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1.
Neurology ; 95(19): e2675-e2682, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32887777

RESUMO

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 CONCLUSIONS: Seven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected.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


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Deficiências do Desenvolvimento/genética , Succinato-Semialdeído Desidrogenase/deficiência , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Ataxia/genética , Ataxia/fisiopatologia , Criança , Simulação por Computador , Deficiências do Desenvolvimento/fisiopatologia , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Células HEK293 , Heterozigoto , Homozigoto , Humanos , Técnicas In Vitro , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Sítios de Splice de RNA , Índice de Gravidade de Doença , Succinato-Semialdeído Desidrogenase/genética
2.
S Afr Med J ; 110(4): 308-312, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32657743

RESUMO

BACKGROUND: Neonatal hypoxic ischaemic encephalopathy (NHIE) is an important cause of long-term handicap in survivors. There is limited information on the burden of handicap from NHIE in sub-Saharan Africa. OBJECTIVES: To determine the developmental outcomes in survivors of NHIE in South Africa (SA). METHODS: In this prospective observational study, the developmental outcomes in 84 infants who had survived hypoxic ischaemic encephalopathy (the NHIE group) were compared with those in 64 unaffected infants (the control group). The Bayley Scales of Infant Development version III were used for assessment of developmental outcomes. RESULTS: Significant differences were found between the developmental outcomes of the two groups, with a significantly lower composite language score and higher proportions with language, motor and cognitive developmental delays in the NHIE group than in the control group. Cerebral palsy (CP) was present in 13 of the infants with NHIE (15.5%) and none in the control group (p<0.001). CP was associated with developmental delay, and also with the severity of NHIE. Therapeutic hypothermia (TH) was administered in 58.3% of the study group, but although it was associated with lower rates of CP and developmental delay than in the group without TH, the only significant difference was for delay on the language subscale. CONCLUSIONS: Survivors of NHIE in SA are at risk of poor developmental outcomes.


Assuntos
Paralisia Cerebral/epidemiologia , Desenvolvimento Infantil , Deficiências do Desenvolvimento/epidemiologia , Hipóxia-Isquemia Encefálica/epidemiologia , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Estudos de Casos e Controles , Paralisia Cerebral/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/terapia , Lactente , Recém-Nascido , Doenças do Recém-Nascido , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , África do Sul/epidemiologia
3.
PLoS One ; 15(4): e0231937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32352985

RESUMO

We examined reading, spelling, and mathematical skills in an unselected group of 129 Italian fifth graders by testing various cognitive predictors for each behaviour. As dependent variables, we measured performance in behaviours with a clear functional value in everyday life, such as reading a text, spelling under dictation and doing mental and written computations. As predictors, we selected cognitive dimensions having an explicit relation with the target behaviour (called proximal predictors), and prepared various tests in order to select which task had the best predictive power on each behaviour. The aim was to develop a model of proximal predictors of reading (speed and accuracy), spelling (accuracy) and maths (speed and accuracy) characterized by efficacy also in comparison to the prediction based on general cognitive factors (i.e., short-term memory, phonemic verbal fluency, visual perceptual speed, and non-verbal intelligence) and parsimony, pinpointing the role of both common and unique predictors as envisaged in the general perspective of co-morbidity. With one exception (reading accuracy), the proximal predictors models (based on communality analyses) explained a sizeable amount of variance, ranging from 27.5% in the case of calculation (accuracy) to 48.7% of reading (fluency). Models based on general cognitive factors also accounted for some variance (ranging from 6.5% in the case of spelling to 19.5% in the case of reading fluency) but this was appreciably less than that explained by models based on the hypothesized proximal predictors. In general, results confirmed the efficacy of proximal models in predicting reading, spelling and maths although they offered only limited support for common predictors across different learning skills; namely, performance in the Orthographic Decision test entered as a predictor of both reading and spelling indicating that a single orthographic lexicon may account for performance in reading and spelling. Possible lines of research to expand on this approach are illustrated.


