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Neurotherapeutics : the Journal of the... Jun 2024
PubMed: 38944637
DOI: 10.1016/j.neurot.2024.e00389 -
Pediatric Neurology Jun 2024Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the...
BACKGROUND
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL.
METHODS
We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed.
RESULTS
We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases.
CONCLUSIONS
Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.
PubMed: 38936258
DOI: 10.1016/j.pediatrneurol.2024.06.001 -
Pharmaceutics Jun 2024Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutation in the X-linked gene methyl-CpG-binding protein 2 (Mecp2), a ubiquitously expressed...
Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutation in the X-linked gene methyl-CpG-binding protein 2 (Mecp2), a ubiquitously expressed transcriptional regulator. RTT results in mental retardation and developmental regression that affects approximately 1 in 10,000 females. Currently, there is no curative treatment for RTT. Thus, it is crucial to develop new therapeutic approaches for children suffering from RTT. Several studies suggested that RTT is linked with defects in cholesterol homeostasis, but for the first time, therapeutic evaluation is carried out by modulating this pathway. Moreover, AAV-based CYP46A1 overexpression, the enzyme involved in cholesterol pathway, has been demonstrated to be efficient in several neurodegenerative diseases. Based on these data, we strongly believe that CYP46A1 could be a relevant therapeutic target for RTT. Herein, we evaluated the effects of intravenous AAVPHP.eB-hCYP46A1-HA delivery in male and female -deficient mice. The applied AAVPHP.eB-hCYP46A1 transduced essential neurons of the central nervous system (CNS). CYP46A1 overexpression alleviates behavioral alterations in both male and female mice and extends the lifespan in males. Several parameters related to cholesterol pathway are improved and correction of mitochondrial activity is demonstrated in treated mice, which highlighted the clear therapeutic benefit of CYP46A1 through the neuroprotection effect. IV delivery of AAVPHP.eB-CYP46A1 is perfectly well tolerated with no inflammation observed in the CNS of the treated mice. Altogether, our results strongly suggest that CYP46A1 is a relevant target and overexpression could alleviate the phenotype of Rett patients.
PubMed: 38931878
DOI: 10.3390/pharmaceutics16060756 -
European Archives of Paediatric... Jun 2024This study aimed to validate qPCR assays for specific microbiota, for use on dental plaque samples stored on Whatman FTA cards to compare relative oral health risk in...
PURPOSE
This study aimed to validate qPCR assays for specific microbiota, for use on dental plaque samples stored on Whatman FTA cards to compare relative oral health risk in Rett syndrome.
METHODS
Supragingival dental plaque samples were collected, using a sterile swab, (COPAN FLOQswab™) swabbed onto Whatman FTA™ cards. DNA extraction was performed using a modified Powersoil™ protocol. Where published assays were unsuitable, species-specific qPCR assays for caries-associated, gingivitis-associated and oral-health-associated bacteria were designed using multiple sequence alignment, Primer3Plus and PrimerQuest. Assays were run using absolute quantification. Limit of detection (LOD) and limit of quantification (LOQ) were calculated, and PCR products verified by Sanger sequencing.
RESULTS
Most assays allowed detection using real-time qPCR with high specificity on samples collected on FTA cards. Several assays showed low or even single gene copy numbers on the test samples.
CONCLUSION
Assays were optimised for detection and evaluation of oral health risk in dental plaque samples stored on FTA cards when cold storage is not feasible, except for F. nucleatum. Several assays showed gene copy numbers less than the LOQ or outside the range of the standard curve, so there is merit in optimising these assays using digital droplet PCR.
PubMed: 38926242
DOI: 10.1007/s40368-024-00912-8 -
Med (New York, N.Y.) Jun 2024Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is...
BACKGROUND
Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER.
METHODS
Females with Rett syndrome aged 5-21 years received open-label treatment with trofinetide for 40 weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40.
FINDINGS
Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea was the most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively.
CONCLUSIONS
Treatment with trofinetide for ≤40 weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER.
FUNDING
The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314).
PubMed: 38917793
DOI: 10.1016/j.medj.2024.05.018 -
Developmental Neurorehabilitation Jun 2024Rett syndrome is a neurodevelopmental disorder in which scoliosis is a common orthopedic complication. This explorative study aims to identify predictors for rapid...
