Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 751
Filtrar
1.
Proc Natl Acad Sci U S A ; 117(28): 16527-16536, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601218

RESUMO

Folate deprivation drives the instability of a group of rare fragile sites (RFSs) characterized by CGG trinucleotide repeat (TNR) sequences. Pathological expansion of the TNR within the FRAXA locus perturbs DNA replication and is the major causative factor for fragile X syndrome, a sex-linked disorder associated with cognitive impairment. Although folate-sensitive RFSs share many features with common fragile sites (CFSs; which are found in all individuals), they are induced by different stresses and share no sequence similarity. It is known that a pathway (termed MiDAS) is employed to complete the replication of CFSs in early mitosis. This process requires RAD52 and is implicated in generating translocations and copy number changes at CFSs in cancers. However, it is unclear whether RFSs also utilize MiDAS and to what extent the fragility of CFSs and RFSs arises by shared or distinct mechanisms. Here, we demonstrate that MiDAS does occur at FRAXA following folate deprivation but proceeds via a pathway that shows some mechanistic differences from that at CFSs, being dependent on RAD51, SLX1, and POLD3. A failure to complete MiDAS at FRAXA leads to severe locus instability and missegregation in mitosis. We propose that break-induced DNA replication is required for the replication of FRAXA under folate stress and define a cellular function for human SLX1. These findings provide insights into how folate deprivation drives instability in the human genome.


Assuntos
Endodesoxirribonucleases/metabolismo , Ácido Fólico/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Mitose , Rad51 Recombinase/metabolismo , DNA/genética , DNA/metabolismo , Reparo do DNA , Endodesoxirribonucleases/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Rad51 Recombinase/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Recombinases/genética , Recombinases/metabolismo
2.
J Neurosci ; 40(27): 5327-5340, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32467357

RESUMO

Channelopathies are implicated in Fragile X syndrome (FXS), yet the dysfunction of a particular ion channel varies with cell type. We previously showed that HCN channel function is elevated in CA1 dendrites of the fmr1 -/y mouse model of FXS, but reduced in L5 PFC dendrites. Using male mice, we tested whether Fragile X Mental Retardation Protein (FMRPO), the protein whose absence causes FXS, differentially modulates HCN channels in CA1 versus L5 PFC dendrites. Using a combination of viral tools, intracellular peptide, and dendritic electrophysiology, we found that FMRP regulates HCN channels via a cell-autonomous protein-protein interaction. Virally expressed FMRP restored WT HCN channel-related dendritic properties in both CA1 and L5 neurons. Rapid intracellular perfusion of the non-mRNA binding N-terminal fragment, FMRP1-298, similarly restored dendritic function. In support of a protein-protein interaction, we found that FMRP associated with HCN-TRIP8b complexes in both hippocampus and PFC. Finally, voltage-clamp recordings showed that FMRP modulated Ih by regulating the number of functional dendritic HCN channels rather than individual channel properties. Together, these represent three novel findings as to the nature of the changes in dendritic function in CA1 and PFC neurons based on the presence or absence of FMRP. Moreover, our findings provide evidence that FMRP can regulate its targets in opposite directions depending upon the cellular milieu.SIGNIFICANCE STATEMENT Changes in dendritic function, and voltage-gated ion channels in particular, are increasingly the focus of neurological disorders. We, and others, previously identified cell type-specific channelopathies in a mouse of model of Fragile X syndrome. The present study shows that replacing Fragile X Mental Retardation Protein, which is absent in Fragile X syndrome, in adult CA1 and L5 PFC neurons regulates the number of functional dendritic HCN channels in a cell type-specific manner. These results suggest that Fragile X Mental Retardation Protein regulates dendritic HCN channels via a cell-autonomous protein--protein mechanism.


