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Pediatric Neurology Nov 2015Survival in Rett syndrome remains unclear. Although early estimates were grim, more recent data suggest that survival into adulthood is typical. We aimed to define...
PURPOSE
Survival in Rett syndrome remains unclear. Although early estimates were grim, more recent data suggest that survival into adulthood is typical. We aimed to define survival in Rett syndrome more clearly and identify risk factors for early death.
METHODS
Participants with clinical Rett Syndrome or methyl-CpG-binding protein 2 mutations without clinical RTT were recruited through the Rett Syndrome Natural History study from 2006 to 2015. Clinical details were collected, and survival was determined using the Kaplan-Meier estimator. Risk factors were assessed using Cox proportional hazards models.
RESULTS
Among 1189 valid participants, 51 died (range 3.9-66.6 years) during the 9-year follow-up period. Those who died included 36 (3.9%) classic Rett syndrome females, 5 (5.9%) atypical severe Rett syndrome females, 1 (2.4%) non-Rett syndrome female, the single atypical severe male, 6 (30%) non-Rett syndrome males, and 2 (7.1%) methyl-CpG-binding protein 2 duplication syndrome males. All atypical mild Rett syndrome females, methyl-CpG-binding protein 2 duplication syndrome females, and the single classic Rett syndrome male remain alive. Most deaths were due to cardiorespiratory issues. Only one died from severe malnutrition, scoliosis, and extreme frailty. Survival for classic and atypical Rett syndrome was greater than 70% at 45 years. Overall severity and several modifiable risk factors, including ambulation, weight, and seizures, were associated with mortality in classic Rett syndrome.
CONCLUSIONS
Survival into the fifth decade is typical in Rett syndrome, and death due to extreme frailty has become rare. Although the leading cause of death remains cardiorespiratory compromise, many risk factors for early death are modifiable. Intense therapeutic interventions could further improve the prognosis for individuals with Rett syndrome.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Methyl-CpG-Binding Protein 2; Middle Aged; Proportional Hazards Models; Rett Syndrome; Risk Factors; United States; Young Adult
PubMed: 26278631
DOI: 10.1016/j.pediatrneurol.2015.06.003 -
The Journal of Clinical Investigation Aug 2015Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication... (Review)
Review
Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG-binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies.
Topics: Animals; Cell Death; Chromatin Assembly and Disassembly; Disease Models, Animal; Humans; Mental Retardation, X-Linked; Methyl-CpG-Binding Protein 2; Mice; Neurons; Rett Syndrome
PubMed: 26237041
DOI: 10.1172/JCI78167 -
Animal Models and Experimental Medicine Dec 2022Rett syndrome (RTT) is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders. MeCP2 protein... (Review)
Review
Rett syndrome (RTT) is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders. MeCP2 protein loss-of-function in neural lineage cells is the main cause of RTT pathogenicity. As it is still hard to understand the mechanism of RTT on the basis of only clinical patients or animal models, cell models cultured in vitro play indispensable roles. Here we reviewed the research progress in the pathogenesis of RTT at the cellular level, summarized the preclinical-research-related applications, and prospected potential future development.
Topics: Animals; Rett Syndrome; Methyl-CpG-Binding Protein 2; Neurons; Autism Spectrum Disorder; Disease Models, Animal
PubMed: 35785421
DOI: 10.1002/ame2.12236 -
Journal of Neurodevelopmental Disorders Sep 2020Rett syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett syndrome display developmental regression at an...
BACKGROUND
Rett syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive, and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome.
METHODS
We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task.
RESULTS
Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT.
CONCLUSIONS
Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.
Topics: Animals; Auditory Perception; Female; Learning; Methyl-CpG-Binding Protein 2; Mice; Mice, Transgenic; Rats; Rett Syndrome
PubMed: 32988374
DOI: 10.1186/s11689-020-09330-5 -
Sultan Qaboos University Medical Journal Nov 2018Rett syndrome (RS) is a severe neurological developmental disorder characterised by stereotypical hand movements, epileptic seizures, craniofacial dysmorphism and...
OBJECTIVES
Rett syndrome (RS) is a severe neurological developmental disorder characterised by stereotypical hand movements, epileptic seizures, craniofacial dysmorphism and digestive dysfunction. This study aimed to examine the correlation between the severity of malocclusion and in patients with RS.
