Three generation families: Analysis of de novo variants in autism.

De novo variants (DNVs) analysis has proven to be a powerful approach to gene discovery in Autism Spectrum Disorder (ASD), which has not yet been shown in a Brazilian ASD cohort. The relevance of inherited rare variants has also been suggested, particularly in oligogenic models. We hypothesized that three-generation analyses of DNVs could provide new insights into the relevance of de novo and inherited variants across generations. To accomplish this goal, we performed whole-exome sequencing of 33 septet families composed of probands, parents, and grandparents (n = 231 individuals) and compared DNV rates (DNVr) between generations and those from two control cohorts. The DNVr in the probands (DNVr = 1.16) was marginally higher than in parents (DNVr = 0.60; p = 0.054), and in controls (DNVr = 0.68; p = 0.035, congenital heart disorder and DNVr = 0.70; p = 0.047, unaffected ASD siblings from Simons Simplex Collection). Moreover, most of the DNVs were found to have paternal origin in both generations (84.6%). Finally, we observed that 40% (6/15) of the DNVs in parents transmitted for probands are in ASD or ASD candidate genes, representing recently emerged risk variants to ASD in their families and suggest ZNF536, MSL2 and HDAC9 as ASD candidate genes. We did not observe an enrichment of risk variants nor sex bias of transmitted variants in the three generations, that can be due to sample size. These results further reinforce the relevance of de novo variants in ASD.

Copy number variations in a Brazilian cohort with autism spectrum disorders highlight the contribution of cell adhesion genes.

Prediction of pathogenicity of rare copy number variations (CNVs), a genomic alteration known to contribute to the etiology of autism spectrum disorder (ASD), represents a serious limitation to interpreting genetic tests, particularly for genetic counseling purposes. Chromosomal microarray analysis (CMA) was conducted in a unique collection of 144 Brazilian individuals with ASD of strong European and African ancestries. Rare CNVs were detected in 39 patients: 41 of unknown significance (VUS), four pathogenic and one likely pathogenic CNVs (clinical yield of 4.1%; 5/122). Based on gene content and recurrence in three large cohorts [a Brazilian neurodevelopmental disorder cohort, the autism MSSNG cohort, and the Canadian-based Centre for Applied Genomics microarray database], this work strengthened the pathogenicity of 14 genes (FAT1, CAMK4, BIRC6, DPP6, CSMD1, CTNNA3, CDH8/CDH11, CDH13, OR1C1, CNTN6, CNTNAP4, FGF2 and PTPRN2) within 14 CNVs. Notably, enrichment of cell adhesion proteins to ASD etiology was identified (p < 0.05), highlighting the importance of these gene families in the etiology of ASD.

Neuroprogenitor Cells From Patients With TBCK Encephalopathy Suggest Deregulation of Early Secretory Vesicle Transport.

Biallelic pathogenic variants in TBCK cause encephaloneuropathy, infantile hypotonia with psychomotor retardation, and characteristic facies 3 (IHPRF3). The molecular mechanisms underlying its neuronal phenotype are largely unexplored. In this study, we reported two sisters, who harbored biallelic variants in TBCK and met diagnostic criteria for IHPRF3. We provided evidence that TBCK may play an important role in the early secretory pathway in neuroprogenitor cells (iNPC) differentiated from induced pluripotent stem cells (iPSC). Lack of functional TBCK protein in iNPC is associated with impaired endoplasmic reticulum-to-Golgi vesicle transport and autophagosome biogenesis, as well as altered cell cycle progression and severe impairment in the capacity of migration. Alteration in these processes, which are crucial for neurogenesis, neuronal migration, and cytoarchitecture organization, may represent an important causative mechanism of both neurodevelopmental and neurodegenerative phenotypes observed in IHPRF3. Whether reduced mechanistic target of rapamycin (mTOR) signaling is secondary to impaired TBCK function over other secretory transport regulators still needs further investigation.

Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort.

Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta-analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta-analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss-of-function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non-previous ASD genes, we prioritized PRPF8 and RBM14. Meta-analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P-value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra-hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199-206. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8).

Actin cytoskeleton dynamics in stem cells from autistic individuals.