Assuntos
Comorbidade , Matemática , Leitura , Redação , Criança , Cognição , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Masculino
4.
Plast Reconstr Surg ; 145(5): 1215-1221, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32332541

RESUMO

BACKGROUND: There is scant literature regarding patient-reported outcomes after reconstruction for congenital hand syndactyly. Understanding patient perceptions of the postoperative outcome may facilitate a more evidence-based discussion of expectations after reconstruction. METHODS: All patients undergoing congenital syndactyly reconstruction at Ann and Robert H. Lurie Children's Hospital of Chicago between January of 2007 and December of 2015 were identified. Patient-Reported Outcomes Measurement Information System questionnaires were completed by patients; parent-proxy questionnaires were completed for patients 10 years of age and younger and those unable to complete the questionnaire independently. A retrospective chart review was also performed to capture demographic and clinical information. RESULTS: The authors identified 124 patients meeting inclusion criteria; 51 completed the Patient-Reported Outcomes Measurement Information System surveys (response rate, 41.1 percent). The survey score for upper extremity function was 41.8 ± 11. Upper extremity function was further impaired in patients with a documented history of developmental delay (23.8 ± 6.2 versus 44.2 ± 10.2). Parents completing surveys on behalf of their children reported higher pain interference scores than self-responders. CONCLUSIONS: The Patient-Reported Outcomes Measurement Information System is a valuable tool for measuring patient-reported outcomes in patients with syndactyly. Patients who have undergone reconstruction for syndactyly experience minor impairments in upper extremity function, but other aspects of their health-related quality of life are comparable to those of the general population. Developmental delay may be associated with additional impairments in upper extremity function and should be discussed when considering surgical reconstruction.


Assuntos
Dedos/anormalidades , Procedimentos Ortopédicos/efeitos adversos , Dor Pós-Operatória/epidemiologia , Medidas de Resultados Relatados pelo Paciente , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Sindactilia/cirurgia , Fatores Etários , Chicago , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Dedos/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/psicologia , Qualidade de Vida , Recuperação de Função Fisiológica , Estudos Retrospectivos , Autorrelato/estatística & dados numéricos , Sindactilia/complicações , Sindactilia/fisiopatologia , Resultado do Tratamento , Extremidade Superior/fisiopatologia
5.
PLoS One ; 15(3): e0229538, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187183

RESUMO

Participation, defined as 'involvement in life situations' according to the World Health Organisation, is a well-recognized concept and critical indicator of quality of life. In addition it has become an important outcome measure in child rehabilitation. However, little is known about the level of participation of young children with Developmental Disabilities. The aim of this study was to capture their subjective experiences of participation. An adapted informed consent based on a comic strip was used to get the children's assent. A Photo Elicitation study was used, in which photographs were taken by the children when they were involved in meaningful activities. The photographs were then used to facilitate communication with the children and to initiate in depth-interviews. Forty-seven interviews with 16 children between five and nine years were conducted based on their photographs. This method generated rich data, confirming that young children with Developmental Disabilities were able to inform us accurately on their experiences of participation. Data was analysed by means of an inductive thematic analysis. Results showed that children perceived their participation as satisfying when they can play, learn and join in family gatherings resulting in feelings of inclusion, recognition and belonging. When there are-on occasions-moments that their participation was obstructed, the children used two strategies to resolve it. Or they walked away from it and choose not to participate, or when autonomously motivated for the activity, they relied primarily on their context (i.e. mothers) as enabling their participation. Related to the data, children discussed themes related to their person, activities, connections and mediators between those themes. These themes fit well within earlier and current research on the subject of participation.


Assuntos
Deficiências do Desenvolvimento/psicologia , Entrevista Psicológica/métodos , Participação Social/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Comunicação , Deficiências do Desenvolvimento/fisiopatologia , Emoções/fisiologia , Família , Feminino , Humanos , Masculino , Motivação/fisiologia , Pais , Fotografação/métodos , Pesquisa Qualitativa , Qualidade de Vida , Percepção Visual/fisiologia
6.
J Appl Res Intellect Disabil ; 33(3): 542-551, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32048401

RESUMO

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


Assuntos
Afeto , Deficiências do Desenvolvimento/diagnóstico , Regulação Emocional , Desenvolvimento Humano , Deficiência Intelectual/diagnóstico , Testes Neuropsicológicos/normas , Psicometria/normas , Adulto , Afeto/fisiologia , Comparação Transcultural , Deficiências do Desenvolvimento/fisiopatologia , Regulação Emocional/fisiologia , Europa (Continente) , Desenvolvimento Humano/fisiologia , Humanos , Deficiência Intelectual/fisiopatologia , Psicometria/instrumentação
7.
J Clin Res Pediatr Endocrinol ; 12(Suppl 1): 41-45, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041391

