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1.
PLoS One ; 13(6): e0196607, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29864120

RESUMO

Preterm children often have language problems. This atypical language development is probably due to atypical brain development. We conducted a systematic review to provide an overview of the extensive and diverse scientific literature on the relations between language outcome and underlying brain structures in school-aged preterm-born children. Embase, Medline Ovid, Web of Science, Cochrane central and Google scholar were searched for relevant studies. Inclusion criteria were: cases are school-aged preterm children; structural MRI (T1- and T2-weighted sequences) or DTI used in combination with a neurocognitive language test; publication in an English-language peer-reviewed journal. Correlational measures between language scores and brain volume or fractional anisotropy of a brain structure were extracted. 23 studies were included. The relations between oral language, verbal fluency and/or written language and MRI/DTI measurements of white matter, gray matter, cerebellum, corpus callosum and/or the fasciculi are presented. Oral language skills and verbal fluency appear to be related to the corpus callosum. Oral language skills are also related to the uncinate fasciculus. There seems to be no clear relation between cerebellar development and verbal fluency skills. Not one single brain area is responsible for atypical language development, but several brain areas and their connections are essential. For future research it is recommended to relate brain areas to oral language skills on a microstructural level in preterm children. We also recommend to use language tests in which it is possible to distinguish between several language domains, such as perceptive and expressive language.


Assuntos
Corpo Caloso , Recém-Nascido Prematuro , Transtornos do Desenvolvimento da Linguagem , Desenvolvimento da Linguagem , Criança , Corpo Caloso/patologia , Corpo Caloso/fisiopatologia , Feminino , Humanos , Recém-Nascido , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , MEDLINE , Masculino
2.
J Speech Lang Hear Res ; 60(11): 3226-3236, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29086795

RESUMO

Purpose: Relative lengths of the index (2D) and ring (4D) fingers in humans represent a retrospective biomarker of prenatal hormonal exposures. For this reason, the 2D:4D digit ratio can be used to investigate potential hormonal contributions to the etiology of neurodevelopmental disorders. This study tested potential group differences in 2D:4D digit ratios in a sample of boys with and without developmental language disorder (DLD) and examined the strength of associations between 2D:4D digit ratio and a battery of verbal and nonverbal measures. Method: A group of 29 boys affected by DLD and a group of 76 boys with typical language abilities participated (age range = 5;6-11;0 years). Scanned images were used to measure finger lengths. Language measures included the core language subtests from the Clinical Evaluation of Language Fundamentals-Fourth Edition (Semel, Wiig, & Secord, 2003), a nonword repetition task, a sentence recall task, and the Test of Early Grammatical Impairment (Rice & Wexler, 2001). Results: Significant group differences indicated lower 2D:4D digit ratios in the group with DLD. Modest associations were found between 2D:4D digit ratios and some Clinical Evaluation of Language Fundamentals-Fourth Edition subtests. Conclusions: Prenatal hormone exposures may play a role in the etiology of some language symptoms.


Assuntos
Dedos/patologia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/patologia , Criança , Pré-Escolar , Feminino , Hormônios/metabolismo , Humanos , Transtornos do Desenvolvimento da Linguagem/metabolismo , Testes de Linguagem , Masculino , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Psicolinguística , Reprodutibilidade dos Testes
3.
Neuroscience ; 367: 211-218, 2017 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-29102664

RESUMO

Speech sound disorder (SSD) is common, yet its neurobiology is poorly understood. Recent studies indicate atypical structural and functional anomalies either in one hemisphere or both hemispheres, which might be accompanied by alterations in inter-hemispheric connectivity. Indeed, abnormalities of the corpus callosum - the main fiber tract connecting the two hemispheres - have been linked to speech and language deficits in associated disorders, such as stuttering, dyslexia, aphasia, etc. However, there is a dearth of studies examining the corpus callosum in SSD. Here, we investigated whether a sample of 18 children with SSD differed in callosal morphology from 18 typically developing children carefully matched for age. Significantly reduced dimensions of the corpus callosum, particularly in the callosal anterior third, were observed in children with SSD. These findings indicating pronounced callosal aberrations in SSD make an important contribution to an understudied field of research and may suggest that SSD is accompanied by atypical lateralization of speech and language function.