Several lines of indirect evidence, such as mutations or dysregulated expression of genes related to cytoskeleton, have suggested that cytoskeletal dynamics, a process essential for axons and dendrites development, is compromised in autism spectrum disorders (ASD). However, no study has yet examined whether cytoskeleton dynamics is functionally altered in cells from ASD patients. Here we investigated the regulation of actin cytoskeleton dynamics in stem cells from human exfoliated deciduous teeth (SHEDs) of 13 ASD patients and 8 control individuals by inducing actin filament depolymerization and then measuing their reconstruction upon activation of the RhoGTPases Rac, Cdc42 or RhoA. We observed that stem cells from seven ASD individuals (53%) presented altered dymanics of filament reconstruction, including a patient recently studied by our group whose iPSC-derived neuronal cells show shorten and less arborized neurites. We also report potentially pathogenic genetic variants that might be related to the alterations in actin repolymerization dynamics observed in some patient-derived cells. Our results suggest that, at least for a subgroup of ASD patients, the dynamics of actin polymerization is impaired, which might be ultimately leading to neuronal abnormalities.

Association between language development and auditory processing disorders.

INTRODUCTION: It is crucial to understand the complex processing of acoustic stimuli along the auditory pathway; comprehension of this complex processing can facilitate our understanding of the processes that underlie normal and altered human communication. AIM: To investigate the performance and lateralization effects on auditory processing assessment in children with specific language impairment (SLI), relating these findings to those obtained in children with auditory processing disorder (APD) and typical development (TD). MATERIAL AND METHODS: Prospective study. Seventy-five children, aged 6-12 years, were separated in three groups: 25 children with SLI, 25 children with APD, and 25 children with TD. All went through the following tests: speech-in-noise test, Dichotic Digit test and Pitch Pattern Sequencing test. RESULTS: The effects of lateralization were observed only in the SLI group, with the left ear presenting much lower scores than those presented to the right ear. The inter-group analysis has shown that in all tests children from APD and SLI groups had significantly poorer performance compared to TD group. Moreover, SLI group presented worse results than APD group. CONCLUSION: This study has shown, in children with SLI, an inefficient processing of essential sound components and an effect of lateralization. These findings may indicate that neural processes (required for auditory processing) are different between auditory processing and speech disorders.

Influence of memory, attention, IQ and age on auditory temporal processing tests: preliminary study.

PURPOSE: To investigate the existence of correlations between the performance of children in auditory temporal tests (Frequency Pattern and Gaps in Noise--GIN) and IQ, attention, memory and age measurements. METHOD: Fifteen typically developing individuals between the ages of 7 to 12 years and normal hearing participated in the study. Auditory temporal processing tests (GIN and Frequency Pattern), as well as a Memory test (Digit Span), Attention tests (auditory and visual modality) and intelligence tests (RAVEN test of Progressive Matrices) were applied. RESULTS: Significant and positive correlation between the Frequency Pattern test and age variable were found, which was considered good (p<0.01, 75.6%). There were no significant correlations between the GIN test and the variables tested. CONCLUSIONS: Auditory temporal skills seem to be influenced by different factors: while the performance in temporal ordering skill seems to be influenced by maturational processes, the performance in temporal resolution was not influenced by any of the aspects investigated.

Association between language development and auditory processing disorders / Associação entre transtornos no desenvolvimento de linguagem e processamento auditivo

INTRODUCTION: It is crucial to understand the complex processing of acoustic stimuli along the auditory pathway ;comprehension of this complex processing can facilitate our understanding of the processes that underlie normal and altered human communication. AIM: To investigate the performance and lateralization effects on auditory processing assessment in children with specific language impairment (SLI), relating these findings to those obtained in children with auditory processing disorder (APD) and typical development (TD). MATERIAL AND METHODS: Prospective study. Seventy-five children, aged 6-12 years, were separated in three groups: 25 children with SLI, 25 children with APD, and 25 children with TD. All went through the following tests: speech-in-noise test, Dichotic Digit test and Pitch Pattern Sequencing test. RESULTS: The effects of lateralization were observed only in the SLI group, with the left ear presenting much lower scores than those presented to the right ear. The inter-group analysis has shown that in all tests children from APD and SLI groups had significantly poorer performance compared to TD group. Moreover, SLI group presented worse results than APD group. CONCLUSION: This study has shown, in children with SLI, an inefficient processing of essential sound components and an effect of lateralization. These findings may indicate that neural processes (required for auditory processing) are different between auditory processing and speech disorders. .

