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1.
Am J Hum Genet ; 108(3): 502-516, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33596411

RESUMO

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos X/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA/genética , Adolescente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Adulto Jovem
2.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33435571

RESUMO

Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.


Assuntos
Proteínas de Ligação a DNA/genética , Epilepsia Generalizada/genética , Predisposição Genética para Doença/genética , Deficiência Intelectual/genética , Mutação , Animais , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Generalizada/patologia , Epilepsia Generalizada/fisiopatologia , Regulação da Expressão Gênica , Humanos , Deficiência Intelectual/fisiopatologia
3.
J Rehabil Med ; 53(2): jrm00152, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33469670

RESUMO

OBJECTIVE: To determine bone quality in adults with severe motor and intellectual disabilities. DESIGN: A retrospective cohort study. PATIENTS: Bone quality of 60 patients with severe motor and intellectual disabilities (28 men, 32 women; mean age 57 years) at a long-term care facility for adults was examined retrospectively. METHODS: Quantitative ultrasonography was used to measure the stiffness index, T-score and Z-score of the calcaneus. A multiple linear regression model, including sex, age, anti-epileptic drug use, tube-feeding status, and current and peak physical abil-ities, was used to identify significant predictors of T-scores. RESULTS: Quantitative ultrasonography revealed that all patients had lower bone quality (based on T-scores, Z-scores, and stiffness index), and all patients had T-scores with standard deviations (SD) below 1.8. Current physical ability, age, and anti-epileptic drug use were significant factors in T-score determination, while tube-feeding and peak physical ability were not. The ability to walk without assistance was the most significant predictor in quantitative ultrasonography. CONCLUSION: Severely low bone quality is observed in patients with severe motor and intellectual disabilities; and it is strongly associated with current physical activity. It is important that patients with severe motor and intellectual disabilities preserve their physical abilities to prevent osteoporosis-related fractures.


Assuntos
Densidade Óssea/fisiologia , Deficiência Intelectual/fisiopatologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
4.
Ann Neurol ; 89(3): 573-586, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33325057

RESUMO

OBJECTIVE: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2, coding for the γ-aminobutyric acid type A (GABAA ) receptor subunit ß2. METHODS: We recruited and systematically evaluated 25 individuals with variants in GABRB2, 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system. RESULTS: Our cohort of 25 individuals from 22 families with variants in GABRB2 demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty-eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease-associated variants cluster in the extracellular N-terminus and transmembrane domains 1-3, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA-evoked anionic currents. INTERPRETATION: GABRB2-related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABAA receptor-encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying GABRB2-associated neurodevelopmental disorders. ANN NEUROL 2021;89:573-586.


Assuntos
Epilepsia/fisiopatologia , Transtornos dos Movimentos/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Receptores de GABA-A/genética , Adolescente , Adulto , Animais , Ataxia/genética , Ataxia/fisiopatologia , Atetose/genética , Atetose/fisiopatologia , Criança , Pré-Escolar , Coreia/genética , Coreia/fisiopatologia , Estudos de Coortes , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/fisiopatologia , Distonia/genética , Distonia/fisiopatologia , Epilepsia/genética , Feminino , Genótipo , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Oócitos , Técnicas de Patch-Clamp , Fenótipo , Domínios Proteicos/genética , Xenopus laevis , Adulto Jovem
5.
Neurology ; 95(19): e2675-e2682, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32887777

RESUMO

OBJECTIVE: To determine genotype-phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency. METHODS: ALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study. RESULTS: Twenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25-Q75, 49-61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype. CONCLUSIONS: Seven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Deficiências do Desenvolvimento/genética , Succinato-Semialdeído Desidrogenase/deficiência , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Ataxia/genética , Ataxia/fisiopatologia , Criança , Simulação por Computador , Deficiências do Desenvolvimento/fisiopatologia , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Células HEK293 , Heterozigoto , Homozigoto , Humanos , Técnicas In Vitro , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Sítios de Splice de RNA , Índice de Gravidade de Doença , Succinato-Semialdeído Desidrogenase/genética
6.
Med. oral patol. oral cir. bucal (Internet) ; 25(5): e576-e583, sept. 2020. graf, tab
Artigo em Inglês | IBECS | ID: ibc-196512