RESUMO

For girls with physical and developmental disabilities and their families/caregivers, puberty and menstruation can present significant problems such as vulnerability, abuse risk, unintended pregnancies, difficulties with managing menstrual hygiene, abnormal uterine bleeding, dysmenorrhea, behavioral difficulties/mood concerns or changes in seizure pattern. Healthcare providers may have an important and positive impact for both the adolescents and their families/caregivers during this stage of life. Whether menstrual manipulation is indicated should be decided after a detailed history is taken from both the patient and the caregivers to determine the impact of current problems on quality of life. It should be explained that complete amenorrhea is difficult to achieve and realistic expectations should be addressed. The goals for the management of menstrual concerns should be a reduction in the amount and total days of menstrual flow, reduction of menstrual pain and suppression of ovulatory or cyclic symptoms, depending on each individual patient's needs. Advantages and disadvantages of available treatment methods should also be discussed.


Assuntos
Deficiências do Desenvolvimento/fisiopatologia , Menstruação , Puberdade/fisiologia , Adolescente , Abuso Sexual na Infância/prevenção & controle , Epilepsia/tratamento farmacológico , Feminino , Humanos , Menstruação/efeitos dos fármacos , Síndrome Pré-Menstrual/tratamento farmacológico , Educação Sexual
8.
Am J Occup Ther ; 74(1): 7401205060p1-7401205060p12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32078517

RESUMO

IMPORTANCE: Adults with intellectual and developmental disabilities (IDD) are twice as likely as their peers without disabilities to have had a physical exam in the past year; however, as a result of challenging behavior during office visits, they are significantly less likely to have received recommended health screenings. Challenging behaviors in clinical settings have been identified as a barrier to providing adequate care for this population. OBJECTIVE: This scoping review examined the within-session effects of multisensory environments (MSEs) on people with IDD to determine the clinical utility of MSEs for this population. DATA SOURCES: Studies published between January 1, 2000, and August 1, 2018, were identified using Summon and Google Scholar. STUDY SELECTION: Studies were included in the review if they systematically collected and reported data on within-session effects of an MSE intervention on people with IDD. FINDINGS: Thirteen studies met criteria for this review: 4 with Level I evidence, 2 with Level II evidence, 3 with Level III evidence, and 4 with Level IV evidence. Studies examined the effects of MSEs on maladaptive behaviors, positive behaviors, distress and discomfort, activity and alertness states, and cost of care for people with IDD. CONCLUSION AND RELEVANCE: Preliminary support was found for the use of MSEs in clinical settings to reduce anxiety and challenging behaviors in patients with IDD during clinical care. Further research is needed to determine the efficacy of MSEs for producing the effects described in this review. WHAT THIS ARTICLE ADDS: The findings support the potential of MSEs as a tool that occupational therapy practitioners can use to support their clients with IDD who have sensory sensitivities in clinical settings. This article also highlights a multidisciplinary approach whereby medical providers and occupational therapy practitioners could work together in nontraditional ways to support this population.


Assuntos
Pessoas com Deficiência , Deficiência Intelectual , Terapia Ocupacional , Adulto , Criança , Deficiências do Desenvolvimento/fisiopatologia , Humanos
9.
Brain Dev ; 42(3): 289-292, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31955925

RESUMO

Atypical phenotype of an imprinting disease can develop with a recessive homozygous variant due to uniparental isodisomy. We present a girl with severe intellectual disability, developmental delay, distinctive facial features, and other neuropsychiatric features. Trio whole exome sequencing revealed a novel homozygous frameshift variant in AP4E1 [NM_007347.5:c.2412dupT:p.(Gly805Trpfs*8)] and uniparental isodisomy of chromosome 15 [iUPD(15)]. Single nucleotide polymorphism mapping analysis of exome data showed that the homozygous AP4E1 variant was derived from her heterozygous carrier father and unmasked by paternal iUPD(15). Brain magnetic resonance imaging confirmed the brain abnormalities characteristic of AP4 deficiency including the dilated ventricles and hypointensity in the globus pallidus in susceptibility-weighted imaging. This is the first case report of a combination of AP4E1 deficiency and Angelman syndrome. Our patient indicates that whole exome sequencing could uncover an atypical phenotype caused by multiple genetic factors including the uniparental isodisomy.