INTRODUÇÃO: Entender como os estímulos acústicos são processados ao longo da via auditiva é fundamental para compreender os processos que subjazem à comunicação humana normal e alterada. OBJETIVO: Investigar o desempenho e efeitos de lateralidade na avaliação do processamento auditivo em crianças com distúrbio específico de linguagem (DEL), comparando os resultados obtidos aos encontrados em crianças com transtorno de processamento auditivo (TPA) e desenvolvimento típico (DT). MATERIAL E MÉTODO: Estudo Prospectivo. 75 crianças (6-12 anos), divididas em três grupos (25 crianças com DEL, 25 crianças com TPA e 25 crianças em DT), foram submetidas aos seguintes testes: Teste de Figura com Ruído, Teste Dicótico de Dígitos e Teste de Padrão de Frequência. RESULTADO: Os efeitos de lateralidade foram observados apenas no grupo DEL, sendo o desempenho na orelha esquerda inferior ao apresentado na orelha direita. Na comparação intergrupos, o desempenho dos grupos TPA e DEL foi significativamente inferior ao observado no grupo DT para todos os testes. Além disso, observamos nas crianças do grupo DEL um desempenho inferior às do grupo TPA. CONCLUSÃO: Este estudo constatou o processamento ineficiente de componentes cruciais de sons e o efeito de lateralidade em crianças com DEL. Esses achados evidenciam que os processos neurais que subjazem ao processamento auditivo são diferentes entre alterações de processamento auditivo e alterações de fala. .

Influence of memory, attention, IQ and age on auditory temporal processing tests: preliminary study / Influência da memória, atenção, QI e idade em testes de processamento auditivo temporal: estudo preliminar

PURPOSE: To investigate the existence of correlations between the performance of children in auditory temporal tests (Frequency Pattern and Gaps in Noise - GIN) and IQ, attention, memory and age measurements. METHOD: Fifteen typically developing individuals between the ages of 7 to 12 years and normal hearing participated in the study. Auditory temporal processing tests (GIN and Frequency Pattern), as well as a Memory test (Digit Span), Attention tests (auditory and visual modality) and intelligence tests (RAVEN test of Progressive Matrices) were applied. RESULTS: Significant and positive correlation between the Frequency Pattern test and age variable were found, which was considered good (p<0.01, 75.6%). There were no significant correlations between the GIN test and the variables tested. CONCLUSIONS: Auditory temporal skills seem to be influenced by different factors: while the performance in temporal ordering skill seems to be influenced by maturational processes, the performance in temporal resolution was not influenced by any of the aspects investigated. .

OBJETIVO: Investigar a existência de correlações entre o desempenho de crianças com desenvolvimento típico em testes temporais auditivos (Padrão de Frequência e Gaps in Noise - GIN) e medidas de memória, atenção, quociente intelectual e a idade. MÉTODO: Quinze participantes, com idades entre 7 e 12 anos, sem queixas envolvendo audição e desenvolvimento cognitivo, foram submetidos aos testes de processamento temporal auditivo (GIN e Padrão de Frequência), teste de Memória (Span de Dígitos), Atenção (auditiva e visual) e testes de inteligência (Matrizes Progressivas de Raven). RESULTADOS: Foram encontradas correlações significantes e positivas entre o teste Padrão de Frequência e a variável idade, sendo essa considerada boa (p<0,01, 75,6%). Não foram verificadas correlações significantes entre o teste GIN e as variáveis testadas. CONCLUSÃO: As habilidades temporais consideradas parecem ser influenciadas por diferentes fatores: enquanto a habilidade de ordenação temporal parece ser influenciada por processos maturacionais, o desempenho para a habilidade de resolução temporal não foi influenciado por nenhum dos aspectos investigados. .

Perfil comportamental e competência social de crianças e adolescentes com distrofia muscular de Duchenne / Behavior profile and social competence in children and adolescents with Duchenne muscular dystrophy

A distrofia muscular de Duchenne é uma doença genética caracterizada por enfraquecimento muscular progressivo e degeneração irreversível, acompanhados por danos sensoriais e neuropsicológicos. Os objetivos do estudo consistiram em avaliar o perfil comportamental de crianças/adolescentes com DMD e a influência do prejuízo motor, da idade no início do uso de cadeira de rodas e da idade no diagnóstico. Participaram 34 pacientes e 20 controles. Os pacientes formaram dois grupos conforme o quociente de inteligência (QI). Os pais responderam ao Inventário de Comportamentos da Infância e da Adolescência. Pacientes com DMD obtiveram escores mais baixos em Atividades e Sociabilidade (p < 0,01; ANCOVA). Os pacientes com QI < 80 apresentaram menores índices de Escolaridade. O prejuízo motor e as idades referentes à cadeira e ao diagnóstico correlacionaram-se com sintomas psiquiátricos/somáticos e problemas escolares. Os achados enfatizam a necessidade de programas educacionais acerca da doença como base para o desenvolvimento de estratégias de inclusão social.