Assuntos
Dendritos/fisiologia , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , RNA Longo não Codificante/genética , Animais , Região CA1 Hipocampal/fisiopatologia , Dendritos/efeitos dos fármacos , Fenômenos Eletrofisiológicos , Feminino , Síndrome do Cromossomo X Frágil/fisiopatologia , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Condução Nervosa/genética , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/farmacologia , Córtex Pré-Frontal/citologia , RNA Longo não Codificante/fisiologia
3.
BMC Neurol ; 20(1): 145, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312236

RESUMO

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset, X-linked genetic, neurodegenerative disorder caused by a "premutation (PM)" in the fragile X mental retardation 1 (FMR1) gene. Here we report a case of FXTAS from mainland of China who presented with rare orthostatic tremor. A review of tremor of FXTAS in the literature is also included. CASE PRESENTATION: A 67-year-old right-handed farmer started with tremor of both legs 8 years ago which was present while standing but absent when sitting or lying and progressed with unsteady gait one and a half years ago. The brain MRI showed high intensity signal in the bilateral middle cerebellar peduncles (MCP) in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images and gene test for premutation for FMR1 was positive with 101 CGG repeats. The patient met the the diagnosis of definite FXTAS. Clonazepam and topiramate were administered to control tremor. We reviewed the literature and identified 64 cases with detailed clinical and genetic information. Orthostatic tremor associated with FXTAS is very rare. We found 85.2% patients reported tremor,42.6% with intention tremor,36.1% with kinetic tremor,32.8% with rest tremor and 29.5% with posture tremor. 37.7% of patients who have tremor showed at least two types of tremor. There were 6 patients with isolated rest tremor. There was 2 patient with voice tremor and 6 with head tremor. We also found that 74.6% FXTAS patients had family history of FMR1 gene associated diseases including Fragile X syndrome (FXS), FXTAS or fragile X-associated primary ovarian insufficiency (FXPOI). CONCLUSIONS: Adding our data to the available literature suggests that orthostatic tremor could be a rare initial manifestation of FXTAS and the review will increasing our understanding the phenotype of tremor in FXTAS. Family history of FMR1 gene associated diseases might be an important clue to the diagnosis.


Assuntos
Ataxia , Síndrome do Cromossomo X Frágil , Tremor , Idoso , Anticonvulsivantes/uso terapêutico , Ataxia/diagnóstico , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Clonazepam/uso terapêutico , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Topiramato/uso terapêutico , Tremor/diagnóstico , Tremor/tratamento farmacológico , Tremor/genética , Tremor/fisiopatologia
4.
Eur J Paediatr Neurol ; 24: 100-104, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31926845

RESUMO

Many pathways have been involved in pathophysiology of the fragile X syndrome, one of the more frequent genetic causes of intellectual disability and autism. This review highlights the recent insights in the role the abnormalities in the GABAergic system play in the disorder. Since the initial observations showed that the expression of specific subunits of the GABA(A) receptor were underexpressed in the fragile X knockout mouse model more than a decade ago, evidence has accumulated that the expression of approximately half of the GABAergic system is compromised in multiple species, including in fragile X patients. Functional consequences of the GABAergic deficiencies could be measured using whole-cell voltage clamp recordings. Pharmalogical treatment with agonist of the receptor was been able to restore several behavioral deficits in the fragile X mouse model, including seizures, marble burying and, in part, prepulse inhibition. Trials in patients with the same agonist have demonstrated encouraging post-hoc results in the most severely affected patients, although no effect could be demonstrated in the patient group as a whole. In conclusion, there can be little doubt that the GABAergic system is compromised in the fragile X syndrome and that these abnormalities contribute to the clinical abnormalities observed. However, at the moment the difference in treatment effectiveness of agonist of the receptor in animal models as opposed to in patients remains unexplained.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Receptores de GABA/genética , Animais , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Camundongos
5.
Res Dev Disabil ; 97: 103549, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31864111

RESUMO

This cross-syndrome study focuses on sleep and its relationship with language development. Children with neurodevelopmental disorders present with language delay. Typical language development is constrained by numerous factors including sleep. Sleep is often disrupted in adolescents/adults with neurodevelopmental disorders. We therefore hypothesised that sleep may be disrupted, and correlate with language development, in infants/toddlers with neurodevelopmental disorders. To test our hypothesis, we obtained sleep and vocabulary size data from 75 infants/toddlers with one of three neurodevelopmental disorders (Down syndrome [DS], fragile X syndrome [FXS], Williams syndrome [WS]). Sleep was indeed disrupted in these children. It was also positively associated with receptive vocabulary size in the infants/toddlers with DS and WS (we could not test the relationship between sleep and language in FXS due to lack of power). We argue that disrupted sleep may be a common occurrence in very young children with neurodevelopmental disorders, and it may relate to their ability to acquire their first language.