Assuntos
Corpo Caloso/patologia , Transtornos do Desenvolvimento da Linguagem/patologia , Transtorno Fonológico/patologia , Adolescente , Estudos de Casos e Controles , Criança , Estudos de Coortes , Corpo Caloso/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Transtornos do Desenvolvimento da Linguagem/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Transtorno Fonológico/diagnóstico por imagem
4.
Mol Autism ; 8: 54, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29034068

RESUMO

BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.


Assuntos
Transtorno do Espectro Autista/genética , Haploinsuficiência/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Adolescente , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
5.
Am J Hum Genet ; 101(4): 503-515, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28942966

RESUMO

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.


Assuntos
Anormalidades Múltiplas/genética , Antígenos Nucleares/genética , Anormalidades Craniofaciais/genética , Regulação da Expressão Gênica no Desenvolvimento , Haploinsuficiência/genética , Transtornos do Desenvolvimento da Linguagem/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Adolescente , Animais , Antígenos Nucleares/metabolismo , Sistemas CRISPR-Cas , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Feminino , Edição de Genes , Haploinsuficiência/fisiologia , Humanos , Transtornos do Desenvolvimento da Linguagem/patologia , Larva/genética , Larva/crescimento & desenvolvimento , Masculino , Microcefalia/patologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
6.
Neuroimage Clin ; 12: 655-665, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27747153

RESUMO

Childhood speech and language deficits are highly prevalent and are a common feature of neurodevelopmental disorders. However, it is difficult to investigate the underlying causal pathways because many diagnostic groups have a heterogeneous aetiology. Studying disorders with a shared genetic cause and shared cognitive deficits can provide crucial insight into the cellular mechanisms and neural systems that give rise to those impairments. The current study investigated structural brain differences of individuals with mutations in ZDHHC9, which is associated with a specific neurodevelopmental phenotype including prominent speech and language impairments and intellectual disability. We used multiple structural neuroimaging methods to characterise neuroanatomy in this group, and observed bilateral reductions in cortical thickness in areas surrounding the temporo-parietal junction, parietal lobule, and inferior frontal lobe, and decreased microstructural integrity of cortical, subcortical-cortical, and interhemispheric white matter projections. These findings are compared to reports for other genetic groups and genetically heterogeneous disorders with a similar presentation. Overlap in the neuroanatomical phenotype suggests a common pathway that particularly affects the development of temporo-parietal and inferior frontal areas, and their connections.


Assuntos
Aciltransferases/genética , Encéfalo/patologia , Epilepsia/genética , Epilepsia/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Transtornos da Linguagem/genética , Transtornos da Linguagem/patologia , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Humanos , Deficiência Intelectual/diagnóstico por imagem , Transtornos do Desenvolvimento da Linguagem/diagnóstico por imagem , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos da Linguagem/diagnóstico por imagem , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
7.
Amino Acids ; 48(8): 1877-95, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26861125

RESUMO

While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood-brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.


Assuntos
Amidinotransferases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Barreira Hematoencefálica/metabolismo , Encefalopatias Metabólicas Congênitas/metabolismo , Capilares/metabolismo , Creatina/biossíntese , Creatina/deficiência , Células Endoteliais/metabolismo , Guanidinoacetato N-Metiltransferase/deficiência , Deficiência Intelectual/metabolismo , Transtornos do Desenvolvimento da Linguagem/metabolismo , Retardo Mental Ligado ao Cromossomo X/metabolismo , Transtornos dos Movimentos/congênito , Proteínas do Tecido Nervoso/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Distúrbios da Fala/metabolismo , Amidinotransferases/genética , Amidinotransferases/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Animais , Barreira Hematoencefálica/patologia , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/patologia , Capilares/patologia , Creatina/genética , Creatina/metabolismo , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Guanidinoacetato N-Metiltransferase/genética , Guanidinoacetato N-Metiltransferase/metabolismo , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/patologia , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/patologia , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/metabolismo , Transtornos dos Movimentos/patologia , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo , Distúrbios da Fala/genética , Distúrbios da Fala/patologia
8.
Amino Acids ; 48(8): 2041-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26898547

