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Journal of Developmental and Physical... Dec 2023Rett syndrome is a severe neurodevelopmental disorder that results in both motor and language skill regression with a wide range of severity in symptom presentation....
Rett syndrome is a severe neurodevelopmental disorder that results in both motor and language skill regression with a wide range of severity in symptom presentation. Communication intervention may be particularly challenging for this population due to the decline in speech, motor skills, and motor planning difficulties that characterize the disorder (Townend et al., 2020), often resulting in the need for augmentative and alternative communication (AAC) technology. Very limited research has evaluated communication interventions for individuals with Rett syndrome and even fewer have targeted expressive communication, an important skill required for improved autonomy and quality of life (Sigafoos et al., 2009; Townend et al., 2020). The current study sought to systematically replicate the Simacek et al. (2017) mand training procedures to teach three girls with Rett Syndrome to use AAC to make requests through caregiver coaching by researchers via telehealth. Results suggest that mand training was successful in increasing AAC use for all three participants. Barriers to intervention for this population and implications of results for future research and clinical practice are discussed.
PubMed: 38053943
DOI: 10.1007/s10882-023-09894-9 -
Neurology. Genetics Dec 2023variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although -related childhood phenotypes are well characterized, the adult...
BACKGROUND AND OBJECTIVES
variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although -related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with variants and epilepsy.
METHODS
Patients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P) variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden.
RESULTS
Fourteen unrelated adult patients (median: 21 years, range: 18-65 years) with -DEE were identified, 11 with novel and 3 with known LP/P de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger.
DISCUSSION
Seventy-one percent of patients with -DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults with -DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.
PubMed: 38045990
DOI: 10.1212/NXG.0000000000200105 -
Neuroscience Jan 2024Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, resulting in severe...
Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, resulting in severe deficits in learning and memory. Alterations in synaptic plasticity have been reported in RTT, however most electrophysiological studies have been performed in male mice only, despite the fact that RTT is primarily found in females. In addition, most studies have focused on excitation, despite the emerging evidence for the important role of inhibition in learning and memory. Here, we performed an electrophysiological characterization in the CA1 region of the hippocampus in both males and females of RTT mouse models with a focus on neurogliaform (NGF) interneurons, given that they are the most abundant dendrite-targeting interneuron subtype in the hippocampus. We found that theta-burst stimulation (TBS) failed to induce long-term potentiation (LTP) in either pyramidal neurons or NGF interneurons in male or female RTT mice, with no apparent changes in short-term plasticity (STP). This failure to induce LTP was accompanied by excitation/inhibition (E/I) imbalances and altered excitability, in a sex- and cell-type specific manner. Specifically, NGF interneurons of male RTT mice displayed increased intrinsic excitability, a depolarized resting membrane potential, and decreased E/I balance, while in female RTT mice, the resting membrane potential was depolarized. Understanding the role of NGF interneurons in RTT animal models is crucial for developing targeted treatments to improve cognition in individuals with this disorder.
Topics: Male; Female; Mice; Animals; Rett Syndrome; Long-Term Potentiation; Methyl-CpG-Binding Protein 2; Hippocampus; Neuronal Plasticity; Disease Models, Animal
PubMed: 38036056
DOI: 10.1016/j.neuroscience.2023.11.028 -
Frontiers in Pharmacology 2023Trofinetide is the first drug approved by the FDA to treat Rett Syndrome in children aged 2 years or above. The drug significantly improved Rett syndrome behavioral...
Trofinetide is the first drug approved by the FDA to treat Rett Syndrome in children aged 2 years or above. The drug significantly improved Rett syndrome behavioral scores Rett syndrome behavioral questionnaire in clinical studies. Although further research is needed to assess potential adverse events, Trofinetide's notable efficacy signifies a significant advancement in Rett syndrome treatment, offering a new therapeutic avenue with the potential to ameliorate the condition.