Assuntos
Síndrome de Down/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Transtornos do Sono-Vigília/fisiopatologia , Síndrome de Williams/fisiopatologia , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Desenvolvimento da Linguagem , Masculino , Fenótipo , Sono/fisiologia , Vocabulário
6.
Behav Neurol ; 2019: 5202808, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885726

RESUMO

Fragile X syndrome (FXS) is a genetic syndrome with intellectual disability due to the loss of expression of the FMR1 gene located on chromosome X (Xq27.3). This mutation can suppress the fragile X mental retardation protein (FMRP) with an impact on synaptic functioning and neuronal plasticity. Among associated sign and symptoms of this genetic condition, sleep disturbances have been already described, but few polysomnographic reports in pediatric age have been reported. This multicenter case-control study is aimed at assessing the sleep macrostructure and at analyzing the presence of EEG abnormalities in a cohort of FXS children. We enrolled children with FXS and, as controls, children with typical development. All subjects underwent at least 1 overnight polysomnographic recording (PSG). All recorded data obtained from patients and controls were compared. In children with FXS, all PSG-recorded parameters resulted pathological values compared to those obtained from controls, and in FXS children only, we recorded interictal epileptiform discharges (IEDs), as diffuse or focal spikes and sharp waves, usually singles or in brief runs with intermittent or occasional incidence. A possible link between IEDs and alterations in the circadian sleep-wake cycle may suggest a common dysregulation of the balance between inhibitory and excitatory pathways in these patients. The alteration in sleep pattern in children with FXS may negatively impact the neuropsychological and behavioral functioning, adding increasing burn of the disease on the overall management of these patients. In this regard, treating physicians have to early detect sleep disturbances in their patients for tailored management, in order to prevent adjunctive comorbidities.


Assuntos
Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/fisiopatologia , Sono/fisiologia , Adolescente , Estudos de Casos e Controles , Criança , Eletroencefalografia/métodos , Feminino , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Masculino , Plasticidade Neuronal/fisiologia , Polissonografia/métodos , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/fisiopatologia
7.
Elife ; 82019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31860442

RESUMO

Loss of the RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown how FMRP function varies across brain regions and cell types and how this contributes to disease pathophysiology. Here we use conditional tagging of FMRP and CLIP (FMRP cTag CLIP) to examine FMRP mRNA targets in hippocampal CA1 pyramidal neurons, a critical cell type for learning and memory relevant to FXS phenotypes. Integrating these data with analysis of ribosome-bound transcripts in these neurons revealed CA1-enriched binding of autism-relevant mRNAs, and CA1-specific regulation of transcripts encoding circadian proteins. This contrasted with different targets in cerebellar granule neurons, and was consistent with circadian defects in hippocampus-dependent memory in Fmr1 knockout mice. These findings demonstrate differential FMRP-dependent regulation of mRNAs across neuronal cell types that may contribute to phenotypes such as memory defects and sleep disturbance associated with FXS.


Assuntos
Transtorno Autístico/metabolismo , Região CA1 Hipocampal/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Transtornos da Memória/genética , Células Piramidais/metabolismo , Animais , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Região CA1 Hipocampal/citologia , Cerebelo/citologia , Cerebelo/metabolismo , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/fisiopatologia , Regulação da Expressão Gênica , Humanos , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo
8.
J Neurodev Disord ; 11(1): 41, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31878865

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55-199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours. METHODS: This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours. RESULTS: Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. CONCLUSIONS: Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.