RESUMO

Deficiency of guanidinoacetate methyltransferase (GAMT) causes creatine depletion and guanidinoacetate accumulation in brain with the latter deemed to be responsible for the severe seizure disorder seen in affected patients. We studied electrical brain activity and GABAA mediated mechanisms of B6J.Cg-Gamt(tm1Isb) mice. Electrocorticographic (ECoG) monitoring of pharmacological treatments with ornithine (5 % in drinking water for 5-18 days) and/or Picrotoxin (PTX) (a GABAA receptor antagonist) (1.5 mg/kg, I.P.) in Gamt(MUT) and Gamt(WT) groups [n = 3, mean age (SEM) = 6.9 (0.2) weeks]. Mice were fitted with two frontal and two parietal epidural electrodes under ketamine/xylazine anesthesia. Baseline and test recordings were performed for determination of seizure activity over a 2 h period. The ECoG baseline of Gamt(MUT) exhibited an abnormal monotonous cortical rhythm (7-8 Hz) with little variability during awake and sleep states compared to wild type recordings. Ornithine treatment and also PTX administration led to a relative normalization of the Gamt(MUT) ECoG phenotype. Gamt(WT) on PTX exhibited electro-behavioral seizures, whereas the Gamt(MUT) did not have PTX induced seizures at the same PTX dose. Gamt(MUT) treated with both ornithine and PTX did not show electro-behavioral seizures while ornithine elevated the PTX seizure threshold of Gamt(MUT) mice even further. These data demonstrate: (1) that there is expression of electrical seizure activity in this Gamt-deficient transgenic mouse strain, and (2) that the systemic availability of guanidinoacetate affects GABAA receptor function and seizure thresholds. These findings are directly and clinically relevant for patients with a creatine-deficiency syndrome due to genetic defects in GAMT and provide a rational basis for a combined ornithine/picrotoxin therapeutic intervention.


Assuntos
Glicina/análogos & derivados , Guanidinoacetato N-Metiltransferase/deficiência , Transtornos do Desenvolvimento da Linguagem , Transtornos dos Movimentos/congênito , Receptores de GABA-A/metabolismo , Convulsões , Animais , Eletrocorticografia , Glicina/farmacocinética , Glicina/farmacologia , Guanidinoacetato N-Metiltransferase/metabolismo , Transtornos do Desenvolvimento da Linguagem/metabolismo , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Camundongos , Camundongos Knockout , Transtornos dos Movimentos/metabolismo , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Receptores de GABA-A/genética , Convulsões/genética , Convulsões/metabolismo , Convulsões/patologia , Convulsões/fisiopatologia
9.
Brain Imaging Behav ; 10(1): 272-82, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25953057

RESUMO

Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.


Assuntos
Encéfalo/diagnóstico por imagem , Dislexia/diagnóstico por imagem , Dislexia/genética , Predisposição Genética para Doença , Transtornos do Desenvolvimento da Linguagem/diagnóstico por imagem , Transtornos do Desenvolvimento da Linguagem/genética , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Dislexia/patologia , Técnicas de Genotipagem , Humanos , Transtornos do Desenvolvimento da Linguagem/patologia , Proteínas do Tecido Nervoso/genética , Tamanho do Órgão , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Tioléster Hidrolases/genética , Substância Branca/diagnóstico por imagem , Substância Branca/crescimento & desenvolvimento , Substância Branca/patologia , Adulto Jovem
10.
Hum Mol Genet ; 25(3): 546-57, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26647308

RESUMO

De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.


Assuntos
Deficiências do Desenvolvimento/genética , Fatores de Transcrição Forkhead/genética , Hipertelorismo/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Adolescente , Sequência de Bases , Criança , DNA/genética , DNA/metabolismo , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Exoma , Feminino , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertelorismo/metabolismo , Hipertelorismo/patologia , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/metabolismo , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Dados de Sequência Molecular , Linhagem , Ligação Proteica , Proteínas Repressoras/metabolismo , Transdução de Sinais , Transcrição Genética
11.
Hum Mol Genet ; 25(3): 597-608, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26647312

RESUMO

De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first single gene disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.


