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1.
BMC Med Genet ; 21(1): 21, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005172

RESUMO

BACKGROUND: More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. METHODS: In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. RESULTS: As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH (p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis (p < 0.05) and of inability to walk (p < 0.05). CONCLUSION: This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.


Assuntos
Doenças Ósseas/genética , Proteína 2 de Ligação a Metil-CpG/genética , Osteoporose/genética , Síndrome de Rett/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/fisiopatologia , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/genética , Fraturas Ósseas/fisiopatologia , Humanos , Masculino , Mutação , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Síndrome de Rett/diagnóstico por imagem , Síndrome de Rett/fisiopatologia , Escoliose/diagnóstico por imagem , Escoliose/genética , Escoliose/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
2.
Orv Hetil ; 160(51): 2036-2039, 2019 Dec.
Artigo em Húngaro | MEDLINE | ID: mdl-31838863

RESUMO

Here we report on a severe, neonatal onset epileptic encephalopathy manifested in a currently 2-year-old boy with no family history of neurological disease. Extensive clinical investigations were unable to clarify the etiology of the infant's condition characterized by drug-resistant seizures and markedly delayed developmental skills. As in this class of disorders a genetic cause might be identified, a next-generation sequencing (NGS) epilepsy panel examination consisting of 128 genes was initiated for a correct diagnosis. The genetic analysis identified a previously undescribed hemizygous missense mutation in the MECP2 gene. Similarly to other, X-linked dominant disorders, Rett syndrome was originally hypothesized to be lethal in males. This theory, however, has been revised. The aim of this report is to review the wide spectrum of neurodevelopmental diseases observed in male patients carrying mutations in the MECP2 gene classically associated with Rett syndrome in girls. To the author's knowledge, this is the first report in Hungary to document MECP2 mutation of a male patient diagnosed by molecular genetic testing. Orv Hetil. 2019; 160(51): 2036-2039.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett/genética , Pré-Escolar , Humanos , Hungria , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Biologia Molecular , Fenótipo , Síndrome de Rett/fisiopatologia
3.
PLoS One ; 14(7): e0218623, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291284

RESUMO

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Minimally invasive and accurate biomarkers of disease progression and treatment response could facilitate screening of therapeutic compounds in animal models, enrollment of better-defined participants into clinical trials, and treatment monitoring. In this study, we used a targeted approach based on analysis of brain-enriched microRNAs (miRNAs) circulating in plasma to identify miRNA biomarkers of RTT using Mecp2-mutant mice as a model system and human plasma samples. An "miRNA pair" approach, i.e. the ratio between two miRNAs, was used for data normalization. Specific miRNA pairs and their combinations (classifiers) analyzed in plasma differentiated wild-type from Mecp2 male and female mice with >90% accuracy. Individual miRNA pairs were more effective in distinguishing male (homozygous) animals than female (heterozygous) animals, suggesting that disease severity correlated with the levels of the miRNA biomarkers. In the human study, 30 RTT patients were compared with age-matched controls. The results of this study showed that miRNA classifiers were able to differentiate RTT patients from controls with 85-100% sensitivity. In addition, a comparison of various age groups demonstrated that the dynamics in levels of miRNAs appear to be associated with disease development (involvement of liver, muscle and lipid metabolism in the pathology). Importantly, certain miRNA biomarker pairs were common to both the animal models and human subjects, indicating the similarity between the underlying pathological processes. The data generated in this feasibility study suggest that circulating miRNAs have the potential to be developed as markers of RTT progression and treatment response. Larger clinical studies are needed to further evaluate the findings presented here.


Assuntos
Encéfalo/metabolismo , MicroRNA Circulante/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Animais , Biomarcadores/sangue , Encéfalo/fisiopatologia , MicroRNA Circulante/sangue , Modelos Animais de Doenças , Progressão da Doença , Estudos de Viabilidade , Feminino , Regulação da Expressão Gênica , Heterozigoto , Homozigoto , Humanos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Mutação , Síndrome de Rett/sangue , Síndrome de Rett/fisiopatologia , Sensibilidade e Especificidade
5.
Int J Mol Sci ; 20(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344879

RESUMO

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40-73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants-one in GABRB2 and, for first time, one in GABRG2-were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.


