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Yonsei Medical Journal May 2012Rett syndrome is a severe neurodevelopmental disorder in females. Most have mutations in the methyl-CpG-binding protein 2 (MECP2) gene (80-90%). Epilepsy is a...
PURPOSE
Rett syndrome is a severe neurodevelopmental disorder in females. Most have mutations in the methyl-CpG-binding protein 2 (MECP2) gene (80-90%). Epilepsy is a significant commonly accompanied feature in Rett syndrome. Our study was aimed at comprehensive analysis of genetic and clinical features in Rett syndrome patients, especially in regards to epileptic features.
MATERIALS AND METHODS
We retrospectively reviewed 20 patients who were diagnosed with MECP2 mutations at Severance Children's Hospital between January 1995 and July 2010. All patients met clinical criteria for Rett syndrome. Evaluations included clinical features, epilepsy classification, electroencephalography analysis, and treatment of seizures.
RESULTS
Ages ranged from 3.6 to 14.3 years (7.7±2.6). Fourteen different types of MECP2 mutations were found, including a novel in-frame mutation (1153-1188 del36). Fourteen of these patients (70.0%) had epilepsy, and the average age of seizure onset was 3.0±1.8 years. Epilepsy was diverse, including partial seizure in four patients (28.5%), secondarily generalized seizure in six (42.8%), generalized tonic seizure in two (14.3%), Lennox-Gastaut syndrome in one (7.1%), and myoclonic status in non-progressive encephalopathy in one (7.1%). Motor functions were delayed so that only 10 patients (50.0%) were able to walk independently: five (35.8%) in the epilepsy group and five (83.3%) in the non-epilepsy group. Average developmental scale was 33.5±32.8 in the epilepsy group and 44.4±21.2 in the non-epilepsy group. A clear genotype-phenotype correlation was not found.
CONCLUSION
There is a tendency for more serious motor impairment and cognitive deterioration in Rett syndrome patients with epilepsy.
Topics: Adolescent; Child; Child, Preschool; Epilepsy; Female; Genotype; Humans; Male; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Retrospective Studies; Rett Syndrome
PubMed: 22476991
DOI: 10.3349/ymj.2012.53.3.495 -
Surface- and voxel-based brain morphologic study in Rett and Rett-like syndrome with MECP2 mutation.International Journal of Developmental... Apr 2019Rett syndrome (RTT) is a rare congenital disorder which in most cases (95%) is caused by methyl-CpG binding protein 2 (MECP2) mutations. RTT is characterized by...
Rett syndrome (RTT) is a rare congenital disorder which in most cases (95%) is caused by methyl-CpG binding protein 2 (MECP2) mutations. RTT is characterized by regression in global development, epilepsy, autistic features, acquired microcephaly, habitual hand clapping, loss of purposeful hand skills, and autonomic dysfunctions. Although the literature has demonstrated decreased volumes of the cerebrum, cerebellum, and the caudate nucleus in RTT patients, surface-based brain morphology including cortical thickness and cortical gyrification analyses are lacking in RTT. We present quantitative surface- and voxel-based morphological measurements in young children with RTT and Rett-like syndrome (RTT-l) with MECP2 mutations. The 8 structural T1-weighted MR images were obtained from 7 female patients with MECP2 mutations (3 classic RTT, 2 variant RTT, and 2 RTT-l) (mean age 5.2 [standard deviation 3.3] years old). Our analyses demonstrated decreased total volumes of the cerebellum in RTT/RTT-l compared to gender- and age-matched controls (t (22)=-2.93, p = .008, Cohen's d = 1.27). In contrast, global cerebral cortical surface areas, global/regional cortical thicknesses, the degree of global gyrification, and global/regional gray and white matter volumes were not statistically significantly different between the two groups. Our findings, as well as literature findings, suggest that early brain abnormalities associated with RTT/RTT-l (with MECP2 mutations) can be detected as regionally decreased cerebellar volumes. Decreased cerebellar volume may be helpful for understanding the etiology of RTT/RTT-l.
Topics: Adolescent; Brain; Child; Child, Preschool; Female; Humans; Infant; Magnetic Resonance Imaging; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Rett Syndrome
PubMed: 30690146
DOI: 10.1016/j.ijdevneu.2019.01.005 -
The Protein Journal Apr 2022The transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2) is an intrinsically disordered protein, mutations in which, are implicated in the onset of Rett...
The transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2) is an intrinsically disordered protein, mutations in which, are implicated in the onset of Rett Syndrome, a severe and debilitating neurodevelopmental disorder. Delivery of this protein fused to the cell-penetrating peptide TAT could allow for the intracellular replenishment of functional MeCP2 and hence potentially serve as a prospective Rett Syndrome therapy. This work outlines the expression, purification and characterization of various TAT-MeCP2 constructs as well as their full-length and shortened eGFP fusion variants. The latter two constructs were used for intracellular uptake studies with subsequent analysis via western blotting and live-cell imaging. All purified MeCP2 samples exhibited high degree of stability and very little aggregation propensity. Full length and minimal TAT-MeCP2-eGFP were found to efficiently transduce into human dermal and murine fibroblasts and localize to cell nuclei. These findings clearly support the utility of MeCP2-based protein replacement therapy as a potential Rett Syndrome treatment option.
Topics: Animals; Cell Nucleus; Humans; Methyl-CpG-Binding Protein 2; Mice; Mutation; Prospective Studies; Rett Syndrome
PubMed: 35546650
DOI: 10.1007/s10930-022-10054-9 -
Brain & Development Jan 2011The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical...
BACKGROUND
The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations.
PATIENTS AND METHODS
We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed.
RESULTS
Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid.
CONCLUSION
A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II.
Topics: Adolescent; Child; Child, Preschool; Humans; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Rett Syndrome
PubMed: 20116947
DOI: 10.1016/j.braindev.2010.01.004 -
American Journal of Human Genetics Dec 2002
Review
Topics: Animals; Chromosomal Proteins, Non-Histone; DNA Methylation; DNA-Binding Proteins; Disease Models, Animal; Gene Expression Profiling; Genotype; Humans; Methyl-CpG-Binding Protein 2; Mutation; Neurons; Phenotype; Repressor Proteins; Rett Syndrome
PubMed: 12442230
DOI: 10.1086/345360 -
Journal of Translational Medicine Oct 2023Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal...
BACKGROUND
Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal growth, which results in the loss of acquired capabilities such as speech or purposeful usage of hands. While altered neurotransmission and brain development are the center of its pathophysiology, alterations in mitochondrial performance have been previously outlined, shaping it as an attractive target for the disease treatment.
METHODS
We have thoroughly described mitochondrial performance in two Rett models, patients' primary fibroblasts and female Mecp2 mice brain, discriminating between different brain areas. The characterization was made according to their bioenergetics function, oxidative stress, network dynamics or ultrastructure. Building on that, we have studied the effect of leriglitazone, a PPARγ agonist, in the modulation of mitochondrial performance. For that, we treated Rett female mice with 75 mg/kg/day leriglitazone from weaning until sacrifice at 7 months, studying both the mitochondrial performance changes and their consequences on the mice phenotype. Finally, we studied its effect on neuroinflammation based on the presence of reactive glia by immunohistochemistry and through a cytokine panel.
RESULTS
We have described mitochondrial alterations in Rett fibroblasts regarding both shape and bioenergetic functions, as they displayed less interconnected and shorter mitochondria and reduced ATP production along with increased oxidative stress. The bioenergetic alterations were recalled in Rett mice models, being especially significant in cerebellum, already detectable in pre-symptomatic stages. Treatment with leriglitazone recovered the bioenergetic alterations both in Rett fibroblasts and female mice and exerted an anti-inflammatory effect in the latest, resulting in the amelioration of the mice phenotype both in general condition and exploratory activity.
CONCLUSIONS
Our studies confirm the mitochondrial dysfunction in Rett syndrome, setting the differences through brain areas and disease stages. Its modulation through leriglitazone is a potential treatment for this disorder, along with other diseases with mitochondrial involvement. This work constitutes the preclinical necessary evidence to lead to a clinical trial.
Topics: Humans; Female; Mice; Animals; Rett Syndrome; Mitochondria; Brain; Oxidative Stress; Disease Models, Animal
PubMed: 37884937
DOI: 10.1186/s12967-023-04622-5 -
Neurochemistry International Sep 2021Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly impacting females. MECP2 is... (Review)
Review
Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly impacting females. MECP2 is an epigenetic transcriptional regulator acting mainly to repress gene expression, though it plays multiple gene regulatory roles and has distinct molecular targets across different cell types and specific developmental stages. In this review, we summarize MECP2 loss-of-function associated transcriptome and proteome disruptions, delving deeper into the latter which have been comparatively severely understudied. These disruptions converge on multiple biochemical and cellular pathways, including those involved in synaptic function and neurodevelopment, NF-κB signaling and inflammation, and the vitamin D pathway. RTT is a complex neurological disorder characterized by myriad physiological disruptions, in both the central nervous system and peripheral systems. Thus, treating RTT will likely require a combinatorial approach, targeting multiple nodes within the interactomes of these cellular pathways. To this end, we discuss the use of dietary supplements and factors, namely, vitamin D and polyunsaturated fatty acids (PUFAs), as possible partial therapeutic agents given their demonstrated benefit in RTT and their ability to restore homeostasis to multiple disrupted cellular pathways simultaneously. Further unravelling the complex molecular alterations induced by MECP2 loss-of-function, and contextualizing them at the level of proteome homeostasis, will identify new therapeutic avenues for this complex disorder.