PubMed: 38035006
DOI: 10.3389/fphar.2023.1284035 -
ACS Omega Nov 2023Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder that has no cure apart from symptomatic treatments. While intense research efforts are required to...
Comprehensive Transcriptomic Investigation of Rett Syndrome Reveals Increasing Complexity Trends from Induced Pluripotent Stem Cells to Neurons with Implications for Enriched Pathways.
Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder that has no cure apart from symptomatic treatments. While intense research efforts are required to fulfill this unmet need, the fundamental challenge is to obtain sufficient patient data. In this study, we used human transcriptomic data of four different sample types from RTT patients including induced pluripotent stem cells, differentiated neural progenitor cells, differentiated neurons, and postmortem brain tissues with an increasing in vivo-like complexity to unveil specific trends in gene expressions across the samples. Based on DEG analysis, we identified F8A3, CNTN6, RPE65, and COL19A1 to have differential expression levels in three sample types and also observed previously reported genes such as MECP2, FOXG1, CACNA1G, SATB2, GABBR2, MEF2C, KCNJ10, and CUX2 in our study. Considering the significantly enriched pathways for each sample type, we observed a consistent increase in numbers from iPSCs to NEUs where MECP2 displayed profound effects. We also validated our GSEA results by using single-cell RNA-seq data. In WGCNA, we elicited a connection among MECP2, TNRC6A, and HOXA5. Our findings highlight the utility of transcriptomic analyses to determine genes that might lead to therapeutic strategies.
PubMed: 38027357
DOI: 10.1021/acsomega.3c06448 -
Intractable & Rare Diseases Research Nov 2023Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls and is caused by mainly mutations in the methyl-CpG-binding protein 2 () gene,...
Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls and is caused by mainly mutations in the methyl-CpG-binding protein 2 () gene, leading to critical issues in normal brain function. The condition has a global prevalence of 5 to 10 cases per 100,000 females, and there is currently no cure for RTT. However, therapy is available to manage the symptoms and improve quality of life. Trofinetide, an insulin-like growth factor 1, was originally developed as a stroke medication and progressed to Phase II clinical trials, where it exhibited favorable safety and efficacy profiles by improving several core RTT symptoms. Recently, Trofinetide received the US Food and Drug Administration (FDA) approval and orphan drug designation for the treatment of RTT, making it the first approved drug for this rare genetic disorder. It has also shown to be safe, well-tolerated and with no known drug interactions. These findings suggest that Trofinetide is a promising treatment option for individuals with RTT.
PubMed: 38024580
DOI: 10.5582/irdr.2023.01060 -
Advances in Orthopedics 2023Pedicle screw placement is a common procedure in spinal surgery. The misplacement rate with lateral and medial cortical perforation is 5-11%. Several techniques are used...
INTRODUCTION
Pedicle screw placement is a common procedure in spinal surgery. The misplacement rate with lateral and medial cortical perforation is 5-11%. Several techniques are used to decrease this rate. Many studies proved that electrical conductivity increases accuracy during pedicle screw placement but no study has interpreted conductivity values.
METHODS
The data are collected from patients operated for scoliosis in a single university hospital. After the posterior surgical approach is made, each pedicle is prepared classically. Instead of the classic curved pedicle probe, the surgeon uses a probe with the same shape that measures the conductivity at its tip. Conductivity values are recorded through a Bluetooth application. Each pedicle trajectory is then qualified after manual palpation with a feeler. A trajectory is qualified as optimal when palpation shows a bone tunnel without any breach, breached when there was a breach, and a modification of the probe direction was needed. A trajectory that does not meet the abovementioned definitions is excluded from the statistical analysis.
RESULTS
21 patients with 457 pedicles are recorded. The average age of the population is 14.71 ± 1.86 years. 17 patients (81%) have idiopathic adolescent scoliosis. One patient has Rett syndrome, one has hypotonia, one has cerebral palsy, and one has congenital malformation. The depth of the instrument is measured semiautomatically. This technique is validated when compared with the manual technique using the Bland-Altman agreement method (mean differences = -0.279 mm, upper limit = 2.2 mm, and lower limit = -2.7 mm) and Deming regression (slope = 1.06 ± 0.004).