Assuntos
Deficiência Intelectual/genética , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas Munc18/genética , Síndrome de Rett/genética , Adolescente , Adulto , Criança , Feminino , Fatores de Transcrição Forkhead/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/fisiopatologia , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Receptores de GABA/genética , Receptores de GABA-A/genética , Síndrome de Rett/fisiopatologia , Sequenciamento Completo do Exoma , Adulto Jovem
6.
Neural Plast ; 2019: 5653180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198418

RESUMO

Genes and environmental stimuli cooperate in the regulation of brain development and formation of the adult neuronal architecture. Genetic alterations or exposure to perturbing environmental conditions, therefore, can lead to altered neural processes associated with neurodevelopmental disorders and brain disabilities. In this context, environmental enrichment emerged as a promising and noninvasive experimental treatment for favoring recovery of cognitive and sensory functions in different neurodevelopmental disorders. The aim of this review is to depict, mainly through the much explicative examples of amblyopia, Down syndrome, and Rett syndrome, the increasing interest in the potentialities and applications of enriched environment-like protocols in the field of neurodevelopmental disorders and the understanding of the molecular mechanisms underlying the beneficial effects of these protocols, which might lead to development of pharmacological interventions.


Assuntos
Encéfalo/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Plasticidade Neuronal/fisiologia , Ambliopia/fisiopatologia , Síndrome de Down/fisiopatologia , Meio Ambiente , Humanos , Síndrome de Rett/fisiopatologia , Meio Social
7.
Int J Mol Sci ; 20(10)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117273

RESUMO

Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible for more than 90% of cases of Rett syndrome (RTT), a progressive neurodevelopmental disorder. As a chromatin modulator, MECP2 can have a key role in the government of stem cell biology. Previously, we showed that deregulated MECP2 expression triggers senescence in mesenchymal stromal cells (MSCs) from (RTT) patients. Over the last few decades, it has emerged that senescent cells show alterations in the metabolic state. Metabolic changes related to stem cell senescence are particularly detrimental, since they contribute to the exhaustion of stem cell compartments, which in turn determine the falling in tissue renewal and functionality. Herein, we dissect the role of impaired MECP2 function in triggering senescence along with other senescence-related aspects, such as metabolism, in MSCs from a mouse model of RTT. We found that MECP2 deficiencies lead to senescence and impaired mitochondrial energy production. Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis of RTT.


Assuntos
Senescência Celular , Proteína 2 de Ligação a Metil-CpG/genética , Mitocôndrias/metabolismo , Mutação , Síndrome de Rett/metabolismo , Animais , Reparo do DNA , Modelos Animais de Doenças , Feminino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Síndrome de Rett/fisiopatologia
8.
BMC Neurol ; 19(1): 77, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043160

RESUMO

BACKGROUND: Rett syndrome (RTT) is a severe neurodevelopmental disorder mainly affecting females. One of the main clinical manifestations is hand stereotypies, which is presumed to based on dysfunction rather than on structural impairment. Reflex interictal discharge precipitated by tapping-lips in electroencephalogram (EEG) is a rare phenomenon among RTT. CASE PRESENTATION: We firstly reported a case of RTT concerning interictal reflex discharge precipitated by tapping- lips. The child, female, 5 years old, presented with a significant regression in motor development and language skills. She almost always tapped the lips with the right hand and stopped only when was interrupted. Her EEG results displayed extensive low amplitude fast wave could be elicited by lightly and slowly- rhythm tapping lips and multifocal bilateral discharges could be precipitated by relatively stronger and quicker rhythm action. It was when the movement stopped that corresponding discharges immediately disappeared. Besides, the reflex discharges were not precipitated by tapping- lips using observer's hand at the certain tempo and intensity. The hand stereotypies did not respond to antiepileptic drugs. CONCLUSIONS: Tapping- lips may be a somatosensory stimulation to precipitate interictal discharges in RTT, which may provide another idea to enrich the insight on hand stereotypies of RTT.