Topics: Animals; Humans; Methyl-CpG-Binding Protein 2; Proteomics; Rett Syndrome; Transcription, Genetic
PubMed: 34048843
DOI: 10.1016/j.neuint.2021.105076 -
Neuropharmacology May 2022Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) have opposing molecular origins in relation to expression and function of the transcriptional regulator...
Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) have opposing molecular origins in relation to expression and function of the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2). Several clinical and preclinical phenotypes, however, are shared between these disorders. Modulation of MeCP2 levels has recently emerged as a potential treatment option for both of these diseases. However, toxicity concerns remain with these approaches. Here, we focus on pharmacologically modulating the group II metabotropic glutamate receptors (mGlu), mGlu and mGlu, which are two downstream targets of MeCP2 that are bidirectionally affected in expression in RTT patients and mice (Mecp2) versus an MDS mouse model (MECP2). Mecp2 and MECP2 animals also exhibit contrasting phenotypes in trace fear acquisition, a form of temporal associative learning and memory, with trace fear deficiency observed in Mecp2 mice and abnormally enhanced trace fear acquisition in MECP2 animals. In Mecp2 mice, treatment with the mGlu agonist LY379268 reverses the deficit in trace fear acquisition, and mGlu antagonism with LY341495 normalizes the abnormal trace fear learning and memory phenotype in MECP2 mice. Altogether, these data highlight the role of group II mGlu receptors in RTT and MDS and demonstrate that both mGlu and mGlu may be potential therapeutic targets for these disorders.
Topics: Animals; Disease Models, Animal; Humans; Mental Retardation, X-Linked; Methyl-CpG-Binding Protein 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Metabotropic Glutamate; Rett Syndrome
PubMed: 35248529
DOI: 10.1016/j.neuropharm.2022.109022 -
Italian Journal of Pediatrics Sep 2022Breathing disturbances are often a primary clinical concern especially during wakefulness of the classic form of Rett syndrome, but data for atypical forms are lacking.
BACKGROUND
Breathing disturbances are often a primary clinical concern especially during wakefulness of the classic form of Rett syndrome, but data for atypical forms are lacking.
CASE PRESENTATION
We report the case of a 20-month-old female affected by Rett syndrome with congenital variant-like onset, characterized by severe hypotonia and neurodevelopment impairment. She presented hypoventilation, persistent periodic breathing, and sustained desaturation during sleep, without obstructive or mixed events. Pulse oximetry and capnography during wakefulness were strictly normal. To the best of our knowledge, this is the first case of a patient affected by a congenital variant of Rett syndrome presenting sleep hypercapnia. Hypotonia may play a major role in the genesis of hypoventilation and hypoxemia in our patient. Non-invasive ventilation led to quality-of-life improvements.
CONCLUSIONS
Thus, we suggest screening patients with congenital-like Rett syndrome through transcutaneous bedtime carbon dioxide and oxygen monitoring. Moreover, assisted control mode was a breakthrough to achieve adequate ventilation in our case.
Topics: Female; Humans; Hypercapnia; Hypoventilation; Infant; Muscle Hypotonia; Rett Syndrome; Sleep
PubMed: 36071486
DOI: 10.1186/s13052-022-01359-7 -
Pediatrics and Neonatology Dec 2011Rett syndrome (RTT), a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects... (Review)
Review
Rett syndrome (RTT), a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic, disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a synaptopathy (disease of the synapse) and thus potentially amenable to rational therapeutic intervention.
Topics: Animals; Brain; Disease Models, Animal; Electroencephalography; Genetic Linkage; Genetic Therapy; Humans; Male; Methyl-CpG-Binding Protein 2; Mice; Mice, Knockout; Neuronal Plasticity; Organ Size; Rett Syndrome
PubMed: 22192257
DOI: 10.1016/j.pedneo.2011.08.002