Assuntos
Transtorno do Espectro Autista , Sintomas Comportamentais , Síndrome do Cromossomo X Frágil , Deficiência Intelectual , Mosaicismo , Adolescente , Adulto , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/genética , Sintomas Comportamentais/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Fenótipo , Fatores Sexuais , Adulto Jovem
9.
eNeuro ; 6(6)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685673

RESUMO

Fragile X syndrome (FXS) is the most common source of intellectual disability and autism. Extensive studies have been performed on the network and behavioral correlates of the syndrome, but our knowledge about intrinsic conductance changes is still limited. In this study, we show a differential effect of FMRP knockout in different subsections of hippocampus using whole-cell patch clamp in mouse hippocampal slices. We observed no significant change in spike numbers in the CA1 region of hippocampus, but a significant increase in CA3, in juvenile mice. However, in adult mice we see a reduction in spike number in the CA1 with no significant difference in CA3. In addition, we see increased variability in spike numbers in CA1 cells following a variety of steady and modulated current step protocols. This effect emerges in adult mice (8 weeks) but not juvenile mice (4 weeks). This increased spiking variability was correlated with reduced spike number and with elevated AHP. The increased AHP arose from elevated SK currents (small conductance calcium-activated potassium channels), but other currents involved in medium AHP, such as I h and M, were not significantly different. We obtained a partial rescue of the cellular variability phenotype when we blocked SK current using the specific blocker apamin. Our observations provide a single-cell correlate of the network observations of response variability and loss of synchronization, and suggest that the elevation of SK currents in FXS may provide a partial mechanistic explanation for this difference.


Assuntos
Potenciais de Ação/fisiologia , Região CA1 Hipocampal/fisiopatologia , Região CA3 Hipocampal/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Fatores Etários , Animais , Apamina/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Reprodutibilidade dos Testes , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores
10.
J Neurosci ; 39(49): 9852-9863, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31666356

RESUMO

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading monogenetic cause of autism. One symptom of FXS and autism is sensory hypersensitivity (also called sensory over-responsivity). Perhaps related to this, the audiogenic seizure (AGS) is arguably the most robust behavioral phenotype in the FXS mouse model-the Fmr1 knock-out (KO) mouse. Therefore, the AGS may be considered a mouse model of sensory hypersensitivity. Hyperactive circuits are hypothesized to underlie dysfunction in a number of brain regions in patients with FXS and Fmr1 KO mice, and the AGS may be a result of this. But the specific cell types and brain regions underlying AGSs in the Fmr1 KO are unknown. We used conditional deletion or expression of Fmr1 in different cell populations to determine whether Fmr1 deletion in those cells was sufficient or necessary, respectively, for the AGS phenotype in males. Our data indicate that Fmr1 deletion in glutamatergic neurons that express vesicular glutamate transporter 2 (VGlut2) and are located in subcortical brain regions is sufficient and necessary to cause AGSs. Furthermore, the deletion of Fmr1 in glutamatergic neurons of the inferior colliculus is necessary for AGSs. When we demonstrate necessity, we show that Fmr1 expression in either the larger population of VGlut2-expressing glutamatergic neurons or the smaller population of inferior collicular glutamatergic neurons-in an otherwise Fmr1 KO mouse-eliminates AGSs. Therefore, targeting these neuronal populations in FXS and autism may be part of a therapeutic strategy to alleviate sensory hypersensitivity.SIGNIFICANCE STATEMENT Sensory hypersensitivity in fragile X syndrome (FXS) and autism patients significantly interferes with quality of life. Audiogenic seizures (AGSs) are arguably the most robust behavioral phenotype in the FXS mouse model-the Fmr1 knockout-and may be considered a model of sensory hypersensitivity in FXS. We provide the clearest and most precise genetic evidence to date for the cell types and brain regions involved in causing AGSs in the Fmr1 knockout and, more broadly, for any mouse mutant. The expression of Fmr1 in these same cell types in an otherwise Fmr1 knockout eliminates AGSs indicating possible cellular targets for alleviating sensory hypersensitivity in FXS and other forms of autism.


Assuntos
Epilepsia Reflexa/genética , Epilepsia Reflexa/fisiopatologia , Proteína do X Frágil de Retardo Mental/genética , Colículos Inferiores/fisiopatologia , Neurônios/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/biossíntese , Animais , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Órgão Espiral/metabolismo , Órgão Espiral/fisiopatologia , Proteína Vesicular 2 de Transporte de Glutamato/genética
11.
Transl Psychiatry ; 9(1): 312, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748507

RESUMO

Fragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.