RESUMO

BACKGROUND: The influence of dental treatment on oral health-related quality of life (OHRQOL) has rarely been evaluated in patients with intellectual disability (ID) through validated questionnaires. The aim of this study was to estimate the changes on OHRQOL in patients with ID after the implementation of an institutional dental treatment program under general anesthesia using the Franciscan Hospital for Children Oral Health-Related Quality of Life questionnaire (FHCOHRQOL-Q). MATERIAL AND METHODS: A prospective longitudinal study was conducted on 85 patients (mean age=24.85 years) classified according to DSM-V whose parents/caregivers completed the FHC-OHRQOL-Q. We analyzed the changes in the questionnaire's overall score and its dimensions from pre-treatment to 12-months of follow-up, considering effect sizes and minimal important differences estimated by the standard measurement error. The impact of clinical and therapeutic factors was evaluated using univariate and multiple linear regression analysis (p < 0.05). RESULTS: Significant improvement of OHRQOL was found after dental treatment in oral symptoms (p ≤ 0.001), daily life problems (p = 0.018), parent's perceptions (p = 0.013) and FHCOHRQOL-Q's overall score (p = 0.001). OHRQOL changes exhibited an intermediate magnitude (0.38-0.21) as estimated by effect sizes. Changes in oral symptoms showed positive correlation with DMFT index (r = 0.375, p = 0.002), decayed teeth (r = 0.244, p = 0.036), dental extractions (r = 0.424, p < 0.001) and number of treatments (r = 0.255, p = 0.019). The improvement was greater in patients with ≥ 4 decayed teeth (p = 0.049) and undergoing ≥ 2 dental extractions (p = 0.002). Multiple regression analysis demonstrated that dental extractions (p < 0.001) and DMFT index ( p= 0.028) were significantly related to oral symptom improvement. CONCLUSIONS: Dental treatment under general anesthesia showed a positive effect on the overall FHC-OHRQOL-Q score and most of its dimensions. At 12-months of follow-up, the improvement of oral symptoms was significantly associated with DMFT index, decayed teeth, dental extractions and number of treatments. In our clinical setting, the implementation of a dental treatment program enhanced the OHRQOL of patients with ID


No disponible


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Qualidade de Vida , Assistência Odontológica , Deficiência Intelectual/fisiopatologia , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento , Estatísticas não Paramétricas , Índice CPO , Fatores Etários , Fatores Sexuais , Seguimentos , Análise de Regressão
7.
Rev. int. med. cienc. act. fis. deporte ; 20(79): 487-506, sept. 2020. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-197050

RESUMO

El objetivo de este trabajo se centra en construir y validar una herramienta que permita, de forma fiable, evaluar el conocimiento de base de jugadores con discapacidad intelectual leve en aspectos de táctica ofensiva en FS, permitiendo usarlo como evaluación inicial complementaria que guíe el proceso de entrenamiento. El tamaño muestral fue de 68 jugadores (Medad=27; SDedad=9.06 y Mexperiencia=11.78; SDexperiencia=1,29). Los resultados muestran valores adecuados de consistencia interna y de fiabilidad (α=0.64, ω=0.74, ICC=0.64 y test-retest). De manera complementaria, se realizó un análisis cualitativo, mediante una entrevista colectiva a un grupo de expertos, sobre la utilidad del instrumento en esta población de deportistas. Los resultados permiten establecer una sólida base para el empleo de este instrumento en futuros estudios


The objective of this work is to build and validate a tool that allows, reliably, evaluate the base knowledge of players with mild intellectual impairment in aspects of offensive tactical in FS, so that it can be used as an additional initial evaluation to guide the training process of coaches. The sample size is constituted by 68 subjects (Mage=27; SDage=9.06 y Mexperience=11.78; SDexperience=1,29). The results show satisfactory internal consistency and reliability values (α=0.64, ω=0.74, ICC=0.64 and test-retest). In a complementary manner, a qualitative analysis was carried out, through a collective interview with a group of experts, about the utility of the instrument in this population of athletes. The results allow to establish a solid base for the use of this instrument in future studies


Assuntos
Humanos , Deficiência Intelectual/fisiopatologia , Desempenho Atlético/fisiologia , Esportes/fisiologia , Futebol/fisiologia , Destreza Motora/fisiologia , Esportes para Pessoas com Deficiência/fisiologia , Esportes/normas , Tomada de Decisões , Futebol/educação , Basquetebol , Tênis , Pessoas com Deficiência/psicologia
8.
Am J Hum Genet ; 107(3): 564-574, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32822602

RESUMO

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.