Assuntos
Deficiências do Desenvolvimento/genética , Insuficiência de Crescimento/genética , Histonas/metabolismo , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação , Fatores de Transcrição/metabolismo , Pré-Escolar , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Insuficiência de Crescimento/metabolismo , Insuficiência de Crescimento/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Genes Dominantes , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/metabolismo , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Cultura Primária de Células , Ligação Proteica , Síndrome , Fatores de Transcrição/genética , Transcriptoma , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação
12.
AJNR Am J Neuroradiol ; 37(1): 169-75, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26381551

RESUMO

BACKGROUND AND PURPOSE: Patients with epilepsy and malformations of cortical development have a high prevalence of language deficits. The purpose of this study was to investigate whether the status of the arcuate fasciculus at diffusion tractography could provide a clinically meaningful marker of language function in patients with cortical malformations. MATERIALS AND METHODS: Thirty-seven patients 3-18 years of age who had DTI performed at 3T and language evaluation by a pediatric neurologist were retrospectively identified. Twenty-two age-matched children without any neurologic, language, or MR imaging abnormalities who had identical DTI performed for an indication of headache were selected as a control cohort. The arcuate fasciculi were constructed and segmented by deterministic tractography for all subjects. RESULTS: Twenty-one patients had intact language; 11 had mild-to-moderate and 5, profound language impairment. All patients with normal language and all control subjects had an identifiable left arcuate. The left arcuate was absent in 11 patients; all 11 were language-impaired. Failure to identify the left arcuate was strongly associated with some degree of language impairment (P < .001). Sensitivity, specificity, and positive predictive value for language dysfunction were 65%, 100%, and 100%, respectively. The absence of the arcuate bilaterally was associated with complete failure to develop oral language (P < .015). CONCLUSIONS: Failure to identify the left arcuate fasciculus at diffusion tractography was a highly specific marker of language dysfunction in a cohort of pediatric patients with malformations of cortical development. Failure to identify the arcuate fasciculus on either side was associated with failure to develop oral language.


Assuntos
Núcleo Arqueado do Hipotálamo/anormalidades , Núcleo Arqueado do Hipotálamo/patologia , Imagem de Tensor de Difusão , Epilepsia/diagnóstico , Epilepsia/patologia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/patologia , Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/patologia , Adolescente , Neoplasias Encefálicas/complicações , Criança , Pré-Escolar , Estudos de Coortes , Dominância Cerebral/fisiologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
13.
J Hum Genet ; 61(4): 283-93, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26657932

RESUMO

Cyclin-dependent kinase 5 (CDK5) and cyclin-dependent kinase 5, regulatory subunit 1 (CDK5R1), encoding CDK5 activator p35, have a fundamental role in central nervous system (CNS) development and function, and are involved in the pathogenesis of several neurodegenerative disorders, thus constituting strong candidate genes for the onset of intellectual disability (ID). We carried out a mutation screening of CDK5 and CDK5R1 coding regions and CDK5R1 3'-UTR on a cohort of 360 patients with non-syndromic ID (NS-ID) using denaturing high performance liquid chromatography (DHPLC) and direct sequencing. We found one novel silent mutation in CDK5 and one novel silent mutation in CDK5R1 coding regions, three novel intronic variations in CDK5, not causing any splicing defect, and four novel heterozygous variations in CDK5R1 3'-UTR. None of these variations was present in 450 healthy controls and single-nucleotide polymorphism (SNP) databases. The functional study of CDK5R1 p.A108V mutation evidenced an impaired p35 cleavage by the calcium-dependent protease calpain. Moreover, luciferase constructs containing the CDK5R1 3'-UTR mutations showed altered gene expression levels. Eight known polymorphisms were also identified displaying different frequencies in NS-ID patients compared with the controls. In particular, the minor allele of CDK5R1 3'-UTR rs735555 polymorphism was associated with increased risk for NS-ID. In conclusion, our data suggest that mutations and polymorphisms in CDK5 and CDK5R1 genes may contribute to the onset of the NS-ID phenotype.