Assuntos
Atividade Motora/fisiologia , Síndrome de Rett/fisiopatologia , Transtorno de Movimento Estereotipado/fisiopatologia , Pré-Escolar , Eletroencefalografia , Feminino , Mãos , Humanos , Lábio
9.
Neurology ; 92(22): e2594-e2603, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31053667

RESUMO

OBJECTIVE: To characterize hand stereotypies (HS) in a large cohort of participants with Rett syndrome (RTT). METHODS: Data from 1,123 girls and women enrolled in the RTT Natural History Study were gathered. Standard tests for continuous and categorical variables were used at baseline. For longitudinal data, we used repeated-measures linear and logistic regression models and nonparametric tests. RESULTS: HS were reported in 922 participants with classic RTT (100%), 73 with atypical severe RTT (97.3%), 74 with atypical mild RTT (96.1%), and 17 females with MECP2 mutations without RTT (34.7%). Individuals with RTT who had classic presentation or severe MECP2 mutations had higher frequency and earlier onset of HS. Heterogeneity of HS types was confirmed, but variety decreased over time. At baseline, almost half of the participants with RTT had hand mouthing, which like clapping/tapping, decreased over time. These 2 HS types were more frequently reported than wringing/washing. Increased HS severity (prevalence and frequency) was associated with worsened measures of hand function. Number and type of HS were not related to hand function. Overall clinical severity was worse with decreased hand function but only weakly related to any HS characteristic. While hand function decreased over time, prevalence and frequency of HS remained relatively unchanged and high. CONCLUSIONS: Nearly all individuals with RTT have severe and multiple types of HS, with mouthing and clapping/tapping decreasing over time. Interaction between HS frequency and hand function is complex. Understanding the natural history of HS in RTT could assist in clinical care and evaluation of new interventions.


Assuntos
Mãos , Síndrome de Rett/epidemiologia , Comportamento Estereotipado , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Mãos/fisiopatologia , Humanos , Lactente , Estudos Longitudinais , Proteína 2 de Ligação a Metil-CpG/genética , Pessoa de Meia-Idade , Movimento , Prevalência , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
10.
Brain Behav ; 9(5): e01250, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30929312

RESUMO

INTRODUCTION: Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that primarily affects girls, with an incidence of 1:10,000-20,000. The diagnosis is based on clinical features: an initial period of apparently normal development (ages 6-12 months) followed by a rapid decline with regression of acquired motor skills, loss of spoken language and purposeful hand use, onset of hand stereotypes, abnormal gait, and growth failure. The course of the disease, in its classical form, is characterized by four stages. Three different atypical variants of the disease have been defined. Epilepsy has been reported in 60%-80% of patients with RTT; it differs among the various phenotypes and genotypes and its severity is an important contributor to the clinical severity of the disease. METHODS: In this manuscript we reviewed literature on RTT, focusing on the different genetic entities, the correlation genotype-phenotype, and the peculiar epileptic phenotype associated to each of them. RESULTS: Mutations in MECP2 gene, located on Xq28, account for 95% of typical RTT cases and 73.2% of atypical RTT. CDKL5 and FOXG1 are other genes identified as causative genes in atypical forms of RTT. In the last few years, a lot of new genes have been identified as causative genes for RTT phenotype. CONCLUSIONS: Recognizing clinical and EEG patterns in different RTT variants may be useful in diagnosis and management of these patients.


Assuntos
Epilepsia/genética , Fatores de Transcrição Forkhead/genética , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas do Tecido Nervoso/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Mutação , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia , Índice de Gravidade de Doença
12.
Brain Behav ; 9(5): e01285, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30980517

RESUMO

INTRODUCTION: Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10-15,000 female live births), is most often caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. METHODS: We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12-19 years) against an archived approximate age-, sex-, body-site matched comparison sample of healthy adolescent females (N = 8, ages 11-17). RESULTS: Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co-stained calcitonin gene-related protein [CGRP]) innervation density compared with healthy female control individuals. CONCLUSIONS: Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.


