio-motor behaviors. No significant differences in social profiles were found concerning the presence of SDB or daytime sleepiness.
CONCLUSIONS
The findings suggest four distinct social profiles in RTT individuals, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. Despite the absence of differences in SDB or daytime sleepiness, the study highlights the relationship between sleep parameters, such as sleep onset latency and rapid eye movement sleep, and socio-behavioral outcomes in RTT with MECP2 mutations.
Topics: Humans; Female; Rett Syndrome; Polysomnography; Sleep; Sleep Apnea Syndromes; Disorders of Excessive Somnolence
PubMed: 38290182
DOI: 10.1016/j.pediatrneurol.2024.01.004 -
Genes Dec 2023Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders...
Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders underscore the conceptual dose-dependent risk posed by gene therapy for mosaic RTT patients. Recently, a miRNA-Responsive Autoregulatory Element (miRARE) mitigated the dose-dependent toxicity posed by self-complementary adeno-associated viral vector serotype 9 (AAV9) mini gene therapy (scAAV9/mini) in mice. Here, we report an efficacy assessment for the human-ready version of this regulated gene therapy (TSHA-102) in male knockout (KO) mice after intracerebroventricular (ICV) administration at postnatal day 2 (P2) and after intrathecal (IT) administration at P7, P14 (±immunosuppression), and P28 (±immunosuppression). We also report qPCR studies on KO mice treated at P7-P35; protein analyses in KO mice treated at P38; and a survival safety study in female adult mice. In KO mice, TSHA-102 improved respiration, weight, and survival across multiple doses and treatment ages. TSHA-102 significantly improved the front average stance and swing times relative to the front average stride time after P14 administration of the highest dose for that treatment age. Viral genomic DNA and mini mRNA were present in the CNS. MiniMeCP2 protein expression was higher in the KO spinal cord compared to the brain. In female mice, TSHA-102 permitted survivals that were similar to those of vehicle-treated controls. In all, these pivotal data helped to support the regulatory approval to initiate a clinical trial for TSHA-102 in RTT patients (clinical trial identifier number NCT05606614).
Topics: Adult; Humans; Female; Male; Animals; Mice; Rett Syndrome; MicroRNAs; Mental Retardation, X-Linked; Brain; DNA, Viral; Genetic Therapy; Mice, Knockout
PubMed: 38254921
DOI: 10.3390/genes15010031 -
Frontiers in Psychiatry 2023We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial...
We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.
PubMed: 38250256
DOI: 10.3389/fpsyt.2023.1301272 -
Pediatric Neurology Mar 2024Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is often identified as the most important caregiver goal for new therapies. This analysis reports the communication-related end points from the phase 3 LAVENDER study of trofinetide in RTT.
METHODS
Females with RTT, aged five to 20 years, were randomized 1:1 to trofinetide or placebo for 12 weeks. Secondary efficacy end points related to communication were based on change from baseline to week 12 and included the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite score (key secondary end point; scores ranged from 0 to 26 [higher scores indicated better communication]) and novel clinician rating scales (0 [normal] to 7 [severe impairment]) measuring the ability to communicate choices nonverbally (RTT-COMC) and verbally (RTT-VCOM).
RESULTS
Trofinetide demonstrated a statistically significant difference versus placebo for the CSBS-DP-IT Social Composite score (least squares mean [LSM] difference = 1.0; 95% confidence interval [CI], 0.3 to 1.7; P = 0.0064; Cohen's d effect size = 0.43) and a nominally significant difference for the RTT-COMC (LSM difference: -0.3; 95% CI, -0.6 to -0.0; P = 0.0257; Cohen's d effect size = 0.36). As expected, there was no difference for the RTT-VCOM.
CONCLUSIONS
Significant treatment benefit for trofinetide versus placebo was observed in scales measuring the ability to communicate. These scales may be appropriate for future clinical studies in RTT and other neurodevelopmental disorders.
Topics: United States; Female; Infant; Humans; Rett Syndrome; Glutamates; Caregivers
PubMed: 38232652
DOI: 10.1016/j.pediatrneurol.2023.11.005 -
Cardiology Research Dec 2023Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies....
BACKGROUND
Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics.
METHODS
A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted.
RESULTS
RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, patients had prolonged QTc compared to and patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients.
CONCLUSIONS
Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.
PubMed: 38187509
DOI: 10.14740/cr1580