Duchenne Muscular Dystrophy is a genetic disease characterized by progressive muscle weakness and degeneration, which are accompanied by sensory and neuropsychological losses. The aims of this study were to evaluate the behavior profile of DMD children and adolescents and examine the influence of motor impairment, age at start using a wheelchair, and age at diagnosis on behavioral characteristics. Thirty-five patients and 20 controls participated. DMD patients formed two different groups according to the intelligence quotient (IQ). Participants' parents completed the Child Behavior Checklist. DMD groups scored lower on the Activities and the Social scales. Patients with QI < 80 presented lower indices in the School scale (p < 0.01, ANCOVA). Motor impairment and age at start using a wheelchair and at diagnosis correlated with psychiatric/somatic symptoms and school problems. The findings highlight the need of educational programs concerning the disease as a basis for the development of social inclusion strategies.

Perfil comportamental e competência social de crianças e adolescentes com distrofia muscular de Duchenne / Behavior profile and social competence in children and adolescents with Duchenne muscular dystrophy

A distrofia muscular de Duchenne é uma doença genética caracterizada por enfraquecimento muscular progressivo e degeneração irreversível, acompanhados por danos sensoriais e neuropsicológicos. Os objetivos do estudo consistiram em avaliar o perfil comportamental de crianças/adolescentes com DMD e a influência do prejuízo motor, da idade no início do uso de cadeira de rodas e da idade no diagnóstico. Participaram 34 pacientes e 20 controles. Os pacientes formaram dois grupos conforme o quociente de inteligência (QI). Os pais responderam ao Inventário de Comportamentos da Infância e da Adolescência. Pacientes com DMD obtiveram escores mais baixos em Atividades e Sociabilidade (p < 0,01; ANCOVA). Os pacientes com QI < 80 apresentaram menores índices de Escolaridade. O prejuízo motor e as idades referentes à cadeira e ao diagnóstico correlacionaram-se com sintomas psiquiátricos/somáticos e problemas escolares. Os achados enfatizam a necessidade de programas educacionais acerca da doença como base para o desenvolvimento de estratégias de inclusão social.(AU)

Duchenne Muscular Dystrophy is a genetic disease characterized by progressive muscle weakness and degeneration, which are accompanied by sensory and neuropsychological losses. The aims of this study were to evaluate the behavior profile of DMD children and adolescents and examine the influence of motor impairment, age at start using a wheelchair, and age at diagnosis on behavioral characteristics. Thirty-five patients and 20 controls participated. DMD patients formed two different groups according to the intelligence quotient (IQ). Participants' parents completed the Child Behavior Checklist. DMD groups scored lower on the Activities and the Social scales. Patients with QI < 80 presented lower indices in the School scale (p < 0.01, ANCOVA). Motor impairment and age at start using a wheelchair and at diagnosis correlated with psychiatric/somatic symptoms and school problems. The findings highlight the need of educational programs concerning the disease as a basis for the development of social inclusion strategies.(AU)

Memory span measured by the spatial span tests of the Cambridge neuropsychological test automated battery in a group of Brazilian children and adolescents / Capacidade de memória medida por testes de retenção espacial da bateria neuropspicologica computadorizada de Cambridge em um grupo de crianças e adolescentes brasileiros

The neuropsychological tests of spatial span are designed to measure attention and working memory. The version of the spatial span test in the Cambridge Neuropsychological Test Automated Battery (CANTAB) evaluates these functions through the recall of sequences of spatial locations presented to the subject. Objective: The present study investigated how age, gender and educational level might affect the performance of the non-verbal system. Methods: A total of 60 children and adolescents aged 6 to 18 years were assessed (25 males and 35 females). Results: The results showed no gender differences in test performance. Children with six or more years of education showed better performance than children with less than three years of education. Older children had more schooling and thus were able to recall a greater number of items. Span length values proved similar to a previous large normative study which also employed the CANTAB Spatial Span (De Luca et al., 2003). Conclusion: The similarity in performance of the Brazilian children and adolescents studied and the group of Australian participants examined by the cited authors, despite the socio-cultural and economical differences, points to the suitability of the task for the assessment of attention and working memory in Brazilian children.