Assuntos
Síndrome de Angelman , Cromossomos Humanos Par 15/genética , Proteínas de Ligação a DNA/deficiência , Deficiências do Desenvolvimento , Transtornos Heredodegenerativos do Sistema Nervoso , Deficiência Intelectual , Dissomia Uniparental/genética , Síndrome de Angelman/genética , Síndrome de Angelman/patologia , Síndrome de Angelman/fisiopatologia , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Pai , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Fenótipo , Proteínas de Ligação a RNA
10.
J Appl Res Intellect Disabil ; 33(3): 584-594, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31960564

RESUMO

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


Assuntos
Adaptação Psicológica , Deficiências do Desenvolvimento/fisiopatologia , Deficiência Intelectual/fisiopatologia , Comportamento Problema , Qualidade de Vida , Adulto , Idoso , Cuidadores , Emprego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Características de Residência , Adulto Jovem
11.
Zhonghua Er Ke Za Zhi ; 58(1): 35-40, 2020 Jan 02.
Artigo em Chinês | MEDLINE | ID: mdl-31905474

RESUMO

Objective: To investigate the genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy (DEE). Methods: Clinical data including the manifestations and electroencephalogram of 8 children with KCNA2 variants treated in the Department of Pediatrics, Peking University First Hospital from March 2017 to June 2019 were collected and analyzed retrospectively. Results: Among the 8 epileptic patients with KCNA2 variants, 5 were males and 3 were females. The age of onset was from 1 day to 11 months. The age at last follow-up ranged from 4 months to 86 months. Two variants including c.1214C>T (loss-of-function) and c.1120A>G (gain-and loss-of-function) were identified. The variant of c.1214C>T was found in six patients (case 1-6). For these patients, the age of onset was from 5 to 11 months and they were characterized by multiple seizure types. All had focal seizures and had normal development before seizure onset with developmental regression after seizure onset. The first electroencephalogram showed epileptic discharges in Rolandic region in two, epileptic discharges in Rolandic region combined with generalized discharge in one, generalized discharge with posterior predominance in two (combined with or transferred to Rolandic region during the course) and epileptic discharges in posterior region combined with generalized discharge in one. And in 5 of them the Rolandic discharges developed into epileptic electrical status (ESES) during sleep. All the six patients were still treated with a combination of multiple antiepileptic drugs. Two of them had seizure controlled at 80 months and 68 months, respectively. The variant of c.1120A>G were identified in two of eight patients (case 7 and 8) and they had seizure onset on the 1st day after birth. Their epileptic seizures were frequent and difficult to control. They had remarkably developmental delay and microcephaly since birth. One case (case 8) had a wide forehead. They had frequent seizures up to the last follow-up. In case 7, the early electroencephalogram showed epileptic discharges in temporal region, and interictal electroencephalogram at 3 months of age showed multifocal discharge with posterior and temporal region predominance. In case 8, the early electroencephalogram was normal and electroencephalogram showed burst suppression at 2 months of age, and it developed epileptiform discharge in posterior region at 1 year of age. Conclusions: KCNA2 gene variants can lead to DEE with multiple seizures types. Among them, loss-of-function c.1214C>T is the most common, and these patients have seizure onset at infancy with Rolandic discharges tended to develop into to ESES pattern. The variant of c.1120A>G is a gain-of- and loss-of-function variant, patients with c.1120A>G have seizure onset in neonatal period, the phenotype overlaps with the former but is more severe.


Assuntos
Encefalopatias/genética , Epilepsia/diagnóstico , Canal de Potássio Kv1.2/genética , Convulsões , Idade de Início , Encéfalo/fisiopatologia , Encefalopatias/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/complicações , Epilepsia/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Estudos Retrospectivos
12.
J Appl Res Intellect Disabil ; 33(3): 529-541, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31851402

RESUMO

BACKGROUND: Children with a significant cognitive and motor developmental delay are pre-symbolic communicators. The primary aim of this study was to reveal the variability within the communicative functioning of this group of children in terms of communication level, the reasons to communicate and behavioural expressions. METHODS: Twenty-six children between 14 and 58 months with a significant cognitive and motor developmental delay were recruited. The Communication Matrix of Rowland (2011, Communication Disorders Quarterly, 32, 190) was used to integrate different sources of information on the children's communicative functioning. RESULTS: These children primarily communicated at the level of pre-intentional and intentional behaviour, aimed at refusing, obtaining and, to a lesser extent, social purposes. CONCLUSIONS: To develop or adapt early intervention strategies, and to monitor progress in communicative development, an even more nuanced view on these children's communicative utterances in terms of frequency, duration, idiosyncrasy and context relatedness is needed.


