scholarly journals IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Giorgio Pini ◽  
Maria Flora Scusa ◽  
Laura Congiu ◽  
Alberto Benincasa ◽  
Paolina Morescalchi ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorders ◽  
Primary Care Physicians ◽  
Safety Assessment ◽  
Neurodevelopmental Disorder ◽  
Synaptic Function ◽  
Subcutaneous Injections ◽  
Clinical Observations ◽  
Mecp2 Protein ◽  
The Central Nervous System

Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3) IGF1, cross the blood brain barrier, and (1–3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration.

Enhanced Hypoxia Susceptibility in Hippocampal Slices From a Mouse Model of Rett Syndrome

2009 ◽  
Vol 101 (2) ◽  
pp. 1016-1032 ◽  
Author(s):  
Marc Fischer ◽  
Julia Reuter ◽  
Florian J. Gerich ◽  
Belinda Hildebrandt ◽  
Sonja Hägele ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Neurodevelopmental Disorder ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Synaptic Function ◽  
Cell Swelling ◽  
Arterial Oxygen ◽  
Ca1 Pyramidal Neurons

Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-chromosomal MECP2 gene encoding for the transcriptional regulator methyl CpG binding protein 2 (MeCP2). Rett patients suffer from episodic respiratory irregularities and reduced arterial oxygen levels. To elucidate whether such intermittent hypoxic episodes induce adaptation/preconditioning of the hypoxia-vulnerable hippocampal network, we analyzed its responses to severe hypoxia in adult Rett mice. The occurrence of hypoxia-induced spreading depression (HSD)—an experimental model for ischemic stroke—was hastened in Mecp2− /y males. The extracellular K+ rise during HSD was attenuated in Mecp2− /y males and the input resistance of CA1 pyramidal neurons decreased less before HSD onset. CA1 pyramidal neurons were smaller and more densely packed, but the cell swelling during HSD was unaffected. The intrinsic optical signal and the propagation of HSD were similar among the different genotypes. Basal synaptic function was intact, but Mecp2− /y males showed reduced paired-pulse facilitation and higher field potential/fiber volley ratios, but no increased seizure susceptibility. Synaptic failure during hypoxia was complete in all genotypes and the final degree of posthypoxic synaptic recovery indistinguishable. Cellular ATP content was normal in Mecp2− /y males, but their hematocrit was increased as was HIF-1α expression throughout the brain. This is the first study showing that in Rett syndrome, the susceptibility of telencephalic neuronal networks to hypoxia is increased; the underlying molecular mechanisms apparently involve disturbed K+ channel function. Such an increase in hypoxia susceptibility may potentially contribute to the vulnerability of male Rett patients who are either not viable or severely disabled.

scholarly journals Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mirko Luoni ◽  
Serena Giannelli ◽  
Marzia Tina Indrigo ◽  
Antonio Niro ◽  
Luca Massimino ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Protein Translation ◽  
Mutant Mice ◽  
Gene Encoding ◽  
Strong Immune Response ◽  
Intravenous Injections ◽  
Protein Levels ◽  
Mecp2 Protein ◽  
The Brain

Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.

scholarly journals Rett syndrome: a sex-biased neurodevelopmental disorder

2017 ◽  
Vol 39 (1) ◽  
pp. 30-33 ◽  
Author(s):  
Eyleen Goh
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorders ◽  
Expression Profiles ◽  
Neurodevelopmental Disorder ◽  
Gene Expression Profiles ◽  
Autism Spectrum ◽  
Related Disorder ◽  
Genetic Sequences ◽  
Biochemical Profiles ◽  
Males And Females

Decades of research on neurodevelopmental disorders have focused on genetics. Although there has been significant progress, the aetiology of many neurodevelopmental disorders still remains unknown. Deciphering genetic sequences of the whole genome can identify disease-causing mutations in individuals. However, the same genetic sequences do not necessarily result in similar gene expression profiles, or the consequential biochemical profiles in every cell and in all individuals. In particular, studies have shown that differential biochemical profiles in males and females, possibly play a role in neurodevelopmental disorders being biased towards a different gender. Interestingly, autism spectrum disorder (ASD) is biased towards boys although it is not an X-linked disorder, whereas Rett syndrome, an ASD-related disorder where the disease-causing gene is located on the X-chromosome, is found almost exclusively in girls.

scholarly journals The Molecular Functions of MeCP2 in Rett Syndrome Pathology

2021 ◽  
Vol 12 ◽  
Author(s):  
Osman Sharifi ◽  
Dag H. Yasui
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Original Research ◽  
Novel Treatments ◽  
Conflicting Evidence ◽  
Mecp2 Protein ◽  
Culture Models ◽  
Biologic Function ◽  
Cell Culture Models

MeCP2 protein, encoded by the MECP2 gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As MECP2 gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with Mecp2 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.