CONCLUSION
This study establishes a protocol to collect electrical conductivity signals in spine surgery with synchronization to the depth of the instrument. Real-time conductivity signal feedback alerts the surgeon of a probable breach in the spinal canal, so he can change the direction of the pedicle aim.
PubMed: 38024482
DOI: 10.1155/2023/9955520 -
Annals of Indian Academy of Neurology 2023To study the clinical spectrum of inherited gray matter degenerative brain disorders (DBD) in children.
OBJECTIVES
To study the clinical spectrum of inherited gray matter degenerative brain disorders (DBD) in children.
METHODS
This cross-sectional study evaluated children up to 12 y of age, diagnosed with an inherited gray matter DBD in a tertiary care pediatric hospital between July 2019 and December 2020.
RESULTS
A total of 314 children with progressive neuroregression were screened. Of these, 117 children with inherited gray matter DBD were included in the study. The clinic-based prevalence of DBD was 8.2%, and inherited gray matter DBD was 3.1%. The proportion of the inherited gray matter DBD was 37.3% among the overall DBD cases. Children were categorized into three groups based on the age at onset of disease: below 2 years (N = 57, 48.7%), between 2 and 5 years (N = 32, 27.3%), and between 6 and 12 years (N = 28, 23.9%). Based on the predominant cerebral structure involved, gray matter DBD were classified as cerebral gray matter disorders (53%), basal ganglia disorders (34.1%), and cerebellar disorders (12.8%). Overall, the most common disorders were Wilson disease (18%), neuronal ceroid lipofuscinosis (NCL) (17%), and neurodegeneration with brain iron accumulation (NBIA) (16%). The most common gray matter DBD in children <2 years of age were NBIA (n = 11), Rett syndrome (n = 11), and gangliosidoses (n = 10). NCL (n = 14) and ataxia telangiectasia (n = 6) were most common in the age group of 2-5 years. Wilson disease (n = 19) was the most common disorder in the age group of 6-12 years followed by NCL (n = 4) and NBIA (n = 3).
CONCLUSION
Our study highlights the burden and spectrum of gray matter DBD in children. The clinic-based prevalence of DBD was 8.2%, and of inherited gray matter DBD was 3.1%. The proportion of inherited gray matter DBD was 37.3% among the overall DBD cases. Wilson disease, NCL, and NBIA are the most common gray matter DBD in children. Timely diagnosis is important for the prevention of recurrence in subsequent pregnancies.
PubMed: 38022460
DOI: 10.4103/aian.aian_117_23 -
Clinical Drug Investigation Jan 2024Trofinetide is the first drug to be approved for the treatment of Rett syndrome, a neurodevelopmental disorder. The purpose of the study is to fully characterize the...
BACKGROUND AND OBJECTIVE
Trofinetide is the first drug to be approved for the treatment of Rett syndrome, a neurodevelopmental disorder. The purpose of the study is to fully characterize the metabolic and excretion profiles of trofinetide in humans.
METHODS
This Phase 1, open-label, single-dose trial conducted in healthy male adults was designed to characterize the pharmacokinetics of trofinetide (absorption, metabolism, and excretion), mass balance of [C]-trofinetide, and safety profile of trofinetide following administration of an oral 12-g dose administered as a mixture of trofinetide and [C]-trofinetide. Blood, urine, and fecal samples were collected at prespecified timepoints. The pharmacokinetics of trofinetide were assessed in blood and urine samples using high-performance liquid chromatography (HPLC) with tandem mass spectrometric detection. Bioanalysis of radioactivity was conducted in blood, plasma, urine, and fecal samples using liquid scintillation counting. Metabolite profiling was conducted in blood, plasma, urine, and fecal samples using HPLC with liquid scintillation counting of chromatographic fractions. Safety and tolerability, including treatment-emergent adverse events (TEAEs), were assessed.