Assuntos
Nociceptividade/fisiologia , Sistema Nervoso Periférico , Síndrome de Rett , Células Receptoras Sensoriais , Pele , Adolescente , Biópsia/métodos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Criança , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Microscopia Confocal/métodos , Sistema Nervoso Periférico/patologia , Sistema Nervoso Periférico/fisiopatologia , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Pele/inervação , Pele/patologia , Adulto Jovem
13.
Transl Psychiatry ; 9(1): 130, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967526

RESUMO

Rett syndrome (RTT), a rare neurodevelopmental disorder caused by mutations in the MECP2 gene, is typified by profound cognitive impairment and severe language impairment, rendering it very difficult to accurately measure auditory processing capabilities behaviorally in this population. Here we leverage the mismatch negativity (MMN) component of the event-related potential to measure the ability of RTT patients to decode and store occasional duration deviations in a stream of auditory stimuli. Sensory memory for duration, crucial for speech comprehension, has not been studied in RTT.High-density electroencephalography was successfully recorded in 18 females with RTT and 27 age-matched typically developing (TD) controls (aged 6-22 years). Data from seven RTT and three TD participants were excluded for excessive noise. Stimuli were 1 kHz tones with a standard duration of 100 ms and deviant duration of 180 ms. To assess the sustainability of sensory memory, stimulus presentation rate was varied with stimulus onset asynchronies (SOAs) of 450, 900, and 1800 ms. MMNs with maximum negativity over fronto-central scalp and a latency of 220-230 ms were clearly evident for each presentation rate in the TD group, but only for the shortest SOA in the RTT group. Repeated-measures ANOVA revealed a significant group by SOA interaction. MMN amplitude correlated with age in the TD group only. MMN amplitude was not correlated with the Rett Syndrome Severity Scale. This study indicates that while RTT patients can decode deviations in auditory duration, the span of this sensory memory system is severely foreshortened, with likely implications for speech decoding abilities.


Assuntos
Percepção Auditiva , Encéfalo/fisiopatologia , Potenciais Evocados Auditivos , Memória , Síndrome de Rett/fisiopatologia , Estimulação Acústica , Adolescente , Estudos de Casos e Controles , Criança , Eletroencefalografia , Feminino , Humanos , Adulto Jovem
14.
Neurosci Biobehav Rev ; 98: 320-332, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832924

RESUMO

Rett syndrome (RTT) is an X-linked genetic disorder that occurs predominantly in females. The clinical picture associated with RTT is defined by core and supportive consensus criteria, with a period of behavioural regression being a conditio sine qua non. This review sheds light on atypical neurofunctions and potential behavioural biomarkers before the onset of regression. The main focus lies on (a) motor development, especially on purposeful hand movements and the occurrence of stereotypies; and (b) speech-language and socio-communicative development. We outline potentially specific atypical behavioural patterns in these domains (e.g., vocalisations on inspiratory airstream) and different developmental traits of regression: (i) non-achievement of certain milestones: 'regression', here, might point to the fact that the lack of respective behavioural patterns appeared more and more worrisome with increasing age; and (ii) developmental milestones were achieved and functions deteriorate or even get lost during regression. To conclude, we are not quite there yet, but seem to be on the right track towards defining new and reliable neurofunctional markers for early detection of RTT.


Assuntos
Transtornos da Comunicação/fisiopatologia , Comunicação não Verbal/fisiologia , Síndrome de Rett/fisiopatologia , Comportamento Estereotipado/fisiologia , Transtornos da Comunicação/genética , Humanos , Fenótipo , Síndrome de Rett/genética , Comportamento Social
15.
Trends Pharmacol Sci ; 40(4): 233-236, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905360

RESUMO

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MeCP2) gene. This Science & Society article focuses on pharmacological strategies that attack RTT treatment from multiple angles, including drug repurposing and de novo discovery efforts, and discusses the impacts of preclinical study design and translationally relevant outcome measures.