Testes neuropsicológicos de span visuoespacial são construídos para avaliar amplitude atencional e memória de trabalho. Na versão do teste de span visuoespacial da Cambridge Neuropsychological Test Automated Battery (CANTAB) essa avaliação é feita através de sequências de localização espacial. Objetivo: O presente estudo investiga como a idade, o sexo e a escolaridade podem afetar o desempenho nesse sistema não-verbal. Métodos: Foram avaliadas 60 crianças e adolescentes com idades entre 6 e 18 anos (25 meninos; 35 meninas). Resultados: Os resultados não mostraram diferenças no desempenho do teste entre os sexos. O grupo de crianças com seis ou mais anos de escolaridade foi melhor do que a de crianças menores de três anos de estudo. Nossos resultados sugerem que as crianças mais velhas e, portanto, com maior tempo de escolaridade conseguem se lembrar de um número maior de itens. Os valores de amplitude foram similares aos obtidos em um experimento normativo prévio amplo no qual foi utilizado o teste Spatial Span do CANTAB (De Luca et al., 2003). Conclusão: Estas concordâncias de desempenhos entre crianças e adolescentes brasileiros e o grupo de participantes australianos examinados pelos autores citados nos mostram que apesar das diferenças sócio-culturais e econômicas existentes, a tarefa é adequada para avaliação de atenção e memória de trabalho em crianças brasileiras.

Memory span measured by the spatial span tests of the Cambridge Neuropsychological Test Automated Battery in a group of Brazilian children and adolescents.

The neuropsychological tests of spatial span are designed to measure attention and working memory. The version of the spatial span test in the Cambridge Neuropsychological Test Automated Battery (CANTAB) evaluates these functions through the recall of sequences of spatial locations presented to the subject. OBJECTIVE: The present study investigated how age, gender and educational level might affect the performance of the non-verbal system. METHODS: A total of 60 children and adolescents aged 6 to 18 years were assessed (25 males and 35 females). RESULTS: The results showed no gender differences in test performance. Children with six or more years of education showed better performance than children with less than three years of education. Older children had more schooling and thus were able to recall a greater number of items. Span length values proved similar to a previous large normative study which also employed the CANTAB Spatial Span (De Luca et al., 2003). CONCLUSION: The similarity in performance of the Brazilian children and adolescents studied and the group of Australian participants examined by the cited authors, despite the socio-cultural and economical differences, points to the suitability of the task for the assessment of attention and working memory in Brazilian children.

Testes neuropsicológicos de span visuoespacial são construídos para avaliar amplitude atencional e memória de trabalho. Na versão do teste de span visuoespacial da Cambridge Neuropsychological Test Automated Battery (CANTAB) essa avaliação é feita através de sequências de localização espacial. OBJETIVO: O presente estudo investiga como a idade, o sexo e a escolaridade podem afetar o desempenho nesse sistema não-verbal. MÉTODOS: Foram avaliadas 60 crianças e adolescentes com idades entre 6 e 18 anos (25 meninos; 35 meninas). RESULTADOS: Os resultados não mostraram diferenças no desempenho do teste entre os sexos. O grupo de crianças com seis ou mais anos de escolaridade foi melhor do que a de crianças menores de três anos de estudo. Nossos resultados sugerem que as crianças mais velhas e, portanto, com maior tempo de escolaridade conseguem se lembrar de um número maior de itens. Os valores de amplitude foram similares aos obtidos em um experimento normativo prévio amplo no qual foi utilizado o teste Spatial Span do CANTAB (De Luca et al., 2003). CONCLUSÃO: Estas concordâncias de desempenhos entre crianças e adolescentes brasileiros e o grupo de participantes australianos examinados pelos autores citados nos mostram que apesar das diferenças sócio-culturais e econômicas existentes, a tarefa é adequada para avaliação de atenção e memória de trabalho em crianças brasileiras.

Preliminary findings on the effects of occupational exposure to mercury vapor below safety levels on visual and neuropsychological functions.

OBJECTIVE: To evaluate whether there are visual and neuropsychological decrements in workers with low exposure to Hg vapor. METHODS: Visual fields, contrast sensitivity, color vision, and neuropsychological functions were measured in 10 workers (32.5 +/- 8.5 years) chronically exposed to Hg vapor (4.3 +/- 2.8 years; urinary Hg concentration 22.3 +/- 9.3 microg/g creatinine). RESULTS: For the worst eyes, we found altered visual field thresholds, lower contrast sensitivity, and color discrimination compared with controls (P <0.05). There were no significant differences between Hg-exposed subjects and controls on neuropsychological tests. Nevertheless, duration of exposure was statistically correlated to verbal memory and depression scores. CONCLUSIONS: Chronic exposure to Hg vapor at currently accepted safety levels was found to be associated with visual losses but not with neuropsychological dysfunctions in the sample of workers studied.