Assuntos
Quinase 5 Dependente de Ciclina/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Proteínas do Tecido Nervoso/genética , Regiões 3' não Traduzidas , Adolescente , Criança , Cromatografia Líquida de Alta Pressão , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/patologia , Íntrons , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Mutação
14.
Rev. logop. foniatr. audiol. (Ed. impr.) ; 35(4): 150-158, oct.-dic. 2015. tab
Artigo em Espanhol | IBECS | ID: ibc-142937

RESUMO

Introducción. Los niños con TEL evidencian especial dificultad en la gramática, que puede manifestarse de manera diferente en la conversación y en la narración. Objetivos. a) Explorar la influencia del discurso narrativo y del conversacional en el desempeño gramatical de niños con TEL de 4 y 6 años, y b) determinar si el desempeño gramatical de los niños con TEL de 4 y 6 años es similar o diferente al de niños con desarrollo típico del lenguaje (DTL) en discurso conversacional y narrativo. Metodología. Participaron 21 niños con TEL y 19 niños con DTL. Se analizaron 3 narraciones, obtenidas a partir del recontado, y una conversación semiespontánea. Los análisis se efectuaron según 2 parámetros: gramaticalidad y complejidad de las oraciones. Resultados. La comparación entre conversación y narración en los niños con TEL permite concluir que el tipo de discurso incide en su desempeño gramatical. La forma en que ambos discursos afectan a dicho desempeño se manifiesta de modo distinto en los grupos etarios estudiados. Se observó que el desempeño gramatical de los grupos con TEL tiende a estar más disminuido que el de los grupos con DTL en ambos discursos, especialmente en la narración. Discusión y conclusiones. Los resultados encontrados sugieren que el discurso narrativo es más apropiado para abordar la agramaticalidad y la complejidad de las oraciones, debido a su mayor demanda lingüística. En cambio, la conversación, por ser un discurso menos exigente lingüísticamente, puede ser utilizada para apoyar a niños con TEL que evidencian una dificultad gramatical severa (AU)


Introduction. Children with specific language impairment (SLI) show a particular difficulty with grammar, which can be differently manifested in conversation and narration. Objectives. a) To explore the influence of narrative and conversational discourse in the grammatical performance of children with SLI, divided into two groups (4 and 6 years-old), and b) to determine whether the grammatical performance of 4 and 6 years-old children with SLI is different from children with typical language development (TLD) in conversational and narrative discourse. Method. The study included 21 children with SLI and 19 children with TLD. Three narratives obtained from a re-telling task and semi-spontaneous conversations were analysed according to two parameters: grammaticality and complexity. Results. Comparison between conversation and narration in children with SLI showed that the type of discourse affects grammatical performance. The way in which both types of discourse affect grammatical performance differs according to age. Grammatical performance of children with SLI tends to be lower than children with DTL in both types of discourse, especially in the narrative. Discussion and conclusions. Results suggest that narrative is more appropriate to address the ungrammaticality and complexity of sentences, due to its greater linguistic demand. Since conversation is a less demanding task, it can be used to support children with SLI that show severe grammatical difficulties (AU)


Assuntos
Criança , Feminino , Humanos , Masculino , Desenvolvimento da Linguagem , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/psicologia , Transtornos da Linguagem/diagnóstico , Transtornos da Linguagem/fisiopatologia , Transtornos da Linguagem/psicologia , Fala/fisiologia , Narração , Linguística/métodos , Fonoaudiologia/instrumentação , Fonoaudiologia/organização & administração , Consentimento Livre e Esclarecido/normas
15.
Rev. logop. foniatr. audiol. (Ed. impr.) ; 35(4): 159-170, oct.-dic. 2015. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-142938

RESUMO

Purpose. Three members of a family, one of each generation, are studied in order to obtain their SLI language profile, together with motor and cognitive data. Additional information on the absence of FOXP2 mutations is also provided. Method. The language profile is twofold: natural conversation and language tests, and an evaluation of their cognitive abilities, oral-motor praxis, and laterality. Results. Cognitive abilities (short term and procedural working memory, perception, conceptual and coherence strategies) are not at the average level. General oral fine mobility (not the speech apraxia), fluency and auditory phonetic discrimination are impaired at different degrees. The language phenotype exhibits lexical as well as syntactic processing difficulties as the main impairments. The language competence of the adult members is simple but sufficient for everyday communication. Conclusions. The long-standing language competence results of SLI show an adaptation in terms of simplicity, high frequency strategies, and pragmatic resources. Language profile, sensory-motor abilities and cognition favour a non-specific approach to the language acquisition impairment (AU)