Assuntos
Descoberta de Drogas/métodos , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos , Feminino , Humanos , Mutação , Projetos de Pesquisa , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia
16.
Eur J Paediatr Neurol ; 23(2): 262-269, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30635145

RESUMO

BACKGROUND: Rett syndrome (RTT) is a neurological disorder characterized by a broad spectrum of symptoms. Communication is a major area of difficulty. Use of eye tracking technology offers a potentially effective method of communication when underpinned by intact oculomotor function. In this study, oculomotor function was assessed using electronystagmography (ENG). However, challenges were encountered when examining individuals with RTT. PURPOSE: To improve oculomotor examination in individuals with RTT by evaluating the challenges encountered during ENG examination. MATERIAL AND METHODS: Oculomotor function was examined in 17 girls and young women with RTT and 16 typically developing (TD) individuals using ENG. Observational analysis of both performance and results indicated that challenges in examination were mainly related to quality of attention and quality of signals. Subsequently these outcome values were explored quantitatively according to percentage looking time for attention and drift for signal quality. RESULTS: A significantly reduced level of attention and suboptimal electrode signals were evident in the RTT group when compared with the TD group for all tests except torsion swing. CONCLUSION: The challenges in testing confirm that regular oculomotor examination should be adjusted to meet the needs of individuals with RTT. It is hypothesized that the RTT group's higher quality of attention on the torsion swing can be explained by the more forceful vestibular rather than visual-ocular stimulus operating in this test. Suggested adaptations include reducing the number of electrodes, changing the picture stimuli and bringing them closer, performing observational assessments rather than ENG, and using virtual reality goggles.


Assuntos
Atenção , Eletronistagmografia/métodos , Movimentos Oculares/fisiologia , Síndrome de Rett/fisiopatologia , Adulto , Feminino , Humanos
17.
Neurosci Biobehav Rev ; 98: 154-163, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639673

RESUMO

Rett syndrome (RTT) is a neurodevelopmental disorder affecting mostly girls. A seemingly normal initial development is followed by developmental stagnation and regression, leading to severe mental impairment with autistic features, motor dysfunction, irregular breathing and epilepsy. Currently, a cure does not exist. Due to the close association of RTT with mitochondrial alterations, cellular redox-impairment and oxidative stress, compounds stabilizing mitochondrial function, cellular redox-homeostasis, and oxidant detoxification are increasingly considered as treatment concepts. Indeed, antioxidants and free-radical scavengers ameliorate certain aspects of the complex and severe clinical presentation of RTT. To further evaluate these strategies, reliable biosensors are needed to quantify redox-conditions in brain and peripheral organs of mouse models or in patient-derived cells. Genetically-encoded redox-sensors meet these requirements. Expressed in transgenic mouse-models such as our unique Rett-redox indicator mice, they will report for any cell type desired the severity of oxidant stress throughout the various disease stages of RTT. Furthermore, these sensors will be crucial to evaluate in vitro and in vivo the outcome of mitochondria- and redox-balance targeted treatments.


Assuntos
Encéfalo/fisiopatologia , Homeostase/fisiologia , Estresse Oxidativo/fisiologia , Síndrome de Rett/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Mitocôndrias/metabolismo , Síndrome de Rett/metabolismo
18.
Int J Dev Neurosci ; 73: 26-31, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30630072

RESUMO

This study examined the feasibility of using auditory event-related potentials to evaluate spoken word processing during passive listening in girls with Rett syndrome (n = 11) and typical peers (n = 33), age 4-12 years. The typical group demonstrated the expected pattern of more negative amplitudes within 200-500 ms in response to words than nonwords at left temporal sites. In participants with Rett syndrome, word-nonword differentiation was observed at the right temporal sites. More negative left hemisphere amplitudes in response to words were associated (at trend level) with better receptive language skills and more adaptive behavior. The results indicate that girls with Rett syndrome differentiate known words from novel nonwords, but may do so using potentially atypical neural processes. Brain-behavior correlations support validity of the proposed neural markers of word processing, making passive listening paradigms a promising approach for assessing speech and language processing in participants with limited spoken language skills.