Avaliação neuropsicológica de pacientes com distrofia muscular de Duchenne / Neuropsychological assessment of patients with Duchenne Muscular Dystrophy

A Distrofia Muscular de Duchenne (DMD) é provocada por mutações no gene distrofina. Este gene codifica a proteína distrofina, que exerce papel importante na manutenção da estabilidade da membrana da fibra muscular. Os objetivos do estudo consistiram em examinar o desempenho neuropsicológico de pacientes com DMD e verificar a influência de deleções downstream ao exon 45 sobre o mesmo. Foram avaliados os perfis de inteligência de 63 pacientes com DMD por meio das Escalas Wechsler de Inteligência ou o Teste de Raven. A faixa etária do grupo variou de 6 a 26 anos de idade e a escolaridade, 1 a 16 anos de estudo formal. Os pacientes com escores de inteligência normais (n=34) foram comparados com controles quanto às funções neuropsicológicas. O grupo controle foi composto por 34 jovens do sexo masculino pareados por idade. Os testes incluíram medidas de memória verbal (Teste de Aprendizado Verbal de Rey), habilidade viso-espacial (Teste de Organização Visual de Hooer), funções executivas (fluência verbal e Teste de Wisconsin de Classificação de Cartas). A avaliação também incluiu testes da bateria Cambridge Neuropsychological Test Automated Battery (CANTAB) para o exame de: tempo de reação simples (Simple Reaction Time); tempo de reação com dupla escolha (Choice Reaction Time), atenção visual sustentada (Rapid Visual Processing), amplitude atencional/memória operacional (Spatial Span, ordem direta e inversa), memória visual de curto e longo prazo (Pattern Recognition Memory), reconhecimento de estímulos complexos apresentados simultaneamente ou após intervalo (Delayed Matching to Sample), memória espacial (Spatial Recognition Memory) e tomada de decisão (Information Sampling Task). (...)

... O Inventário de Depressão de Beck (BDI) foi administrado para exame de sintomas de depressão e o Inventário de Comportamentos da Infância e Adolescência (CBCL) foi utilizado como medida de alterações de comportamento. Utilizou-se a análise de variância (one-way ANOVA) na comparação entre grupos. As covariáveis foram controladas por meios estatísticos. Os pacientes com DMD obtiveram medias de QIs com 1 desvio padrão abaixo da media da população. Após controle para covariáveis, os pacientes com DMD mostraram desempenhos significantemente inferiores nos testes de Aritmética, Vocabulário, Compreensão, Dígitos e no Teste de Wisconsin (número de erros totais, erros perseverativos, respostas de nível conceitual e categorias completas). Também mostraram tempos de reação mais longos (Simple Reaction Time), menor amplitude atencional tanto na ordem direta, quanto inversa (Spatial Span) e menor número de acertos no teste de tomada de decisão (Information Sampling Task) (p<0,05). A proporção de pacientes com deleções no gene distrofina foi de 54% (34/63). Não foi encontrada associação entre os resultados de inteligência e dados genéticos. Comparados com controles, os 14 pacientes com deleção downstream ao exon 45 e QI≥80 mostraram dificuldades mais específicas. O tempo de reação foi discutido conforme a complexidade da tarefa. Os participantes do grupo controle apresentaram escores mais altos no BDI e CBCL, indicando maior ocorrência de sintomas. Possíveis fatores relacionados foram discutidos. Há evidências de que as deleções downstream ao exon 45 (relacionadas à isoforma cerebral da distrofina Dp140) estão envolvidas com a menor eficiência de tomada de decisão dentre os pacientes com DMD. Os achados também sugerem a associação entre a DMD e disfunções frontais