Objetivo. Estudiar tres miembros de una familia con Trastorno Específico del Lenguaje (TEL), uno de cada generación, para obtener su perfil de lenguaje, junto a otros datos de tipo motriz y cognitivo. Se aporta información adicional sobre la ausencia de mutaciones en el gen FOXP2. Método. El perfil del lenguaje que se presenta es doble: Los datos provienen de conversaciones naturales y de tests de lenguaje. También son evaluadas sus habilidades cognitivas, sus praxias oro- motrices y su lateralidad. Resultados. Las habilidades cognitivas de las memorias a corto termino y procedimental de trabajo, la percepción, la conceptuación y las estrategias de construcción de coherencia (texto), no alcanzan un nivel de normalidad. La movilidad fina oral general (no la apraxia de habla), la fluidez, y la fonética auditiva son deficientes en grados diversos. El fenotipo del lenguaje manifiesta sus máximas dificultades de procesamiento en los niveles léxico y sintáctico. Los adultos tienen un lenguaje coloquial muy simple pero normal. Conclusiones. La competencia lingüística de los miembros mayores muestra una buena adaptación, resaltando sus estrategias de simplicidad, usos de alta frecuencia y buena pragmática comunicativa. El perfil del lenguaje, las habilidades sensorio - motrices y las cognitivas favorecen una aproximación no especifica al TEL (AU)


Assuntos
Adolescente , Adulto , Feminino , Humanos , Masculino , Fonoaudiologia/organização & administração , Fonoaudiologia/normas , Desenvolvimento da Linguagem , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos da Linguagem/epidemiologia , Transtornos da Linguagem/patologia , Transtornos da Linguagem/psicologia , Terapia Cognitivo-Comportamental , Supressão Genética/genética , Aptidão/fisiologia , Lateralidade Funcional/genética , Lateralidade Funcional/fisiologia , Apraxias/complicações , Apraxias/epidemiologia , Apraxias/psicologia
16.
Rev. Asoc. Esp. Neuropsiquiatr ; 35(128): 831-835, oct.-dic. 2015. ilus
Artigo em Espanhol | IBECS | ID: ibc-146287

RESUMO

El cavum septum pellucidum (CSP) es una alteración morfológica del septum pellucidum que debe desaparecer entre los tres y los seis meses de vida. Los CSP que persisten después de esa fecha y los de tipo no comunicante se consideran una alteración del neurodesarrollo y se han relacionado con la esquizofrenia y otros trastornos psicóticos, especialmente los de gran tamaño. La prevalencia es variable en función del método de medida, de modo que encontramos cifras que oscilan entre el 0,1% a 85% en la población general y entre el 15 a 44,8% en la esquizofrenia. En los pacientes con trastornos psicóticos y CSP grandes se han observado una serie de características clínicas tales como, mayor presencia de síntomas negativos, alteraciones cognitivas del aprendizaje verbal y de la comprensión de frases, entre otras. Presentamos el caso clínico de una paciente de 19 años diagnosticada de esquizofrenia hebefrénica en la que se halló mediante tomografía computerizada (TC) un CSP de tamaño gigante (2,6 cm) y en la que destaca la importante presencia de síntomas negativos, el deterioro cognitivo, las alteraciones del aprendizaje verbal y de la comprensión de frases e importantes trastornos de conducta (AU)


Cavum septum pellucidum (CSP) is a morphological alteration of the septum pellucidum that should disappear at 3-6 months of age. CSPs that persist for longer, and non-communicating CSP, are classified as a neurodevelopmental disorders and have been associated with schizophrenia and other psychotic disorders, especially in cases with large CSPs. Prevalence rates vary according to the measurement method, and the figures range from 0,1% to 85% in the general population and from 15% to 44,8% in schizophrenia. A series of clinical features such as cognitive disorders, more negative symptoms and verbal learning and sentence comprehension disorders has been found in patients with psychotic disorders and large CSP. We present the clinical case of a 19-year old patient diagnosed with hebephrenic schizophrenia in which a CT scan revealed a giant CSP (2,6 cm) and who presented significant negative symptoms, cognitive deterioration, verbal learning and sentence comprehension disorders and important behavioural disorders (AU)


Assuntos
Adulto , Feminino , Humanos , Septo Pelúcido/patologia , Esquizofrenia/complicações , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Dissonância Cognitiva , Transtornos Psicóticos/complicações , Transtornos Psicóticos/psicologia , Terapia Cognitivo-Comportamental , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/psicologia , Transtornos da Linguagem/patologia , Transtornos da Linguagem/psicologia , Competência Mental/psicologia , Septo Pelúcido
17.
Folia Phoniatr Logop ; 67(1): 29-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25967922

RESUMO

OBJECTIVES: The verbal abilities of autistic children differ from those of typically developing ones and they also differ among autistic children themselves. Neuroanatomical changes and an abnormal organization of functional networks are expected to accompany such a neurodevelopmental disorder. The aim of this study was to delineate the brain neuroanatomical changes in Egyptian children with autism and to compare them with previous studies in order to add more insight into the global brain imaging deviations linked to autism. PATIENTS AND METHODS: Twenty-five autistic children and 25 typically developing children underwent MRI. Further analysis was performed using surface-based morphometry to obtain cortical thickness, brain volume, and cortical complexity. RESULTS: MRI analysis results revealed significantly greater cortical thickness, cortical complexity, and gray matter volume in the autistic as compared to the control group. On the other hand, the white matter volume was significantly smaller. CONCLUSION: These findings generally align with findings in previous studies, except for occasional differences.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Comparação Transcultural , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Encéfalo/patologia , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Criança , Pré-Escolar , Egito , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Transtornos do Desenvolvimento da Linguagem/diagnóstico por imagem , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Valores de Referência
18.
Am J Med Genet A ; 167(6): 1315-22, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847113

RESUMO

We detail here the clinical description and the family genetic study of a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features and a combination of two rare genetic variants: a maternally inherited 16p13.11-p12.3 duplication and a de novo 12p12.1 deletion affecting SOX5. The 16p13.11 microduplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance. The causes of this variation in phenotypic expression are not fully clear, representing a challenge in genetic diagnosis and counseling. However, several authors have proposed the two-hit model as one of the underlying mechanisms for this phenotypic heterogeneity. Our data could also support this two-hit model in which the 16p13.11-p12.3 duplication might contribute to the phenotype, not only as a single event but also in association with the SOX5 deletion. The SOX5 gene plays important roles in various developmental processes and has been associated with several neurodevelopmental disorders, mainly intellectual disability, developmental delay and language and/or speech delay as well as with behavior problems and dysmorphic features. However, many of the physical features and behavioral manifestations as well as language deficiencies present in our patient are consistent with those previously reported for SOX5 deletions. Patients carrying multiple genomic variants, as the one presented here, illustrate the difficulty in analyzing genotypes when the contribution of each variant results in overlapping phenotypes and/or, alternatively, in the modification of the clinical manifestations defined by the coexisting variant.


Assuntos
Duplicação Cromossômica , Deficiências do Desenvolvimento/genética , Deleção de Genes , Transtornos do Desenvolvimento da Linguagem/genética , Comportamento Obsessivo/genética , Fatores de Transcrição SOXD/genética , Criança , Cromossomos Humanos Par 16 , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Facies , Genótipo , Humanos , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Modelos Genéticos , Comportamento Obsessivo/patologia , Comportamento Obsessivo/fisiopatologia , Linhagem , Fenótipo
19.
Am J Med Genet A ; 167(6): 1330-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25899669

RESUMO

Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.


Assuntos
Códon sem Sentido , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Insuficiência de Crescimento/genética , Transtornos do Desenvolvimento da Linguagem/genética , Proteínas de Membrana/genética , Doenças Mitocondriais/genética , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Adolescente , Adulto , Criança , Consanguinidade , Progressão da Doença , Complexo III da Cadeia de Transporte de Elétrons/genética , Insuficiência de Crescimento/patologia , Insuficiência de Crescimento/fisiopatologia , Feminino , Variação Genética , Genótipo , Homozigoto , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Doenças Mitocondriais/fisiopatologia , Encefalomiopatias Mitocondriais/patologia , Encefalomiopatias Mitocondriais/fisiopatologia , Linhagem , Fenótipo , Retina/metabolismo , Retina/patologia
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