Rett syndrome is a neurodevelopmental disorder in which scoliosis is a common orthopedic complication. This explorative study aims to identify predictors for rapid progression of scoliosis in Rett syndrome to enable variable selection for future prediction model development. A univariable logistic regression model was used to identify variables that discriminate between individuals with and without rapid progression of scoliosis (>10Cobb angle/6 months) based on multi-center data. Predictors were identified using univariable logistic regression with OR (95% CI) and AUC (95% CI). Age at inclusion, Cobb angle at baseline and epilepsy have the highest discriminative ability for rapid progression of scoliosis in Rett syndrome.
PubMed: 38907992
DOI: 10.1080/17518423.2024.2365794 -
Journal of Peptide Science : An... Jun 2024Peptides exhibit significant specificity and effective interaction with therapeutic targets, positioning themselves as key players in the global pharmaceutical market.... (Review)
Review
Peptides exhibit significant specificity and effective interaction with therapeutic targets, positioning themselves as key players in the global pharmaceutical market. They offer potential treatments for a wide range of diseases, including those that pose significant challenges. Notably, the peptide trofinetide (Daybue) marked a groundbreaking achievement by providing the first-ever cure for Rett syndrome, and several peptides have secured FDA approval as first-in-class medications. Furthermore, peptides are expanding their presence in areas traditionally dominated by either small or large molecules. A noteworthy example is the FDA approval of motixafortide (Aphexda) as the first peptide-based chemokine antagonist. Here, the focus will be on the analysis of FDA-approved peptides, particularly those targeting cardiovascular diseases, human immunodeficiency, central nervous system diseases, and various other intriguing classes addressing conditions such as osteoporosis, thrombocytopenia, Cushing's disease, and hypoglycemia, among others. The review will explore the chemical structures of the peptides, their indications and modes of action, the developmental trajectory, and potential adverse effects.
PubMed: 38885943
DOI: 10.1002/psc.3627 -
Disease Models & Mechanisms Jun 2024MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of the MECP2 locus and its surrounding genes, including IRAK1. Current MDS...
MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of the MECP2 locus and its surrounding genes, including IRAK1. Current MDS mouse models involve transgenic expression of MECP2 only, limiting their applicability to the study of the disease. Herein, we show that an efficient and precise CRISPR/Cas9 fusion proximity-based approach can be utilized to generate an Irak1-Mecp2 tandem duplication mouse model ("Mecp2 Dup"). The Mecp2 Dup mouse model recapitulates the genomic landscape of human MDS by harbouring a 160 kb tandem duplication encompassing Mecp2 and Irak1, representing the minimal disease-causing duplication, and the neighbouring genes Opnmw1 and Tex28. The Mecp2 Dup model exhibits neuro-behavioral abnormalities, and an abnormal immune response to infection not previously observed in other mouse models, possibly owing to Irak1 overexpression. The Mecp2 Dup model thus provides a tool to investigate MDS disease mechanisms and develop potential therapies applicable to patients.
PubMed: 38881329
DOI: 10.1242/dmm.050528 -
Neurotherapeutics : the Journal of the... Jun 2024Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X chromosome-linked gene Methyl-CpG Binding Protein 2 (MECP2). Restoring MeCP2...
Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X chromosome-linked gene Methyl-CpG Binding Protein 2 (MECP2). Restoring MeCP2 expression after disease onset in a mouse model of RTT reverses phenotypes, providing hope for development of treatments for RTT. Translatable biomarkers of improvement and treatment responses have the potential to accelerate both preclinical and clinical evaluation of targeted therapies in RTT. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials, that correlate with disease severity, suggesting that they could be useful as biomarkers of disease improvement or early treatment response. We recently demonstrated that treatment of RTT mice with a positive allosteric modulator (PAM) of muscarinic acetylcholine subtype 1 receptor (M) improved phenotypes, suggesting that modulation of M activity is a potential therapy in RTT. To evaluate whether neurophysiological features could be useful biomarkers to assess the effects of M PAM treatment, we acutely administered the M PAM VU0486846 (VU846) at doses of 1, 3, 10 and 30 mg/kg in wildtype and RTT mice. This resulted in an inverted U-shaped dose response with maximal improvement of AEP features at 3 mg/kg but with no marked effect on basal EEG power or epileptiform discharges in RTT mice and no significant changes in wildtype mice. These findings suggest that M potentiation can improve neural circuit synchrony to auditory stimuli in RTT mice and that neurophysiological features have potential as pharmacodynamic or treatment-responsive biomarkers for preclinical and clinical evaluation of putative therapies in RTT.
PubMed: 38880672
DOI: 10.1016/j.neurot.2024.e00384 -
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