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene. This gene codes for dystrophin, a protein important for maintaining the stability of muscle-fiber membranes. The objectives of the study were to examine neuropsychological performance in patients with DMD and the influence of deletions in the dystrophin gene (the Dp140 regulatory region) on neuropsychological function. General intelligence was investigated in 63 DMD patients using the Wechsler Intelligence Scale or the Raven's Matrices Test. The age range for DMD participants was from 6 to 26 years, with a range of 1 to 16 years of formal education. The participants who had intellectual scores in the normal range (n=34) were compared to controls in terms of neuropsychological function. The control group was composed of 34 male age-matched subjects. Patients were divided into groups according to the region of mutation in the dystrophin gene and those with delection downstream of exon 45 were also compared to controls. The battery included the Wechsler scale subtests and measures of verbal memory (Rey Auditory Verbal Learning Test), viso-perceptual skills (Hooper Visual Organization Test), executive function (FAS, animals and Wisconsin Card Sorting Test). The assessment also included tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) to examine reaction time (Simple Reaction Time and Choice Reaction Time), sustained attention (Rapid Visual Processing), working memory (Spatial Span, forward and reverse), short and long term visual memory (Pattern Recognition Memory), recognition memory for complex stimuli presented (...)

... simultaneously or after short interval (Delayed Matching to Sample), spatial memory (Spatial Recognition Memory), and decision making (Information Sampling Task). The Beck Depression Inventory (BDI) was administered for depression symptoms assessment and the Child Behavior Checklist (CBCL) was used as a measure of disruptive behavior. Analysis of variance (one-way ANOVA) was used. Covariates were controlled statistically. The DMD patients had mean IQs about one standard deviation lower than population means. Verbal IQ was significantly lower than Performance IQ. After controlling for covariates, significant difference (p<0.05) appeared between DMD patients and controls and DMD was associated to lower IQs (Full Scale, Verbal, and Performance) and worse performances on Arithmetic, Vocabulary, Comprehension, Digit Span, Wisconsin Test (total errors, perseverative errors, conceptual level responses, and categories completed), Spatial Span (forward and reverse recall), and on the number of correct trials on Information Sampling Task. They also showed slower simple reaction times (Simple Reaction Time). The proportion of patients with dystrophin gene deletions was 54% (34/63). No relationship was established between intelligence results and genetic data. Compared to controls, 14 patients with delection downstream of exon 45 and normal IQs showed more specific deficits. Reaction time was discussed in terms of complexity of the task. Controls showed significant higher BDI and CBCL scores than DMD patients. Possible related factors were discussed. There is evidence to indicate that delections downstream of exon 45 (related to cerebral dystrophin isoform Dp140) are involved in decision making impairment in patients with DMD. The findings suggest that DMD may be related to frontal dysfunction

Neuropsychological alterations in mercury intoxication persist several years after exposure.

Elemental mercury is a liquid toxic metal widely used in industry. Occupational exposure occurs mainly via inhalation. Previously, neuropsychological assessment detected deficits in former workers of a fluorescent lamp plant who had been exposed to elemental mercury vapor and were away from exposure for several years at the time of examination. OBJECTIVES: The purpose of this work was to reexamine these functions after 18 months in order to evaluate their progression. METHODS: Thirteen participants completed tests of attention, inhibitory control, verbal/visual memory, psychomotor speed, verbal fluency, visuomotor ability, executive function, semantic knowledge, and depression and anxiety inventories on 2 separate occasions. RESULTS: At baseline, the former workers indicated slower psychomotor and information processing speed, verbal spontaneous recall memory impairment, and increased depression and anxiety symptoms compared to controls (P<0.05). Paired comparisons of neuropsychological functioning within the exposed group at baseline and 1.5 years later showed poorer immediate memory performance (P<0.05). There were no differences on other measures. CONCLUSIONS: Although the literature show signs of recovery of functions, the neuropsychological effects related to mercury exposure are found to persist for many years.

Mercúrio metálico é um metal líquido e tóxico com ampla aplicação industrial. A exposição ocupacional ao metal ocorre principalmente por inalação. Previamente, comprometimento em várias funções neuropsicológicas foi constatado em ex-trabalhadores de fábrica de lâmpadas fluorescentes que haviam sido expostos ao vapor de mercúrio e estavam afastados da fonte de exposição por vários anos no momento do exame. OBJETIVOS: Reexaminar estas funções após 18 meses, com a finalidade de verificar a possível progressão do comprometimento. MÉTODOS: Treze participantes foram submetidos a testes de atenção, controle inibitório, memória verbal e visual, funções executivas, conhecimento semântico e inventários de depressão e ansiedade. RESULTADOS: Na linha de base, os ex-trabalhadores mostraram lentificação psicomotora e no processamento de informações, déficit de memória verbal espontânea, além de maiores sintomas de depressão e ansiedade comparados com controles (P<0,05). Comparações pareadas do grupo exposto na linha de base e 18 meses após indicaram pior desempenho em memória imediata (P<0,05). Não houve diferença nas demais medidas. CONCLUSÕES: Embora a literatura mostre indícios de recuperação das funções, os efeitos neuropsicológicos relacionados ao mercúrio podem persistir por muitos anos.