METHODS
This preliminary study was conducted at the Ear, Nose & Throat Clinic of the University Hospital of Siena, Siena, Italy, from January 2014 to December 2017. A total of 56 patients with RS were examined and grouped according to the severity of (absent, mild, moderate or severe) and malocclusion (<2 mm, 2-3 mm, 3-4 mm or >4 mm).
RESULTS
All of the patients were female and the mean age was 11.3 years. Eight (14.3%) patients had mild, 18 (32.1%) had moderate and 30 (53.6%) had severe . Four (7.1%) patients had <2 mm occlusion, 10 (17.9%) had 2-3 mm occlusion, 26 (46.4%) had 3-4 mm occlusion and 16 (28.6%) had >4 mm occlusion. Mild was observed in 100% and 40% of patients with <2 and 2-3 mm malocclusion, respectively, while moderate was present in 60% and 38.5% of patients with 2-3 and 3-4 mm malocclusion, respectively. Severe was observed in 28.6% and 87.5% of patients with 3-4 and >4 mm malocclusion, respectively. There was a significant correlation between and malocclusion severity ( <0.001).
CONCLUSION
A higher degree of malocclusion was associated with more severe among a cohort of patients with RS.
Topics: Adolescent; Child; Cohort Studies; Deglutition Disorders; Disabled Persons; Female; Humans; Italy; Male; Malocclusion; Rett Syndrome
PubMed: 30988968
DOI: 10.18295/squmj.2018.18.04.010 -
Pediatric Research Apr 2011This study used densitometry to investigate the areal bone mineral density (aBMD) and bone mineral content (BMC) in an Australian Rett syndrome cohort and to assess how...
This study used densitometry to investigate the areal bone mineral density (aBMD) and bone mineral content (BMC) in an Australian Rett syndrome cohort and to assess how factors such as genotype, epilepsy, BMI, and mobility affect these parameters. The influence of lean tissue mass (LTM) and bone area (BA) on total body BMC (TBBMC) was also investigated. Participants, recruited from the Australian Rett Syndrome Database (ARSD), had TBBMC and lumbar spine (LS) and femoral neck (FN) aBMD measured using Dual energy x-ray absorptiometry. Mean height standardized Z scores and CIs for the bone outcomes were obtained from multiple regression models. The mean height Z score for the FN aBMD was low at -2.20, while the LS aBMD was -0.72. The TBBMC mean height Z score was -0.62, although once adjusted for BA and LTM, the mean was above zero, suggesting that low BMC can be explained by narrow bones and decreased muscle mass, likely secondary to decreased mobility. Multiple linear regression identified the p.R168× and p.T158M mutations as the strongest predictors of low aBMC and BMD for all bone outcomes. The strong relationship between genotype, BMC, and aBMD is likely underpinned by the strong relationship between LTM, mobility, and bone outcome measures.
Topics: Absorptiometry, Photon; Adult; Australia; Body Composition; Body Height; Bone Density; Child; Databases, Factual; Female; Humans; Rett Syndrome; Surveys and Questionnaires
PubMed: 21178825
DOI: 10.1203/PDR.0b013e31820b937d -
Human Molecular Genetics Oct 2015Loss-of-function mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2) cause a devastating pediatric neurological disorder called Rett syndrome. In males,... (Review)
Review
Loss-of-function mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2) cause a devastating pediatric neurological disorder called Rett syndrome. In males, these mutations typically result in severe neonatal encephalopathy and early lethality. On the other hand, owing to expression of the normal allele in ∼50% of cells, females do not suffer encephalopathy but instead develop Rett syndrome. Typically females with Rett syndrome exhibit a delayed onset of neurologic dysfunction that manifests around the child's first birthday and progresses over the next few years. Features of this disorder include loss of acquired language and motor skills, intellectual impairment and hand stereotypies. The developmental regression observed in patients with Rett syndrome arises from altered neuronal function and is not the result of neurodegeneration. Maintenance of an appropriate level of MeCP2 appears integral to the function of healthy neurons as patients with increased levels of MeCP2, owing to duplication of the Xq28 region encompassing the MECP2 locus, also present with intellectual disability and progressive neurologic symptoms. Despite major efforts over the past two decades to elucidate the molecular functions of MeCP2, the mechanisms underlying the delayed appearance of symptoms remain unclear. In this review, we will highlight recent findings that have expanded our knowledge of MeCP2's functions, and we will discuss how epigenetic regulation, chromatin organization and circuit dynamics may contribute to the postnatal onset of Rett syndrome.