Assuntos
Síndrome do Cromossomo X Frágil/fisiopatologia , Córtex Motor/fisiopatologia , Rede Nervosa/fisiopatologia , Inibição Neural , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Síndrome do Cromossomo X Frágil/diagnóstico , Humanos , Masculino , Estimulação Magnética Transcraniana , Adulto Jovem , Ácido gama-Aminobutírico/fisiologia
12.
Am J Intellect Dev Disabil ; 124(6): 511-534, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31756147

RESUMO

This study was designed to establish the extent of delay in complex sentence use by females with fragile X syndrome (FXS) and to identify sources of variability among individuals. Females with FXS (n = 16; 10;2-15;7) and younger typically developing girls (n = 17; 4;1-8;11) were group-wise matched on nonverbal cognition and receptive syntax. Language samples (conversation and narration) yielded syntactic complexity in terms of mean length of C-unit (MLCU) and Developmental Level sentence coding (DLevel; Rosenberg & Abbeduto, 1987 ). Complex syntax was not weaker than developmental expectations; however, MLCU was lower than expected for age. Phonological memory and verbal working memory correlated with measures of syntactic complexity in narration. Discourse demands may play an important role in the language produced by females with FXS.


Assuntos
Síndrome do Cromossomo X Frágil/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Desenvolvimento da Linguagem , Memória de Curto Prazo/fisiologia , Adolescente , Criança , Pré-Escolar , Feminino , Síndrome do Cromossomo X Frágil/complicações , Humanos , Individualidade , Transtornos do Desenvolvimento da Linguagem/etiologia , Estudos Longitudinais
13.
J Neurodev Disord ; 11(1): 25, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619160

RESUMO

BACKGROUND: Receptive and expressive vocabulary in adult and adolescent males with fragile X syndrome (FXS) have been shown as significantly lower than their chronological age; however, receptive vocabulary has been considered a strength relative to mental age. This has not been formally examined, however, and data are needed to compare receptive vocabulary with other language skills and with mental age in individuals with FXS. This is especially important as vocabulary measures are sometimes used as a proxy to estimate language ability. METHODS: This preliminary study examined receptive vocabulary, global language, and cognitive skills in 42 adults (33 males and 9 females) with FXS as a portion of the baseline evaluation prior to randomization in a clinical trial of ampakine CX516. The battery of standardized tests addressed receptive vocabulary with the Peabody Picture Vocabulary Test, Third Edition (PPVT-III), receptive and expressive language (termed henceforth as global language) via the Preschool Language Scale, Fourth Edition or the Clinical Evaluation of Language Fundamentals, Third Edition, and non-verbal cognition via the Stanford-Binet Intelligence Scales, Fourth Edition (SB-IV). RESULTS: Results showed (1) significantly higher receptive vocabulary than global language, (2) significantly better receptive vocabulary than non-verbal cognition, (3) equivalent non-verbal cognition and global language, and (4) severity of autism symptomatology was not correlated to receptive vocabulary or global language once non-verbal cognition was removed as factor. The scores from the PPVT-III did not represent the global language skills in our sample of adults with FXS. CONCLUSIONS: Findings from this investigation strongly suggest that the PPVT-III should not be used as a screening tool for language levels or cognitive function in clinical studies since the scores from the PPVT-III were not representative of global language or non-verbal cognitive skills in adults with intellectual disabilities. This finding is critical in order to understand how to evaluate, as well as to treat, language in individuals with FXS. Development of efficient and appropriate tools to measure language, cognition, and behavior in individuals with FXS is essential.


Assuntos
Compreensão/fisiologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Testes de Linguagem/normas , Idioma , Vocabulário , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
14.
Front Neural Circuits ; 13: 57, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616256

RESUMO

Fragile X syndrome (FXS) is the most prevalent inherited cause of autism and is accompanied by behavioral and sensory deficits. Errors in the wiring of the brain during early development likely contribute to these deficits, but the underlying mechanisms are unclear. Spontaneous activity patterns, which are required for fine-tuning neuronal networks before the senses become active, are perturbed in rodent models of FXS. Here, we investigated spontaneous network activity patterns in the developing visual cortex of the Fmr1 knockout mouse using in vivo calcium imaging during the second postnatal week, before eye opening. We found that while the frequency, mean amplitude and duration of spontaneous network events were unchanged in the knockout mouse, pair-wise correlations between neurons were increased compared to wild type littermate controls. Further analysis revealed that interneuronal correlations were not generally increased, rather that low-synchronization events occurred relatively less frequently than high-synchronization events. Low-, but not high-, synchronization events have been associated with retinal inputs previously. Since we found that spontaneous retinal waves were normal in the knockout, our results suggest that peripherally driven activity is underrepresented in the Fmr1 KO visual cortex. Therefore, we propose that central gating of retinal inputs may be affected in FXS and that peripherally and centrally driven activity patterns are already unbalanced before eye opening in this disorder.