Assuntos
Comportamento Infantil/fisiologia , Transtornos da Comunicação/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Deficiência Intelectual/fisiopatologia , Transtornos Motores/fisiopatologia , Pré-Escolar , Transtornos da Comunicação/etiologia , Deficiências do Desenvolvimento/complicações , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Intenção , Masculino , Transtornos Motores/complicações
13.
Clin Dysmorphol ; 29(1): 10-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31577543

RESUMO

With the increasing availability and clinical use of exome and whole-genome sequencing, reverse phenotyping is now becoming common practice in clinical genetics. Here, we report a patient identified through the Wellcome Trust Deciphering Developmental Disorders study who has homozygous pathogenic variants in CC2D2A and a de-novo heterozygous pathogenic variant in KIDINS220. He presents with developmental delay, intellectual disability, and oculomotor apraxia. Reverse phenotyping has demonstrated that he likely has a composite phenotype with contributions from both variants. The patient is much more mildly affected than those with Joubert Syndrome or Spastic paraplegia, intellectual disability, nystagmus, and obesity, the conditions associated with CC2D2A and KIDINS220 respectively, and therefore, contributes to the phenotypic variability associated with the two conditions.


Assuntos
Anormalidades Múltiplas , Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento , Anormalidades do Olho , Deficiência Intelectual , Doenças Renais Císticas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/fisiopatologia , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Doenças Renais Císticas/fisiopatologia , Masculino , Retina/patologia , Retina/fisiopatologia
14.
Elife ; 82019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31843053

RESUMO

Social visual engagement difficulties are hallmark early signs of autism (ASD) and are easily quantified using eye tracking methods. However, it is unclear how these difficulties are linked to atypical early functional brain organization in ASD. With resting state fMRI data in a large sample of ASD toddlers and other non-ASD comparison groups, we find ASD-related functional hypoconnnectivity between 'social brain' circuitry such as the default mode network (DMN) and visual and attention networks. An eye tracking-identified ASD subtype with pronounced early social visual engagement difficulties (GeoPref ASD) is characterized by marked DMN-occipito-temporal cortex (OTC) hypoconnectivity. Increased DMN-OTC hypoconnectivity is also related to increased severity of social-communication difficulties, but only in GeoPref ASD. Early and pronounced social-visual circuit hypoconnectivity is a key underlying neurobiological feature describing GeoPref ASD and may be critical for future social-communicative development and represent new treatment targets for early intervention in these individuals.


Assuntos
Transtorno Autístico/fisiopatologia , Movimentos Oculares/fisiologia , Rede Nervosa/fisiopatologia , Vias Neurais/fisiologia , Comportamento Social , Atenção/fisiologia , Transtorno Autístico/classificação , Transtorno Autístico/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Modelos Neurológicos
15.
Behav Brain Funct ; 15(1): 11, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653253

RESUMO

Traumatic injury (TI) during pregnancy increases the risk for developing neurological disorders in the infants. These disorders are a major concern for the well-being of children born after TI during pregnancy. TI during pregnancy may result in preterm labor and delivery, abruptio placentae, and/or fetomaternal hemorrhage. Drosophila melanogaster (fruit fly) is a widely used model to study brain and behavioral disorders in humans. In this study, we analyzed the effects of TI to female fruit flies on the development timing of larvae, social interaction and the behavior of offspring flies. TI to the female flies was found to affect the development of larvae and the behavior of offspring flies. There was a significant increase in the length of larvae delivered by traumatically injured maternal flies as compared to larvae from control maternal flies (without TI). The pupae formation from larvae, and the metamorphosis of pupae to the first generation of flies were faster in the TI group than the control group. Negative geotaxis and distance of the fly to its nearest neighbor are parameters of behavioral assessment in fruit flies. Negative geotaxis significantly decreased in the first generation of both male (p = 0.0021) and female (p = 0.0426) flies. The distance between the first generation of flies to its nearest neighbor was shorter in both male and female offspring flies in the TI group as compared to control group flies. These results indicate that TI to the female flies affected the development of larvae and resulted in early delivery, impaired social interaction and behavioral alterations in the offspring.