Auditory Profile of Children With Some Rare Neurodevelopmental Disorders

2019 ◽  
pp. 32-55
Author(s):  
Saransh Jain ◽  
Vijaya Kumar Narne
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hearing Loss ◽  
Sensory Processing ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Sensory System ◽  
Prevalence Rates ◽  
Human Beings ◽  
The Central Nervous System

Neurodevelopmental disorder is an umbrella term comprising many muscular, skeletal, metabolic, endocrinal, systemic, and immune-related diseases, which are caused due to the improper/inaccurate development of the central nervous system. Most of these disorders are highly prevalent, but some express rarely in human beings. Such disorders with least prevalence rates are known as rare neurodevelopmental disorders. The sensory system is affected in all individuals with these rare neurodevelopmental disorders, although to a varying extent. Sensory processing in terms of hearing loss is reported by many researchers in many rare neurodevelopmental disorders, but the pathophysiology of audiological findings are seldom investigated. In this chapter, the authors highlight the possible relationship between underlying cause and the resultant audiological symptoms in some of the rare neurodevelopmental disorders. Further, the research studies on the audiological profiling in such disorders are discussed.

scholarly journals Wide phenotypic spectrum of human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations

2020 ◽  
Author(s):  
Rebecca SF Mok ◽  
Wenbo Zhang ◽  
Taimoor I Sheikh ◽  
Isabella R Fernandes ◽  
Leah C DeJong ◽  
...  
Keyword(s):  
Stem Cell ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Synaptic Function ◽  
Proper Function ◽  
Loss Of Function ◽  
Electrode Arrays ◽  
Burst Frequency ◽  
Wide Range ◽  
Excitatory Neurons

ABSTRACTRett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) that is a global transcriptional regulator. Mutations in the methyl-binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA required for proper function in the brain. Here, we investigate the effect of a novel MECP2 L124W missense mutation in the MBD in comparison to MECP2 null mutations. L124W protein had a limited ability to disrupt heterochromatic chromocenters due to decreased binding dynamics. We isolated two pairs of isogenic WT and L124W induced pluripotent stem cell lines. L124W induced excitatory neurons expressed stable protein, exhibited only increased input resistance and impaired voltage-gated Na+ and K+ currents, and their neuronal dysmorphology was limited to reduced dendritic complexity. Three isogenic pairs of MECP2 null neurons had the expected more pronounced morphological and electrophysiological phenotypes, exhibiting decreased soma area, dendrite length, capacitance and excitatory synaptic function. We examined development and maturation of excitatory neural networks using micro-electrode arrays to detect alterations in RTT connectivity. The L124W neurons had no detectable changes in network circuitry features, in contrast to MECP2 null neurons that suffered a significant change in synchronous network burst frequency and a transient extension of network burst duration. Our results from stem cell-derived RTT excitatory neurons reveal a wide range of morphological, electrophysiological and circuitry phenotypes that reflect the severity of the MECP2 mutation.

scholarly journals Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome

2020 ◽  
Vol 29 (15) ◽  
pp. 2461-2470
Author(s):  
Jonathan K Merritt ◽  
Bridget E Collins ◽  
Kirsty R Erickson ◽  
Hongwei Dong ◽  
Jeffrey L Neul
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Therapeutic Approach ◽  
Neurodevelopmental Disorder ◽  
Intraperitoneal Administration ◽  
Full Length ◽  
Nonsense Suppression ◽  
Null Mouse ◽  
Peripheral Tissues ◽  
Mecp2 Protein

Abstract Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete null mouse models; however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof of concept for future preclinical studies of nonsense suppression agents in RTT.

scholarly journals Effects ofω-3 Polyunsaturated Fatty Acids on Plasma Proteome in Rett Syndrome