Assuntos
Encéfalo/fisiopatologia , Potenciais Evocados/fisiologia , Síndrome de Rett/fisiopatologia , Percepção da Fala/fisiologia , Estimulação Acústica , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Tempo de Reação/fisiologia
19.
Dev Neurorehabil ; 22(6): 376-379, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30273509

RESUMO

Background: Stereotypical hand movements have been observed in most individuals diagnosed with Rett syndrome. Objectives: To investigate factors that increase or decrease hand stereotypies in individuals with Rett syndrome. Methods: A questionnaire regarding hand stereotypies or purposeful hand behaviours was sent to 1016 schools for special needs education and 204 facilities in Japan. Results: Information was acquired from 216 cases (3-53 years old) with Rett syndrome; 81.9% and 87.6% of individuals had factors that increased and decreased stereotypical hand movements, respectively. Stereotypies were mainly increased by displeasure (63.8%) or pleasure (48.5%), and decreased by somnolence (43.5%), pleasure (30.0%), or food (24.1%). Conclusion: Emotion was the main factor increasing stereotypical hand movements, whereas there were a large number of factors that decreased these movements. The factors that decrease stereotypies could be useful to prevent the skin problems or joint contracture observed in patients with Rett syndrome.


Assuntos
Mãos/fisiopatologia , Síndrome de Rett/fisiopatologia , Comportamento Estereotipado , Adolescente , Adulto , Criança , Pré-Escolar , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Movimento
20.
Eur J Paediatr Neurol ; 23(1): 214-221, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30262236

RESUMO

INTRODUCTION: Rett syndrome (RS) is a severe neurodevelopment disorder associated with abnormal breathing during wakefulness and disturbed nocturnal behaviour. Breathing abnormalities during daytime have been extensively reported but polysomnographic (PSG) findings have been poorly studied. MATERIALS AND METHODS: Consecutive patients with RS carrying distinct mutations in MECP2 gene, who underwent a PSG between October 2014 and January 2018, were included in the study. Clinical and PSG data were collected. RESULTS: Seventeen RS girls, mean age 9.5 ± 2.8 years, were included in the study. Mean total sleep time was 366 ± 102 min. Mean sleep efficiency was reduced (66 ± 19%) with only 3 girls presenting a sleep efficiency above 80%. Wake after sleep onset was increased (33 ± 20%) with an arousal index of 7 ± 6 events/hour. Sleep stages were altered with a normal N1 (2 ± 3%), a decreased N2 (34 ± 20%), an increase of N3 (51 ± 23%) and a decrease of REM sleep (12 ± 9%). Mean apnea hypopnea index (AHI) was increased at 19 ± 37 events/hour, with a predominance of obstructive events. Thirteen patients had an AHI > 1.5 event/hour. Four patients had an obstructive AHI >10 events/hour with one patient having associated tonsillar hypertrophy. Two patients had predominant severe central apneas (central AHI 53 and 132 events/hour) which resolved with noninvasive ventilation and nocturnal oxygen therapy respectively. CONCLUSION: Girls with RS have poor sleep quality with alterations in slow wave and REM sleep stages. Obstructive respiratory events are uncommon in patients without adenotonsillar hypertrophy. Central respiratory events are rare. Longitudinal studies should help understanding the natural history of sleep disturbances in RS and their relationship with the neurocognitive decline.


Assuntos
Síndrome de Rett/complicações , Transtornos do Sono-Vigília/etiologia , Criança , Feminino , Humanos , Estudos Longitudinais , Polissonografia , Síndrome de Rett/fisiopatologia , Transtornos do Sono-Vigília/fisiopatologia
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