Assuntos
Deficiências do Desenvolvimento/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Lesões Pré-Natais/fisiopatologia , Animais , Comportamento Animal/fisiologia , Drosophila melanogaster/metabolismo , Feminino , Larva , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Problema , Ferimentos e Lesões/fisiopatologia
16.
J Hum Genet ; 64(11): 1097-1106, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471553

RESUMO

Early-onset developmental and epileptic encephalopathy (DEE) is a group of devastating disorders that appear during the neonatal and infantile periods. Despite great progress in the discovery of genes leading to early-onset DEE, many cases with unexplained etiology remain. Furthermore, to date, the association of copy number variations (CNVs) with early-onset DEE has seldom been addressed. Here, we investigated the contribution of CNVs to epilepsy in a cohort of Japanese children with a variety of early-onset DEEs. Single nucleotide polymorphism (SNP) array analysis was performed for 83 cases that were previously negative for pathogenic single nucleotide variants (SNVs) in 109 genes known or suspected to cause epileptic seizures. Rare CNVs were detected in a total of 12 cases (14.4%), of which three cases (3.6%) involved clearly pathogenic CNVs and nine cases (10.8%) were CNVs of uncertain significance. The three pathogenic CNVs included two de novo heterozygous deletions involving known epileptic encephalopathy genes, such as GABRG2 and PCDH19, and one maternally inherited duplication encompassing MECP2. Our findings indicate rare CNVs are also relevant for the diagnosis of early-onset DEEs, highlighting the importance of not relying only on the investigation of SNVs/small indels at the risk of missing large deletions and duplications.


Assuntos
Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/genética , Convulsões/genética , Espasmos Infantis/genética , Caderinas/genética , Criança , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de GABA-A/genética , Convulsões/fisiopatologia , Espasmos Infantis/fisiopatologia
17.
Yi Chuan ; 41(9): 801-815, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31549679

RESUMO

Development of the human brain is a strictly complex and precisely regulated process. Brain development includes the proliferation and differentiation of neural progenitor cells, migration and maturation of neurons, myelination of neuronal axons, synaptogenesis and organization of the neural circuits. Abnormalities of these developmental processes can lead to severe malformation and dysfunction of the brain, which may result in brain developmental diseases which have a high medical burden and have attracted global attention. Brain developmental diseases are typically divided into two categories according to abnormal brain morphology and dysfunction: malformation of cortical development (MCD) and neuropsychopathy. Microcephaly and autism spectrum disorder (ASD) are representative disorders of MCD and neuropsychopathy respectively. In this review, we summarize the progresses of these two typical and relevant brain developmental diseases including the mechanism and etiology of their development, gene expression, symptoms, and related to provide theoretical guidance for basic research and management and treatment.


Assuntos
Encéfalo/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/psicologia , Transtorno do Espectro Autista/fisiopatologia , Humanos , Microcefalia/fisiopatologia , Neurogênese , Neurônios
18.
Stem Cell Res ; 40: 101557, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31505389

RESUMO

An induced pluripotent stem cell (iPSC) line was generated from human urine-derived cells of a 4 year-old boy with autism spectrum disorder(ASD) and developmental delay (DD) carrying a 830 kb de novo deletion at chromosome 7q11.22 disrupting the first exon and promoter region of AUTS2. The iPSC retained the original deletion of AUTS2, and had a normal karyotype, express pluripotency markers and bear differentiation potential in vitro.


Assuntos
Transtorno do Espectro Autista/genética , Linhagem Celular/citologia , Cromossomos Humanos Par 7/genética , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento/genética , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Transcrição/genética , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Diferenciação Celular , Linhagem Celular/metabolismo , Pré-Escolar , Deleção Cromossômica , Proteínas do Citoesqueleto/metabolismo , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/fisiopatologia , Éxons , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Fatores de Transcrição/metabolismo
19.
Muscle Nerve ; 60(6): 732-738, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520483

RESUMO

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is caused by a CTG (cytosine-thymine-guanine) trinucleotide repeat expansion. Congenital DM (CDM) presents in the first month of life, whereas individuals with infantile and juvenile DM1 have later onset of symptoms. METHODS: We performed a retrospective chart review of patients with childhood-onset DM1 seen at one of three locations in Dallas, Texas between 1990 and 2018. Symptoms, disease course, cognitive features, and family history were reviewed. RESULTS: Seventy-four patients were included; CDM was diagnosed in 52 patients. There was maternal inheritance in 74% of patients. CTG repeat number ranged from 143 to 2300. Neuropsychiatric and cognitive deficits were common. Over half of the patients had GI disturbances, and orthopedic complications were common. DISCUSSION: Myotonic dystrophy type 1 in children requires a multidisciplinary approach to management. Presenting symptoms vary, and repeat expansion size does not necessarily directly relate to severity of symptoms. A consensus for outcome measures is required.