Assuntos
Atrofia/genética , Doenças Cerebelares/genética , Deficiência Intelectual/genética , Lisina Acetiltransferase 5/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Atrofia/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/fisiopatologia , Pré-Escolar , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Processamento de Proteína Pós-Traducional/genética
9.
Artigo em Inglês | MEDLINE | ID: mdl-32859080

RESUMO

The Convention on the Rights of Persons with Disabilities have proclaimed the basic right of people to make one's own choices, have an effective participation and inclusion. Research in the field of disability have stressed self-determination as a key construct because of its impact on their quality of life and the achievement of desired educational and adulthood related outcomes. Self-determination development must be promoted through specific strategies and especially, by providing tailored opportunities to practice those skills. Providing these opportunities across environments could be especially relevant as a facilitator of self-determination development. This manuscript aims to ascertain if opportunities at home and in the community to engage in self-determined actions are mediating the relationship between people intellectual disability level and their self-determination. Results have confirmed direct effects of intellectual disability level on self-determination scores. Indirect effects also predicted self-determination and almost all its related components (self-initiation, self-direction, self-regulation, self-realization, and empowerment) through opportunities in the community and at home. Autonomy was predicted by the intellectual disability level through an indirect effect of opportunities at home, but not in the community. These results highlight the need for further research to better operationalize and promote contextually rooted opportunities for people with intellectual disability to become more self-determined.


Assuntos
Pessoas com Deficiência/psicologia , Deficiência Intelectual/fisiopatologia , Autonomia Pessoal , Qualidade de Vida , Logro , Adolescente , Adulto , Criança , Feminino , Humanos , Deficiência Intelectual/psicologia , Masculino , Adulto Jovem
10.
Am J Hum Genet ; 107(3): 544-554, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730804

RESUMO

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Criança , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Variação Genética/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Locomoção/genética , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , RNA Polimerase II/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
11.
Epilepsia ; 61(7): e71-e78, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645220

RESUMO

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Fatores de Crescimento de Fibroblastos/genética , Deficiência Intelectual/genética , Fenótipo , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsia/diagnóstico por imagem , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Estudos Retrospectivos , Adulto Jovem
14.
Pediatr. aten. prim ; 22(86): 207-209, abr.-jun. 2020.
Artigo em Espanhol | IBECS | ID: ibc-198538

RESUMO

CONCLUSIONES DE LOS AUTORES DEL ESTUDIO: los análisis no sugieren una relación entre el autismo o la discapacidad intelectual con ninguno de los 25 compuestos químicos analizados. COMENTARIO DE LOS REVISORES: con este modelo probabilístico bayesiano, los autores reducen, por el momento, la alarma sobre la relación entre los principales disruptores endocrinos y los trastornos del espectro autista o discapacidad intelectual, al no demostrarse la asociación que mostraban estudios previos con análisis "frecuentistas". Es un resultado importante dada la preocupación general sobre los efectos de estos contaminantes universales


AUTHORS' CONCLUSIONS: our mixtures analysis does not suggest an independent relationship of autism spectrum disorder or intellectual disability with any of the 25 chemicals examined together in this mixtures analysis. REVIEWERS' COMMENTARY: with this Bayesian probabilistic model, the authors clear up, at this moment, the uncertainty about the relationship between the main endocrine disruptors and autism spectrum disorders or intellectual disability, as the association shown in previous studies with "frequentist" analyzes is not demonstrated. It is an important result given the general concern about the effects of these universal pollutants


Assuntos
Humanos , Disruptores Endócrinos/análise , Transtorno Autístico/fisiopatologia , Deficiência Intelectual/fisiopatologia , Teorema de Bayes , Prática Clínica Baseada em Evidências/tendências , Fatores de Risco , Exposição Materna/efeitos adversos
15.
Sci Rep ; 10(1): 7834, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398858