Assuntos
Cálcio/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Neurônios/fisiologia , Córtex Visual/fisiologia , Animais , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/fisiopatologia , Camundongos , Camundongos Knockout , Córtex Visual/crescimento & desenvolvimento
15.
J Neurodev Disord ; 11(1): 23, 2019 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-31586494

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is highly prevalent in fragile X syndrome (FXS), affecting 50-70% of males. Motor impairments are a shared feature across autism and FXS that may help to better characterize autism in FXS. As motor skills provide a critical foundation for various language, cognitive, and social outcomes, they may serve an important mechanistic role for autism in FXS. As such, this study aimed to identify differences in motor trajectories across direct assessment and parent-report measures of fine and gross motor development between FXS with and without autism, and typical development, while controlling for cognitive functioning. METHODS: This prospective longitudinal study included 42 children with FXS, 24 of whom also had ASD (FXS + ASD), as well as 40 typically developing children. The Mullen Scales of Early Learning provided a direct measure of fine and gross motor skills, and the Vineland Adaptive Behavior Scales provided a measure of parent-reported fine and gross motor skills. Random slopes and random intercepts multilevel models were tested to determine divergence in developmental motor trajectories between groups when controlling for cognitive level. RESULTS: Model results indicated the children with FXS + ASD diverged from TD children by 9-months on all measures of gross and fine motor skills, even when controlling for cognitive level. Results also indicated an early divergence in motor trajectories of fine and gross motor skills between the FXS + ASD and FXS groups when controlling for cognitive level. This divergence was statistically significant by 18 months, with the FXS + ASD showing decelerated growth in motor skills across direct observation and parent-report measures. CONCLUSIONS: This study is the first to examine longitudinal trends in motor development in children with FXS with and without comorbid ASD using both direct assessment and parent-report measures of fine and gross motor. Furthermore, it is among the first to account for nonverbal cognitive delays, a step towards elucidating the isolated role of motor impairments in FXS with and without ASD. Findings underscore the role of motor impairments as a possible signal representing greater underlying genetic liability, or as a potential catalyst or consequence, of co-occurring autism in FXS.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Desenvolvimento Infantil/fisiologia , Deficiências do Desenvolvimento/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Destreza Motora/fisiologia , Pré-Escolar , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino
16.
J Neurodev Disord ; 11(1): 22, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519170

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is a genetic disorder that is highly comorbid with anxiety and autism spectrum disorder (ASD). Elevated negative affect in young children has been associated with increased risk for both anxiety and ASD; however, these relations remain poorly understood in FXS. METHODS: The present prospective longitudinal study examined the trajectory of negative affect from infancy through preschool in males and females with FXS and typical development and its relation to anxiety and ASD. RESULTS: Results indicate a complex association reflecting group, developmental, and sex effects. Specifically, the group with FXS displayed a trajectory of increasing negative affect across age that was distinct from the typical controls. This atypical trajectory of negative affect in FXS was driven by sex effects in that males showed lower negative affect during infancy followed by steep increases across the toddler and preschool years whereas the females displayed a flatter trajectory. Finally, elevated negative affect predicted anxiety symptoms in males, but not females, with no relationship to ASD in males or females with FXS. CONCLUSIONS: The current work addresses the importance of studying the development of psychopathology in a specific neurogenetic population. Temperamental negative affect was shown to be an important early marker for anxiety in young children with FXS, with subtle differences observed between males and females.