Assuntos
Distrofia Miotônica/fisiopatologia , Asma/etiologia , Asma/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Doença do Sistema de Condução Cardíaco/etiologia , Doença do Sistema de Condução Cardíaco/fisiopatologia , Criança , Pré-Escolar , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Constipação Intestinal/etiologia , Constipação Intestinal/fisiopatologia , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Refluxo Gastroesofágico/etiologia , Refluxo Gastroesofágico/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Herança Materna , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Transtornos do Humor/etiologia , Transtornos do Humor/fisiopatologia , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Miotonina Proteína Quinase/genética , Estudos Retrospectivos , Expansão das Repetições de Trinucleotídeos
20.
PLoS Med ; 16(9): e1002920, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31560687

RESUMO

BACKGROUND: Approximately 250 million (43%) children under the age of 5 years in low- and middle-income countries (LMICs) are failing to meet their developmental potential. Risk factors are recognised to contribute to this loss of human potential. Expanding understanding of the risks that lead to poor outcomes and which protective factors contribute to resilience in children may be critical to improving disparities. METHODS AND FINDINGS: The Drakenstein Child Health Study is a population-based birth cohort in the Western Cape, South Africa. Pregnant women were enrolled between 20 and 28 weeks' gestation from two community clinics from 2012 to 2015; sociodemographic and psychosocial data were collected antenatally. Mothers and children were followed through birth until 2 years of age. Developmental assessments were conducted by trained assessors blinded to background, using the Bayley-III Scales of Infant and Toddler Development (BSID-III), validated for use in South Africa, at 24 months of age. The study assessed all available children at 24 months; however, some children were not able to attend, because of loss to follow-up or unavailability of a caregiver or child at the correct age. Of 1,143 live births, 1,002 were in follow-up at 24 months, and a total of 734 children (73%) had developmental assessments, of which 354 (48.2%) were girls. This sample was characterised by low household employment (n = 183; 24.9%) and household income (n = 287; 39.1% earning 1 domain affected, and 75 (10.2%) had delay in all domains. Bivariate and multivariable analyses revealed several factors that were associated with developmental outcomes. These included protective factors (maternal education, higher birth weight, and socioeconomic status) and risk factors (maternal anaemia in pregnancy, depression or lifetime intimate partner violence, and maternal HIV infection). Boys consistently performed worse than girls (in cognition [ß = -0.74; 95% CI -1.46 to -0.03, p = 0.042], receptive language [ß = -1.10; 95% CI -1.70 to -0.49, p < 0.001], expressive language [ß = -1.65; 95% CI -2.46 to -0.84, p < 0.001], and fine motor [ß = -0.70; 95% CI -1.20 to -0.20, p = 0.006] scales). There was evidence that child sex interacted with risk and protective factors including birth weight, maternal anaemia in pregnancy, and socioeconomic factors. Important limitations of the study include attrition of sample from birth to assessment age and missing data in some exposure areas from those assessed. CONCLUSIONS: This study provides reliable developmental data from a sub-Saharan African setting in a well-characterised sample of mother-child dyads. Our findings highlight not only the important protective effects of maternal education, birth weight, and socioeconomic status for developmental outcomes but also sex differences in developmental outcomes and key risk and protective factors for each group.


Assuntos
Comportamento Infantil , Desenvolvimento Infantil , Deficiências do Desenvolvimento/epidemiologia , Determinantes Sociais da Saúde , Fatores Socioeconômicos , Fatores Etários , Peso ao Nascer , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/prevenção & controle , Deficiências do Desenvolvimento/psicologia , Escolaridade , Feminino , Humanos , Masculino , Saúde Materna , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores Sexuais , África do Sul/epidemiologia
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