RESUMO

Inhibitory interneurons are essential for proper brain development and function. Dysfunction of interneurons is implicated in several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID). We have previously shown that Arid1b haploinsufficiency interferes with interneuron development and leads to social, cognitive, and emotional impairments consistent with ASD and ID. It is unclear, however, whether interneurons play a major role for the behavioral deficits in Arid1b haploinsufficiency. Furthermore, it is critical to determine which interneuron subtypes contribute to distinct behavioral phenotypes. In the present study, we generated Arid1b haploinsufficient mice in which a copy of the Arid1b gene is deleted in either parvalbumin (PV) or somatostatin (SST) interneurons, and examined their ASD- and ID-like behaviors. We found that Arid1b haploinsufficiency in PV or SST interneurons resulted in distinct features that do not overlap with one another. Arid1b haploinsufficiency in PV neurons contributed to social and emotional impairments, while the gene deletion in the SST population caused stereotypies as well as learning and memory dysfunction. These findings demonstrate a critical role of interneurons in Arid1b haploinsufficient pathology and suggest that PV and SST interneurons may have distinct roles in modulating neurological phenotypes in Arid1b haploinsufficiency-induced ASD and ID.


Assuntos
Transtorno do Espectro Autista/genética , Haploinsuficiência , Deficiência Intelectual/genética , Interneurônios/metabolismo , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Fatores de Transcrição/genética , Animais , Ansiedade/complicações , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Depressão/complicações , Regulação da Expressão Gênica , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Interneurônios/patologia , Memória , Fenótipo , Comportamento Social , Aprendizagem Espacial
16.
Medicina (B Aires) ; 80 Suppl 2: 7-11, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32150705

RESUMO

Autistic spectrum disorders (ASD) are neurodevelopmental disorders that affect social communication and present repetitive, stereotyped and inflexible behaviour. A third of the people with a diagnosis of ASD also have intellectual disability associated and two thirds present an intellectual capacity within the average range. The nuclear autistic and others associated symptoms can affect the affective and sexual development. This article exposes which are the problems people with ASD present in the affective and sexual development, the most frequently described and brief guides for evaluation and support for an adequate affective-sexual development in people with ASD.


Assuntos
Sintomas Afetivos/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Desenvolvimento Sexual/fisiologia , Sintomas Afetivos/psicologia , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Relações Interpessoais , Masculino , Fatores Sexuais
17.
J Neurosci ; 40(13): 2776-2788, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32098904

RESUMO

Oligophrenin-1 (Ophn1) encodes a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID) in humans. Loss of function of Ophn1 leads to impairments in the maturation and function of excitatory and inhibitory synapses, causing deficits in synaptic structure, function and plasticity. Epilepsy is a frequent comorbidity in patients with Ophn1-dependent XLID, but the cellular bases of hyperexcitability are poorly understood. Here we report that male mice knock-out (KO) for Ophn1 display hippocampal epileptiform alterations, which are associated with changes in parvalbumin-, somatostatin- and neuropeptide Y-positive interneurons. Because loss of function of Ophn1 is related to enhanced activity of Rho-associated protein kinase (ROCK) and protein kinase A (PKA), we attempted to rescue Ophn1-dependent pathological phenotypes by treatment with the ROCK/PKA inhibitor fasudil. While acute administration of fasudil had no impact on seizure activity, seven weeks of treatment in adulthood were able to correct electrographic, neuroanatomical and synaptic alterations of Ophn1 deficient mice. These data demonstrate that hyperexcitability and the associated changes in GABAergic markers can be rescued at the adult stage in Ophn1-dependent XLID through ROCK/PKA inhibition.SIGNIFICANCE STATEMENT In this study we demonstrate enhanced seizure propensity and impairments in hippocampal GABAergic circuitry in Ophn1 mouse model of X-linked intellectual disability (XLID). Importantly, the enhanced susceptibility to seizures, accompanied by an alteration of GABAergic markers were rescued by Rho-associated protein kinase (ROCK)/protein kinase A (PKA) inhibitor fasudil, a drug already tested on humans. Because seizures can significantly impact the quality of life of XLID patients, the present data suggest a potential therapeutic pathway to correct alterations in GABAergic networks and dampen pathological hyperexcitability in adults with XLID.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas do Citoesqueleto/genética , Neurônios GABAérgicos/efeitos dos fármacos , Proteínas Ativadoras de GTPase/genética , Hipocampo/efeitos dos fármacos , Deficiência Intelectual/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Convulsões/fisiopatologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Neurônios GABAérgicos/fisiologia , Hipocampo/fisiopatologia , Deficiência Intelectual/genética , Camundongos , Camundongos Knockout , Convulsões/genética
18.
J Appl Res Intellect Disabil ; 33(3): 542-551, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32048401