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Claudio De Felice ◽  
Alessio Cortelazzo ◽  
Cinzia Signorini ◽  
Roberto Guerranti ◽  
Silvia Leoncini ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Rett Syndrome ◽  
Clinical Symptoms ◽  
Neurodevelopmental Disorder ◽  
Plasma Proteome ◽  
Omega 3 ◽  
Gene Encoding ◽  
Mecp2 Protein ◽  
Novel Therapeutic Strategies

The mechanism of action of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) is only partially known. Prior reports suggest a partial rescue of clinical symptoms and oxidative stress (OS) alterations followingω-3 PUFAs supplementation in patients with Rett syndrome (RTT), a devastating neurodevelopmental disorder with transient autistic features, affecting almost exclusively females and mainly caused by sporadic mutations in the gene encoding the methyl CpG binding protein 2 (MeCP2) protein. Here, we tested the hypothesis thatω-3 PUFAs may modify the plasma proteome profile in typical RTT patients withMECP2mutations and classic phenotype. A total of 24 RTT girls at different clinical stages were supplemented withω-3 PUFAs as fish oil for 12 months and compared to matched healthy controls. The expression of 16 proteins, mainly related to acute phase response (APR), was changed at the baseline in the untreated patients. Followingω-3 PUFAs supplementation, the detected APR was partially rescued, with the expression of 10 out of 16 (62%) proteins being normalized.ω-3 PUFAs have a major impact on the modulation of the APR in RTT, thus providing new insights into the role of inflammation in autistic disorders and paving the way for novel therapeutic strategies.

Three-dimensional structure of dendritic spines, neuronal specializations that impart both stability and flexibility to synaptic function

1993 ◽  
Vol 51 ◽  
pp. 92-93
Author(s):  
Kristen M. Harris
Keyword(s):  
Dendritic Spines ◽  
Three Dimensional ◽  
Synaptic Function ◽  
Dimensional Structure ◽  
Excitatory Synapses ◽  
Concept Of Function ◽  
Section Electron ◽  
High Quality Information ◽  
The Central Nervous System ◽  
Mathematical Analyses

Dendritic spines are the tiny protrusions that stud the surface of many neurons and they are the location of over 90% of all excitatory synapses that occur in the central nervous system. Their small size and variable shapes has in large part made detailed study of their structure refractory to conventional light microscopy and single section electron microscopy (EM). Yet their widespread occurrence and likely involvement in learning and memory has motivated extensive efforts to obtain quantitative descriptions of spines in both steady state and dynamic conditions. Since the seminal mathematical analyses of D’Arcy Thompson, the power of establishing quantitatively key parameters of structure has become recognized as a foundation of successful biological inquiry. For dendritic spines highly precise determinations of structure and its variation are proving themselves as the kingpin for establishing a valid concept of function. The recent conjunction of high quality information about the structure, function, and theoretical implications of dendritic spines has produced a flurry of new considerations of their role in synaptic transmission.

Response to Steroids in IQSEC2-Related Encephalopathy Presenting with Rett-Like Phenotype and Infantile Spasms

2020 ◽  
Author(s):  
Divya Nagabushana ◽  
Aparajita Chatterjee ◽  
Raghavendra Kenchaiah ◽  
Ajay Asranna ◽  
Gautham Arunachal ◽  
...  
Keyword(s):  
Late Onset ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
The Past ◽  
Resource Limited ◽  
The Central Nervous System ◽  
Motor Milestone ◽  
Behavior And Cognition ◽  
Atypical Rett Syndrome

Abstract Introduction IQSEC2-related encephalopathy is an X-linked childhood neurodevelopmental disorder with intellectual disability, epilepsy, and autism. This disorder is caused by a mutation in the IQSEC2 gene, the product of which plays an important role in the development of the central nervous system. Case Report We describe the symptomatology, clinical course, and management of a 17-month-old male child with a novel IQSEC2 mutation. He presented with an atypical Rett syndrome phenotype with developmental delay, autistic features, midline stereotypies, microcephaly, hypotonia and epilepsy with multiple seizure types including late-onset infantile spasms. Spasms were followed by worsening of behavior and cognition, and regression of acquired milestones. Treatment with steroids led to control of spasms and improved attention, behavior and recovery of lost motor milestone. In the past 10 months following steroid therapy, child lags in development, remains autistic with no further seizure recurrence. Conclusion IQSEC2-related encephalopathy may present with atypical Rett phenotype and childhood spasms. In resource-limited settings, steroids may be considered for spasm remission in IQSEC2-related epileptic encephalopathy.

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