A aplicação da neuropsicologia na pesquisa experimental: o exemplo da intoxicação por vapor de mercúrio / Neuropsychology in experimental research: mercury intoxication as an example of application

O desenvolvimento da neuropsicologia acompanhou a evolução do estudo do cérebro desde os registros mais antigos. A ciência neuropsicológica faz uso de medidas quantitativas de desempenho e tecnologias para produção de neuroimagem que, em conjunto, permitem a observação das relações cérebro-comportamento. No âmbito experimental, a neuropsicologia tem revelado novos conhecimentos na investigação de alterações cognitivas, psicomotoras ou comportamentais associadas a patologias congênitas ou adquiridas. No presente artigo são abordados aspectos históricos da neuropsicologia experimental e apresentados os principais resultados de um estudo referente às alterações neuropsicológicas de pacientes com histórico de intoxicação por vapor de mercúrio, presentes anos após o período de exposição ao metal

A aplicação da neuropsicologia na pesquisa experimental: o exemplo da intoxicação por vapor de mercúrio / Neuropsychology in experimental research: mercury intoxication as an example of application

O desenvolvimento da neuropsicologia acompanhou a evolução do estudo do cérebro desde os registros mais antigos. A ciência neuropsicológica faz uso de medidas quantitativas de desempenho e tecnologias para produção de neuroimagem que, em conjunto, permitem a observação das relações cérebro-comportamento. No âmbito experimental, a neuropsicologia tem revelado novos conhecimentos na investigação de alterações cognitivas, psicomotoras ou comportamentais associadas a patologias congênitas ou adquiridas. No presente artigo são abordados aspectos históricos da neuropsicologia experimental e apresentados os principais resultados de um estudo referente às alterações neuropsicológicas de pacientes com histórico de intoxicação por vapor de mercúrio, presentes anos após o período de exposição ao metal (AU)

Avaliação neuropsicológica de pacientes expostos ao vapor de mercúrio e de pacientes diabéticos do tipo 2 / Neuropsychological assessments of patients exposed to mercury vapor and of type 2 diabetic patients

Exposição a substâncias tóxicas e distúrbios metabólicos são fatores que afetam as funções neuropsicológicas. Foram realizados 2 estudos descritivos com os objetivos de verificar a possibilidade de disfunções neuropsicológicas em indivíduos com histórico de exposição ocupacional ao vapor de mercúrio e em pacientes diabéticos do tipo 2 sem diagnóstico de retinopatia, em ambos os casos, comparados com controles. A bateria neuropsicológica incluiu testes de atenção (Dígitos), controle inibitório (teste de stroop), memória verbal (teste de Buschke) e visual (Reprodução Visual), destreza manual (Grooved Pegboard), fluência verbal (FAS), habilidade viso-motora (Cubos), funções executivas (teste de Wisconsin), conhecimento semântico (Vocabulário) e sintomas de depressão (Inventário Beck de Depressão) e ansiedade (Inventário de Ansiedade Traço-Estado). Adotou-se p < 0,05 como nível de significância. As avaliações neuropsicológicas de 26 ex-trabalhadores de fábricas de lâmpadas de mercúrio foram comparadas com 20 controles. Os ex-trabalhadores têm diagnóstico de mercurialismo crônico ocupacional, foram expostos ao vapor de mercúrio no trabalho durante 10,2 ± 3,8 anos e estão afastados da função há 6 ± 4,7 anos. A concentração de mercúrio urinário medida um ano após o afastamento da exposição teve média de 1,8 ± 0,9 µg/gCr. Comparados com os controles, os ex-trabalhadores demonstraram pior desempenho no teste de Stroop partes 1 (p=0,004) e 2 (0,010), no teste de Buschke para recuperação de longo prazo (p=0,028), armazenamento de longo prazo (p=0,045), recuperação consistente longo prazo (p=0,006), e recuperação tadia (p=0,008), fluência verbal (p=0,010) e no Grooved Pegboard tanto para a mão dominante (p=0,019) quanto a não dominante (p=0,008). Os escores de depressão, de estado e traço de ansiedade foram significantemente superiores aos do grupo controle (p < 0,001)...(AU)