RESUMO

OBJECTIVE: The Scale of Emotional Development-Short (SED-S) is an instrument to assess the level of emotional development (ED) in people with intellectual and developmental disability. Index cases are developed as a didactic tool to standardize the application of the scale. METHOD: In a stepwise process, a European working group from six countries developed five index cases, one for each level of ED. All cases were first scored by 20 raters using the SED-S and then rephrased to reduce inter-rater variations (SD > 0.5). RESULTS: All five index cases yielded overall ratings that matched the intended level of ED. Across the range of ED, Regulating Affect needed rephrasing most to ensure a distinct description within each level of ED. CONCLUSIONS: The tri-lingual, cross-cultural evolution of five index cases contributes to a standardized application of the SED-S and can serve as training material to improve the inter-rater reliability of the SED-S across different cultures and languages.


Assuntos
Afeto , Deficiências do Desenvolvimento/diagnóstico , Regulação Emocional , Desenvolvimento Humano , Deficiência Intelectual/diagnóstico , Testes Neuropsicológicos/normas , Psicometria/normas , Adulto , Afeto/fisiologia , Comparação Transcultural , Deficiências do Desenvolvimento/fisiopatologia , Regulação Emocional/fisiologia , Europa (Continente) , Desenvolvimento Humano/fisiologia , Humanos , Deficiência Intelectual/fisiopatologia , Psicometria/instrumentação
19.
Epileptic Disord ; 22(1): 111-115, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32031527

RESUMO

Mowat-Wilson syndrome is a genetic disorder associated with a variable phenotype including peculiar facial features associated with intellectual disability, epilepsy, language impairment, and multiple congenital anomalies caused by heterozygous mutation of the ZEB2 gene. The ZEB2 protein is a complex transcription factor that encompasses multiple functional domains that interact with the regulatory regions of target genes including those involved in brain development. Recently, it has been documented that ZEB2 regulates the differentiation of interneuron progenitors migrating from the medial ganglionic eminence to cortical layers by repression of the Nkx2-1 homeobox transcription factor. It has therefore been suggested that the deficit in ZEB2 may induce an imbalance of neuronal inhibition/excitation leading to epileptic seizures. Given the phenotypic variability of Mowat-Wilson syndrome, to date, a distinctive genotype-phenotype correlation has not been delineated. Here, we report a patient with a severe phenotype of Mowat-Wilson syndrome, associated with a novel heterozygous de novo frame-shift variant in the ZEB2 gene, as well as an additional novel heterozygous missense variant in the SCN1A gene, the mutation of which is known to affect NaV1.1-mediated sodium current in GABAergic interneurons. We hypothesize that the severe neurological phenotype of our patient may be influenced by the coexistence of both genetic mutations. [Published with video sequence].


Assuntos
Epilepsia , Facies , Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Criança , Eletroencefalografia , Epilepsia/etiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Estudos de Associação Genética , Doença de Hirschsprung/complicações , Doença de Hirschsprung/genética , Doença de Hirschsprung/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Microcefalia/complicações , Microcefalia/genética , Microcefalia/fisiopatologia
20.
J Appl Res Intellect Disabil ; 33(3): 584-594, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31960564

RESUMO

BACKGROUND: This study evaluated the role of adaptive behaviour, individual variables (age, gender and problem behaviours) and environmental variables (living arrangements, employment status and city dimension) in affecting the quality of life of individuals with IDD measured from third-party (caregiver) and individuals with IDD' perspective. METHOD: For 93 adults with an IDD diagnosis (47% males) aged 19-65 years, third-party and participants' perspective on participants' quality of life (Personal Outcome Scale), adaptive behaviour (Vineland-II scale), problem behaviours (PIMRA and DASH-II scales), and individual and environmental variables were collected. RESULTS: Adaptive behaviour was the main determinant of quality of life for individuals with IDD. The effect of adaptive behaviour was significant and relevant from both third-party and participants' perspectives. Problem behaviours had a modest negative impact on the quality of life. CONCLUSIONS: Adaptive behaviour is relevant for planning support and interventions for people with IDD to increase their quality of life.


Assuntos
Adaptação Psicológica , Deficiências do Desenvolvimento/fisiopatologia , Deficiência Intelectual/fisiopatologia , Comportamento Problema , Qualidade de Vida , Adulto , Idoso , Cuidadores , Emprego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Características de Residência , Adulto Jovem
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