Topics: Brain; Chromatin; Epigenesis, Genetic; Female; Humans; Male; Methyl-CpG-Binding Protein 2; Neurodevelopmental Disorders; Neurons; Rett Syndrome; Transcription, Genetic
PubMed: 26060191
DOI: 10.1093/hmg/ddv217 -
Epilepsia Jul 2022Rett syndrome (RTT), commonly caused by methyl-CpG-binding protein 2 (MECP2) pathogenic variants, has many comorbidities. Fifty to ninety percent of children with RTT...
OBJECTIVE
Rett syndrome (RTT), commonly caused by methyl-CpG-binding protein 2 (MECP2) pathogenic variants, has many comorbidities. Fifty to ninety percent of children with RTT have epilepsy, which is often drug-resistant. Cannabidivarin (CBDV), a non-hallucinogenic phytocannabinoid, has shown benefit in MECP2 animal models. This phase 1 trial assessed the safety and tolerability of CBDV in female children with RTT and drug-resistant epilepsy, as well as the effect on mean monthly seizure frequency (MMSF), the electroencephalogram (EEG), and non-epilepsy comorbid symptoms.
METHODS
Five female children with drug-resistant epilepsy and a pathogenic MECP2 variant were enrolled. Baseline clinical and laboratory assessments, including monthly seizure frequency, were recorded. CBDV oral solution (50 mg/ml) was prescribed and titrated to 10 mg/kg/day. Data collected included pharmacokinetics, seizure type and frequency, adverse events, EEG, and responses to the Rett Syndrome Behaviour Questionnaire and Rett Syndrome Symptom Severity Index, and were compared to baseline data.
RESULTS
All five children reached the maximum CBDV dose of 10 mg/kg/day and had a reduction in MMSF (median = 79% reduction). Three children had MMSF reduction > 75%. This corresponded to an overall reduction in seizure frequency from 32 to 7.2 seizures per month. Ninety-one percent of adverse events were mild or moderate, and none required drug withdrawal. Sixty-two percent were judged to be unrelated to CBDV. Thirty-one percent of adverse events were identified as possibly related, of which nearly all were mild, and the remainder were later assessed as RTT symptoms. Hypersomnolence and drooling were identified as related to CBDV. No serious adverse events reported were related to CBDV. No significant change was noted in EEG or non-epilepsy-related symptoms of RTT.
SIGNIFICANCE
A dose of 10 mg/kg/day of CBDV is safe and well tolerated in a pediatric RTT cohort and suggests improved seizure control in children with MECP2-related RTT.
Topics: Animals; Cannabinoids; Epilepsy; Female; Humans; Methyl-CpG-Binding Protein 2; Rett Syndrome; Seizures
PubMed: 35364618
DOI: 10.1111/epi.17247 -
Archives of Biochemistry and Biophysics Jul 2024To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered a broad-spectrum pathology, instead of... (Review)
Review
To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered a broad-spectrum pathology, instead of just a neurodevelopmental disease, due to the multitude of peripheral co-morbidities and the compromised metabolic pathways, affecting the patients. The altered molecular processes include an impaired mitochondrial function, a perturbed redox homeostasis, a chronic subclinical inflammation and an improper cholesterol metabolism. The persistent subclinical inflammatory condition was first defined ten years ago, as a previously unrecognized feature of RTT, playing a role in the pathology progress and modulation of phenotypical severity. In light of this, the present work aims at reviewing the current knowledge on the chronic inflammatory status and the altered immune/inflammatory functions in RTT, as well as investigating the emerging mechanisms underlying this condition with a special focus on the latest findings about inflammasome system, autoimmunity responses and intestinal micro- and mycobiota. On these bases, although further research is needed, future therapeutic strategies able to re-establish an adequate immune/inflammatory response could represent potential approaches for RTT patients.
Topics: Rett Syndrome; Humans; Inflammation; Inflammasomes; Methyl-CpG-Binding Protein 2; Animals; Gastrointestinal Microbiome
PubMed: 38815782
DOI: 10.1016/j.abb.2024.110046 -
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