Assuntos
Sintomas Afetivos/fisiopatologia , Ansiedade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Sintomas Afetivos/epidemiologia , Ansiedade/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Pré-Escolar , Comorbidade , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Humanos , Lactente , Estudos Longitudinais , Masculino , Caracteres Sexuais , Fatores Sexuais
17.
Adv Exp Med Biol ; 1155: 155-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468394

RESUMO

Fragile X syndrome is an X-linked dominant disorder and the most common cause of inherited mental retardation. It is caused by trinucleotide repeat expansion in the fragile X mental retardation 1 gene (FMR1) at the Xq27.3. The expansion blocks expression of the gene product, Fragile X Mental Retardation Protein (FMRP). The syndrome includes mild to moderate mental retardation and behavioral manifestations such as tactile defensiveness, gaze avoidance, repetitive motor mannerisms, perseverative (repetitive) speech, hyperarousal and it frequently includes seizures. This behavioral phenotype overlaps significantly with autism spectrum disorder. The knockout mice lack normal Fmr1 protein and show macro-orchidism, learning deficits, and hyperactivity. Consequently, this knockout mouse may serve as a valuable tool in the elucidation of the physiological role of FMR1 and the mechanisms involved in macroorchidism, abnormal behavior, abnormalities comparable to those of human fragile X patients. In this study we evaluated the effects of taurine on the testicular physiology to better understand the cellular mechanisms underlying macro-orchidism. We found that there was a significant decrease in the number of Leydig cells in the testis of fragile X mouse. Furthermore, the expression of somatostatin was drastically decreased and differential expression pattern of CDK5 in fragile X mouse testis. In the control testis, CDK is expressed in primary and secondary spermatids whereas in the Fmr1 ko mice CDK 5 is expressed mainly in spermatogonia. Taurine supplementation led to an increase in CDK5 expression in both controls and Ko mice. CDKs (Cyclin-dependent kinases) are a group of serine/threonine protein kinases activated by binding to a regulatory subunit cyclin. Over 20 functionally diverse proteins involved in cytoskeleton dynamics, cell adhesion, transport, and membrane trafficking act as CDK5 substrates elucidating the molecular mechanisms of CDK5 function. CDK5 phosphorylates a diverse list of substrates, implicating it in the regulation of a range of cellular processes. CDK5 is expressed in Leydig cells, Sertoli cells, spermatogonia and peritubular cells indicating a role in spermatogenesis. In this study we examined the expression levels of CDK5 and how it is affected by taurine supplementation in the testes and found that taurine plays an important role in testicular physiology and corrected some of the pathophysiology observed in the fragile x mouse testis.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Taurina/farmacologia , Testículo/fisiopatologia , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Expansão das Repetições de Trinucleotídeos
18.
PLoS One ; 14(7): e0219924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31348790

RESUMO

The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes' lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Mutação , Fala , Adulto , Estudos de Casos e Controles , Função Executiva , Movimentos Oculares , Feminino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/psicologia , Heterozigoto , Humanos , Testes de Linguagem , Pessoa de Meia-Idade , Desempenho Psicomotor , Autorrelato , Expansão das Repetições de Trinucleotídeos
20.
J Speech Lang Hear Res ; 62(7): 2386-2399, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31251678

RESUMO

Purpose Infant siblings of children with autism spectrum disorder (ASIBs) and infants with fragile X syndrome (FXS) are both at risk for developing autism spectrum disorder (ASD) and communication disorders; however, very few studies have examined 1 of the earliest forms of intentional communication in infants from these groups: gestures. This study examined the frequency and function of gesture use across 12-month-old infant ASIBs, infants with FXS, and low-risk controls. Method Participants included 23 ASIBs who did not later meet diagnostic criteria for ASD, 18 infants with FXS, and 21 low-risk controls. Gestures were coded from a semistructured play-based interaction. Results Overall, infants with FXS displayed fewer gestures than low-risk infants, whereas ASIBs did not differ from the FXS or low-risk groups in overall gesture frequency. In terms of the communicative function of the gestures used, the FXS and ASIB groups displayed significantly fewer social interaction gestures than the low-risk controls, with large effect sizes. Conclusion This study contributes to scant knowledge of early communication phenotypes of infant ASIBs who do not meet criteria for ASD and infants with FXS. Results indicated that gesture function, not frequency, best discriminated at-risk infants from low-risk infants at 12 months of age. Findings have implications for the clinical evaluation and treatment of infants at high risk for ASD and communication disorders.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Gestos , Irmãos , Criança , Estudos Transversais , Feminino , Humanos , Relações Interpessoais , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA