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1.
J Appl Oral Sci ; 27: e20180564, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365710

RESUMO

OBJECTIVE: Studies on the oral health of individuals with intellectual disability (ID) have identified problems that include a high prevalence of periodontal disease. The use of probiotics to treat periodontal disease has been the focus of considerable research, and bovine milk fermented with Lactobacillus rhamnosus L8020 (L8020 yogurt) has been shown to reduce the oral prevalence of four periodontal pathogens. The aim of this randomized, double-blind, placebo-controlled trial was to compare the effects of L8020 yogurt (test group) with those of placebo yogurt (placebo group) on the papillary-marginal-attached (PMA) index, gingival index (GI), and probing depth (PD) in 23 individuals with ID. METHODOLOGY: All patients were required to consume the allocated yogurt after breakfast for 90 days. PMA index and GI scores as well as PDs were assessed before the start of yogurt consumption (baseline), after 45 and 90 days of consumption, and 30 days after the cessation of consumption. Student's t-test, Mann-Whitney U test or Fisher's exact test was used for inter-group comparisons, and the mixed effect model of repeated measurements was used for data analysis. RESULTS: The decrease in PMA index score was significantly greater in the test group than in the placebo group (p<0.001). The GI score also decreased during the study, with a tendency for greater decrease in the test group. Furthermore, decreases in PD between baseline, 45 and 90 days tended to be greater in the test group than in the placebo group. CONCLUSION: These results suggest that regular consumption of bovine milk fermented with L. rhamnosus L8020 can lower the risk of periodontal disease in individuals with ID.


Assuntos
Deficiência Intelectual/fisiopatologia , Lactobacillus rhamnosus , Leite , Doenças Periodontais/prevenção & controle , Iogurte , Adulto , Animais , Método Duplo-Cego , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino , Pessoa de Meia-Idade , Doenças Periodontais/patologia , Índice Periodontal , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Risco , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
Epilepsy Res ; 152: 1-6, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30852339

RESUMO

BACKGROUND: Body weight (BW) gain may be induced by perampanel (PER) administration, similar to the well-known adverse effects of valproic acid and gabapentin. Intellectual disability (ID) and serum PER concentration may be risk factors of BW gain. PURPOSE: This study investigated how ID and serum PER concentration are associated with PER-induced BW gain. METHODS: Subjects were 76 patients with epilepsy (41 men, aged 16-70 years). All patients were divided by intelligence quotient (IQ) into no ID (IQ ≥ 70, n = 24), mild to moderate ID (70 > IQ ≥35, n = 31), and severe to profound ID (IQ < 35, n = 21) groups. BW was measured before and 2, 4, 6, and 12 months after initiation of PER treatment, and serum PER concentration at 12 months. RESULTS: BW gains in the mild to moderate ID group at 4, 6, and 12 months were significantly (p < 0.05) higher than in the no ID and in the severe to profound ID groups. At 12 months, BW gain was associated with serum PER concentrations in the no ID (p = 0.034) and the mild to moderate ID (p = 0.001) groups but not in the severe to profound ID group. Multiple linear regression analysis found BW gain at 12 months was positively correlated with the mild to moderate ID group (ß = 0.373, p = 0.002) and serum PER concentration (ß = 0.241, p = 0.047). CONCLUSIONS: The mild to moderate ID group gained more BW than the no ID group, suggesting that PER-induced food intake was greater due to weaker behavioral control in the mild to moderate ID group. The present study suggests a linear correlation between serum PER concentration and BW change.


Assuntos
Anticonvulsivantes/sangue , Deficiência Intelectual/sangue , Piridonas/sangue , Ganho de Peso/efeitos dos fármacos , Adolescente , Adulto , Idoso , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Feminino , Seguimentos , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Tempo , Adulto Jovem
3.
Ital J Pediatr ; 45(1): 38, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885247

RESUMO

BACKGROUND: In order to give a new contribution to the knowledge of the psycho-physical, behavioral and socio-relational development of the individuals who were born at neurological risk, we have carried out a research work through a retrospective and observational analysis in such people, followed in their neuro-evolutionary development from the Department of Pediatrics and Neonatology of the Hospital of Jesi. The purpose of this work is to value the quality of life of the individuals born at neurological risk at a distance of time from the birth. In the literature only recently there are studies on the quality of life of some categories of people, but survey does not seem to be performed in individuals previously born at neurological risk. METHODS: A statistical descriptive and inferential survey has been carried out on 812 individuals who were born at neurological risk, 442 preterm newborns and 370 term newborns, followed from 1977 until to 2007. They were classed in order to their age at the time of our observation. We have submitted the entire sample to a Questionnaire to investigate some areas of their life, ranging from their clinical and psycho-social history to their personal coming of life. Then the same persons, subdivided according to the various age groups, were subjected to other Questionnaires on the quality of life, internationally used. RESULTS: Neurological outcomes were found in 14.7% of the preterm newborns and in 6% of the term newborns, with a significant correlation between neurological outcomes and gestational age, low birth-weight, hypoxic-ischemic encephalopathy and low APGAR-index. Neuro-disabilities were found prevalently belong to the small for gestational age preterm newborns. A low quality of life emerged in those who had neurological outcomes. CONCLUSIONS: Our study on the individuals who were born at neurological risk, analyzed at a distance, shows that a good health is associated with a good quality of life, while a low quality of life occurs to those who had neurological outcome, especially in the physical, cognitive, emotional and socio-relational aspects. As far as the few neurological outcomes which we have found in this survey, we think that they are due, other than to the natural factors, also to the high quality of the obstetric and neonatal care, to the early habilitation physiotherapy and to the important collaboration with the family.


Assuntos
Deficiências do Desenvolvimento/fisiopatologia , Recém-Nascido Prematuro , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/epidemiologia , Qualidade de Vida , Inquéritos e Questionários , Adulto , Fatores Etários , Índice de Apgar , Criança , Pré-Escolar , Doença Crônica , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/etiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Masculino , Doenças Neurodegenerativas/terapia , Testes Neuropsicológicos , Gravidez , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais
4.
Mol Med ; 25(1): 6, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813884

RESUMO

BACKGROUND: Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. METHODS: To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. RESULTS: The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. CONCLUSIONS: Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.


Assuntos
Epilepsia Neonatal Benigna/genética , Síndromes Epilépticas/genética , Deficiência Intelectual/genética , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Adolescente , Criança , Epilepsia Neonatal Benigna/fisiopatologia , Síndromes Epilépticas/fisiopatologia , Estudos de Associação Genética , Células HEK293 , Humanos , Deficiência Intelectual/fisiopatologia , Fenótipo , Adulto Jovem
5.
J Pharmacol Sci ; 139(3): 249-253, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30718079

RESUMO

The duplication of human chromosome 15q11-13 is known to be associated with an estimated 1.1% of autism cases. Here, we investigated whether differentiation into neurons and astrocytes is altered in fetal neural stem cells (FNSCs) isolated from the mouse model of 15q11-13 duplication syndrome (patDp/+ mice). In patDp/+ mice-derived FNSCs, multipotency was maintained for a longer period, the population of neurons was downregulated, and that of astrocytes was upregulated significantly after differentiation induction. These results suggest that the dysregulation of FNSCs differentiation could affect cortical development and behavioral deficits in the early postnatal stage shown in the patDp/+ mice.


Assuntos
Transtorno do Espectro Autista/genética , Diferenciação Celular/fisiologia , Deficiência Intelectual/fisiopatologia , Células-Tronco Neurais/citologia , Animais , Astrócitos/citologia , Transtorno do Espectro Autista/fisiopatologia , Aberrações Cromossômicas , Cromossomos Humanos Par 15 , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia
6.
Genes Brain Behav ; 18(4): e12553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30786142

RESUMO

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cognição , Deficiência Intelectual/fisiopatologia , Fenótipo , Anormalidades Dentárias/fisiopatologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Adolescente , Adulto , Idoso , Atenção , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/psicologia , Criança , Função Executiva , Facies , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Inteligência , Masculino , Memória , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Comportamento Social , Anormalidades Dentárias/genética , Anormalidades Dentárias/psicologia , Percepção Visual
7.
J Autism Dev Disord ; 49(6): 2337-2347, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30726535

RESUMO

To date, the phenotypic significance of EEG abnormalities in patients with ASD is unclear. In a population affected by ASD we aimed to evaluate: the phenotypic characteristics; the prevalence of EEG abnormalities; the potential correlations between EEG abnormalities and behavioral and cognitive variables. Sixty-nine patients with ASD underwent cognitive or developmental testing, language assessment, and adaptive behavior skills evaluation as well as sleep/wake EEG recording. EEG abnormalities were found in 39.13% of patients. EEG abnormalities correlated with autism severity, hyperactivity, anger outbursts, aggression, negative or destructive behavior, motor stereotypies, intellectual disability, language impairment and self-harm. Our findings confirmed that EEG abnormalities are present in the ASD population and correlate with several associated phenotypic features.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Eletroencefalografia/métodos , Índice de Gravidade de Doença , Adolescente , Agressão/fisiologia , Agressão/psicologia , Transtorno do Espectro Autista/psicologia , Biomarcadores , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Masculino , Projetos Piloto , Estudos Retrospectivos , Comportamento Estereotipado/fisiologia , Adulto Jovem
8.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808755

RESUMO

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b -/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b -/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b -/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b -/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Assuntos
Anormalidades do Olho/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Animais , Encéfalo/fisiopatologia , Criança , Anormalidades do Olho/fisiopatologia , Facies , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Microcefalia/fisiopatologia , Mutação , Fenótipo , Ubiquitina/genética
9.
J Hum Genet ; 64(4): 313-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30655572

RESUMO

Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c.571C>T, p.(Arg191*) and a recurrent variant c.593A>G, p.(Lys198Arg), and two novel de novo variants in CSNK2B in Japanese and Malaysian patients, c.494A>G, p.(His165Arg) and c.533_534insGT, p.(Pro179Tyrfs*49), respectively. All four patients showed mild to profound intellectual disabilities, developmental delays, and various types of seizures. This and previous studies have found a total of 20 CSNK2A1 variants in 28 individuals with syndromic intellectual disability. The hotspot variant c.593A>G, p.(Lys198Arg) was found in eight of 28 patients. Meanwhile, only five CSNK2B variants were identified in five individuals with neurodevelopmental disorders. We reviewed the previous literature to verify the phenotypic spectrum of CSNK2A1- and CSNK2B-related syndromes.


Assuntos
Caseína Quinase II/genética , Deficiências do Desenvolvimento/genética , Convulsões/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Convulsões/complicações , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
10.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
11.
J Hum Genet ; 64(4): 341-346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692597

RESUMO

The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland. A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency.


Assuntos
Perda Auditiva Neurossensorial/genética , Hipopituitarismo/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Hipopituitarismo/complicações , Hipopituitarismo/diagnóstico por imagem , Hipopituitarismo/fisiopatologia , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação , Sítios de Splice de RNA/genética , Sequenciamento Completo do Exoma
12.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
13.
Orphanet J Rare Dis ; 14(1): 3, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616629

RESUMO

BACKGROUND: Dysregulation of the inositol cycle is implicated in a wide variety of human diseases, including developmental defects and neurological diseases. A homozygous frameshift mutation in IMPA1, coding for the enzyme inositol monophosphatase 1 (IMPase), has recently been associated with severe intellectual disability (ID) in a geographically isolated consanguineous family in Northeastern Brazil (Figueredo et al., 2016). However, the neurophysiologic mechanisms that mediate the IMPA1 mutation and associated ID phenotype have not been characterized. To this end, resting EEG (eyes-open and eyes-closed) was collected from the Figueredo et al. pedigree. Quantitative EEG measures, including mean power, dominant frequency and dominant frequency variability, were investigated for allelic associations using multivariate family-based association test using generalized estimating equations. RESULTS: We found that the IMPA1 mutation was associated with relative decreases in frontal theta band power as well as altered alpha-band variability with no regional specificity during the eyes-open condition. For the eyes-closed condition, there was altered dominant theta frequency variability in the central and parietal regions. CONCLUSIONS: These findings represent the first human in vivo phenotypic assessment of brain function disturbances associated with a loss-of-function IMPA1 mutation, and thus an important first step towards an understanding the pathophysiologic mechanisms of intellectual disability associated with the mutation that affects this critical metabolic pathway.


Assuntos
Encéfalo/fisiopatologia , Mutação/genética , Monoéster Fosfórico Hidrolases/genética , Encéfalo/metabolismo , Eletroencefalografia , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Linhagem
14.
Neurosci Biobehav Rev ; 98: 234-255, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30615933

RESUMO

Down syndrome (DS) is a genetic disease that occurs due to an aneuploidy of human chromosome 21. Trisomy of chromosome 21 is a primary genetic cause of developmental abnormalities leading to cognitive and learning deficits. Impairments in GABAergic transmission, noradrenergic neuronal loss, anomalous glutamatergic transmission and N-methyl-d-aspartate receptor signalling, mitochondrial dysfunction, increased oxidative stress and inflammation, differentially expressed microRNAs, increased expression of crucial chromosome 21 genes, and DNA hyper-methylation and hyperactive homocysteine trans-sulfuration pathway, are common incongruities that have been reported in DS and might contribute to cognitive impairment and intellectual disability. This review provides an update on metabolic and neurobiological alterations in DS. It also provides an overview of the currently available pharmacological therapies that may influence and/or reverse these alterations in DS.


Assuntos
Síndrome de Down/fisiopatologia , Deficiência Intelectual/fisiopatologia , Aprendizagem/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Aneuploidia , Animais , Modelos Animais de Doenças , Síndrome de Down/terapia , Humanos
15.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
16.
Res Dev Disabil ; 85: 172-186, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30572148

RESUMO

BACKGROUND & AIMS: Previous research indicates that young children with a significant cognitive and motor developmental delay show low levels of interactive engagement, their parents are generally responsive towards them and these variables are positively correlated. Adapting a micro-level approach, we aim to go beyond macro-level and correlational analyses by charting the frequency, intra-individual co-occurrence and inter-individual temporal dependency of specific interactive behaviors. METHODS & PROCEDURES: Twenty-nine parent-child dyads (with children aged 6-59 months) were video-taped during a 15-minute unstructured play situation. Based on a self-developed coding scheme, interactive behaviors were coded continuously and analyzed using a three-step sequential analysis approach. OUTCOMES & RESULTS: Parents and children systematically combine either more socially-oriented or more object-oriented behaviors. Socially-oriented behaviors are less frequent in children, especially looking at and touching the partner occurs less. Socially- and object-oriented behavioral clusters are generally independent from each other and instigate/maintain the same type of behaviors in the interaction partner. While children's socially oriented behavior(al cluster)s seem to need a parental 'trigger', parents will more often independently engage with their child despite low child responsiveness. CONCLUSIONS AND IMPLICATIONS: Further intervention-oriented research is needed to confirm this study's results and translate them into concrete guidelines for parents.


Assuntos
Comportamento Infantil , Deficiências do Desenvolvimento/fisiopatologia , Deficiência Intelectual/fisiopatologia , Comportamento Materno , Transtornos das Habilidades Motoras/fisiopatologia , Relações Pais-Filho , Comportamento Paterno , Comportamento Social , Adulto , Pré-Escolar , Cognição , Contratura , Feminino , Perda Auditiva , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Hipertonia Muscular , Hipotonia Muscular , Escoliose , Transtornos da Visão
17.
Res Dev Disabil ; 85: 187-196, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30576945

RESUMO

BACKGROUND: Better daily living skills (DLS) are associated with increased independence and positive functional outcomes in Autism Spectrum Disorder (ASD). METHOD: The present study aimed to investigate daily living skills (DLS) and the associated factors in 51 children with ASD and intellectual disability (ASD group) and 51 age- and gender-matched controls with intellectual disability (ID group). The severity of the autistic symptoms was measured with the clinician-rated Childhood Autism Rating Scale and the parent-reported Autism Behavior Checklist (ABC) in all children. The mothers also completed the Pediatric Quality of Life Inventory and the Basic DLS Questionnaire. RESULTS: The ASD group scored lower than the comparison group in the total DLS score, personal hygiene, dressing, safety and interpersonal skills, despite being comparable in the parent-reported quality of life. Regression analysis of the whole sample demonstrated that the child's age, intellectual level, speech level, autism symptom severity and the monthly household income were independent correlates of the total DLS. Exploratory analyses for each group revealed differential effects of these variables: in the ASD group; a higher speech level and monthly income, while in the ID group; an older age, a higher intellectual level and monthly income and a lower ABC score emerged as significant predictors of higher DLS. CONCLUSIONS: Deficient DLS in Turkish children with ASD, given their IQ, suggest that lower level of adaptive skills is inherent in ASD, rather than culture-specific to US and Western Europe.


Assuntos
Atividades Cotidianas , Transtorno do Espectro Autista/fisiopatologia , Deficiência Intelectual/fisiopatologia , Adolescente , Fatores Etários , Transtorno do Espectro Autista/psicologia , Estudos de Casos e Controles , Criança , Características da Família , Feminino , Humanos , Higiene , Renda , Deficiência Intelectual/psicologia , Masculino , Qualidade de Vida , Segurança , Habilidades Sociais , Fala , Inquéritos e Questionários , Turquia
18.
Res Dev Disabil ; 85: 217-228, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30580152

RESUMO

Most research does not address the overlap between neurodevelopmental disorders when investigating concomitant mental health problems. The purpose of the present study was to examine the association of intellectual disability (ID), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) with the presence of behavioural and emotional problems after controlling for other well-known correlates and risk factors. The sample included 4- to 18-year-old children who attended neuropaediatric clinics (N = 331). After controlling for adversity, age, gender, other developmental/neurological disorders, parental emotional problems, and parenting strategies, the presence of ADHD but not ASD or ID was uniquely associated with behaviour problems. Neither ADHD nor ASD nor ID was significantly associated with emotional problems after controlling for other risk factors. However, ADHD, ASD and behavioural/emotional disorders but not ID were significantly associated with functional impairment in everyday activities after controlling for other risk factors. Because children with neurodevelopmental disorders have complex needs, a holistic approach to diagnosis and interventions is highly warranted, including the assessment and treatment of behavioural and emotional disorders.


Assuntos
Atividades Cotidianas , Transtornos de Ansiedade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Transtorno da Conduta/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Deficiência Intelectual/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adolescente , Transtornos de Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/fisiopatologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Transtorno da Conduta/psicologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Deficiência Intelectual/psicologia , Masculino , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia , Razão de Chances , Poder Familiar , Pais/psicologia , Classe Social , Transtornos de Estresse Pós-Traumáticos/psicologia
19.
Medicine (Baltimore) ; 97(51): e13749, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572518

RESUMO

RATIONALE: Epilepsy with mental retardation limited to females (EFMR) is a rare type of X-linked epilepsy disorder, affecting heterozygous females disproportionately. The pathogenesis of EFMR has been identified as mutations in the protocadherin 19 (PCDH19) gene. To data, more than 60 different mutations in PCDH19 have been identified. Most of them are located at exon 1, but we describe a novel deletion mutation c.2468delT at exon 3 of PCDH19. PATIENT CONCERNS: The patient was an 11-year-old girl with onset of seizures at the age of 18 months and followed by progressive intellectual disability (ID) later. DIAGNOSIS: The girl was diagnosed as EFMR when a novel deletion mutation c.2468delT at exon 3 of PCDH19 was found. The deletion mutation c.2468delT was predicted to have caused a frameshift mutation of amino acid at position 823 (p.L823fs). There was no family history of seizures or ID. Her father was asymptomatic, but the mutation screening shows that he had a hemizygous mutation c.2468delT at the same site of PCDH19. The secondary structure of PCDH19 (wide type) showed that the sequences undergoing frameshift mutations were located in the cytoplasm and contain 9 phosphorylation sites. The p.L823fs mutation caused a totally different amino sequence after position of 823, thereby resulting in the disappearance of phosphorylation sites. The frameshift mutation of amino acid at position 823 might affect its binding capability with GABAA receptor and results in migration and morphological maturation of hippocampal neurons. INTERVENTIONS: The patient has received antiepileptic treatments, including sodium valproate, carbamazepine, levetiracetam, topiramate and clonazepam et al. OUTCOMES:: The antiepileptic treatment effects were limited. LESSONS: This case report describes a novel PCDH19 gene mutation (c.2468delT) at exon 3 in a girl suffering from EFMR. The deletion mutation was predicted to cause a frameshift mutation-p.L823fs, which is highly conserved across different species.


Assuntos
Caderinas/genética , Epilepsia/genética , Mutação da Fase de Leitura , Deficiência Intelectual/genética , Criança , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/fisiopatologia
20.
Medicine (Baltimore) ; 97(41): e12737, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30313077

RESUMO

This cross-sectional study examines differences in gross motor proficiency as a function of different intellectual functioning profiles. Two motor areas have been investigated as being equally essential to gross motor functions in every-day life: locomotion and object control.It aims to compare gross motor skills endorsed by children with Down syndrome (DS), children with borderline intellectual functioning (BIF), and typically developing children (TDC).Group 1 was composed of 18 children with DS (chronological age = 8.22), group 2 was composed of 18 children with BIF (chronological age = 9.32), and group 3 was composed of 18 children with typical development (TD) (chronological age = 9.28).Gross motor skills were measured through the test of gross motor development (TGMD-Test) composed of locomotion and object control tasks.Children with DS showed worse gross motor skills compared with children with BIF and typically developing children by underscoring both on all locomotion (e.g., walking, running, hopping, galloping, jumping, sliding, and leaping) and all object control tasks (e.g., throwing, catching, striking, bouncing, kicking, pulling, and pushing).In DS group strengths were found on run and slide skills, in BIF group strengths were on run, long jump and slide skills and in TDC group strengths were on run and slide skills. For all of the 3 groups the locomotor worst performed task was jump forward with arm swing.Findings suggest implications for further practice to develop evidence-based exercise programs aimed to rehabilitate gross motor skills through the regular participation in structured exercise activities.


Assuntos
Desenvolvimento Infantil/fisiologia , Síndrome de Down/fisiopatologia , Deficiência Intelectual/fisiopatologia , Transtornos das Habilidades Motoras/fisiopatologia , Criança , Estudos Transversais , Feminino , Humanos , Locomoção , Masculino
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