RESULTS
Blood concentration-time profiles of trofinetide and total radioactivity were almost superimposable up to ~12 h after dosing. Urine concentration-time profiles of trofinetide and total radioactivity were similar. Trofinetide was rapidly absorbed into the circulation with an initial rapid decline (half-life [t] ~2.6 h), followed by a relatively slow terminal elimination phase (t ~20 h). The blood-to-plasma total radioactivity ratios were 0.529-0.592, indicating a lack of affinity for the cellular portion of blood. Renal excretion accounted for 83.8% of the administered radiochemical dose; 15.1% was recovered in feces. Urine and fecal recovery of radioactivity accounted for 99% of the administered dose at 168 h after dosing. Parent [C]-trofinetide was the major radiolabeled entity in blood and plasma (88.4% and 93.1% in area under the concentration-time curves from 0 to 12 h [AUC] in pooled blood and plasma samples, respectively) and the major entity excreted in urine (91.5% in 0-48-h pooled urine samples) and in feces (52.7% in 0-192-h pooled fecal samples). Only small levels of metabolites were present. In blood and plasma, only two minor metabolites were identified (each metabolite ≤ 2.24% of the AUC pool). These two metabolites were also observed in urine and fecal samples (≤ 2.41% of dose). In feces, one additional metabolite (0.84% of dose) was identified. Two mild TEAEs were reported in two participants and were not considered related to trofinetide. There were no clinically meaningful changes in individual laboratory parameters, vital signs, physical findings, or electrocardiogram results.
CONCLUSIONS
Metabolic and excretion profiles confirm that trofinetide undergoes minimal hepatic or intestinal metabolism and is primarily excreted unchanged in the urine. Trofinetide containing radiolabeled [C]-trofinetide was well tolerated.
Topics: Adult; Humans; Male; Administration, Oral; Chromatography, High Pressure Liquid; Feces; Liver
PubMed: 38017349
DOI: 10.1007/s40261-023-01322-2 -
International Journal of Molecular... Nov 2023Rett Syndrome is an X-linked neurodevelopmental disorder (RTT; OMIM#312750) associated to mutations. MeCP2 dysfunction is seen as one cause for the deficiencies found...
Rett Syndrome is an X-linked neurodevelopmental disorder (RTT; OMIM#312750) associated to mutations. MeCP2 dysfunction is seen as one cause for the deficiencies found in brain-derived neurotrophic factor (BDNF) signaling, since BDNF is one of the genes under MeCP2 jurisdiction. BDNF signaling is also dependent on the proper function of the adenosinergic system. Indeed, both BDNF signaling and the adenosinergic system are altered in -null mice (), a representative model of severe manifestation of RTT. Considering that symptoms severity largely differs among RTT patients, we set out to investigate the BDNF and ADO signaling modifications in heterozygous female mice () presenting a less severe phenotype. Symptomatic mice have lower BDNF levels in the cortex and hippocampus. This is accompanied by a loss of BDNF-induced facilitation of hippocampal long-term potentiation (LTP), which could be restored upon selective activation of adenosine A receptors (AR). While no differences were observed in the amount of adenosine in the cortex and hippocampus of mice compared with healthy littermates, the density of the AR and AR subtype receptors was, respectively, upregulated and downregulated in the hippocampus. Data suggest that significant changes in BDNF and adenosine signaling pathways are present in an RTT model with a milder disease phenotype: female animals. These features strengthen the theory that boosting adenosinergic activity may be a valid therapeutic strategy for RTT patients, regardless of their genetic penetrance.
Topics: Animals; Female; Humans; Mice; Adenosine; Brain-Derived Neurotrophic Factor; Cross-Sectional Studies; Disease Models, Animal; Methyl-CpG-Binding Protein 2; Mice, Knockout; Rett Syndrome
PubMed: 38003438
DOI: 10.3390/ijms242216249