Evaluation of genomic factors and early childhood stimulation on intelligence in children from a Brazilian birth cohort: The primary role of independent factors.

BACKGROUND: Childhood cognitive abilities are a predictor of health outcomes and adult income potential. Identifying factors associated with childhood intelligence and their interactions is essential in behavioral research. We assessed the impact of genetic variants and early child stimulation (ECS) on child intelligence and examined their possible interaction as potential modifiers of IQ in a population-based longitudinal study. METHODS: Participants of the 2004 Pelotas Birth Cohort study (N = 4231) underwent intelligent quotient (IQ) by WISC-III assessment at 6 years of age. At 24 and 48-months, mothers answered five ECS marker questions, whose sum was used to create a score. The polygenic score for intelligence (IQ-PGS) was constructed from the GWAS-weighted estimate of cognition. Association was assessed using multiple linear regression models adjusted for maternal, family, and child confounding variables. To explore the possible influence of skin color and ethnoracial classification, the regression models were stratified according to the skin color variable, as a sensitivity analysis. RESULTS: In the adjusted analysis, IQ-PGS (ß = 0.79, 95% confidence interval [95% CI] 0.26;1.31) as well as ECS (ß = 2.34; 95% CI: 1.76;2.92) were associated with IQ in this sample. The association between IQ-PGS and IQ was significant only in the white Brazilian group in the sensitivity analysis. However, there was no interaction between IQ-PGS and ECS on IQ (p(IQ-PGS x ECS) = 0.46). CONCLUSIONS: ECS did not modify the impact of genetic potential on intellectual development during childhood, suggesting that genetic factors and ECS exert independent effects on the IQ levels of children.

The contribution of whole-exome sequencing to intellectual disability diagnosis and knowledge of underlying molecular mechanisms: A systematic review and meta-analysis.

Whole-exome sequencing (WES) is useful for molecular diagnosis, family genetic counseling, and prognosis of intellectual disability (ID). However, ID molecular diagnosis ascertainment based on WES is highly dependent on de novo mutations (DNMs) and variants of uncertain significance (VUS). The quantification of DNM frequency in ID molecular diagnosis ascertainment and the biological mechanisms common to genes with VUS may provide objective information about WES use in ID diagnosis and etiology. We aimed to investigate and estimate the rate of ID molecular diagnostic assessment by WES, quantify the contribution of DNMs to this rate, and biologically and functionally characterize the genes whose mutations were identified through WES. A PubMed/Medline, Web of Science, Scopus, Science Direct, BIREME, and PsycINFO systematic review and meta-analysis was performed, including studies published between 2010 and 2022. Thirty-seven articles with data on ID molecular diagnostic yield using the WES approach were included in the review. WES testing accounted for an overall diagnostic rate of 42% (Confidence interval (CI): 35-50%), while the estimate restricted to DNMs was 11% (CI: 6-18%). Genetic information on mutations and genes was extracted and split into two groups: (1) genes whose mutation was used for positive molecular diagnosis, and (2) genes whose mutation led to uncertain molecular diagnosis. After functional enrichment analysis, in addition to their expected roles in neurodevelopment, genes from the first group were enriched in epigenetic regulatory mechanisms, immune system regulation, and circadian rhythm control. Genes from uncertain diagnosis cases were enriched in the renin angiotensin pathway. Taken together, our results support WES as an important approach to the molecular diagnosis of ID. The results also indicated relevant pathways that may underlie the pathogenesis of ID with the renin-angiotensin pathway being suggested to be a potential pathway underlying the pathogenesis of ID.

The D-score: a metric for interpreting the early development of infants and toddlers across global settings.

INTRODUCTION: Early childhood development can be described by an underlying latent construct. Global comparisons of children's development are hindered by the lack of a validated metric that is comparable across cultures and contexts, especially for children under age 3 years. We constructed and validated a new metric, the Developmental Score (D-score), using existing data from 16 longitudinal studies. METHODS: Studies had item-level developmental assessment data for children 0-48 months and longitudinal outcomes at ages >4-18 years, including measures of IQ and receptive vocabulary. Existing data from 11 low-income, middle-income and high-income countries were merged for >36 000 children. Item mapping produced 95 'equate groups' of same-skill items across 12 different assessment instruments. A statistical model was built using the Rasch model with item difficulties constrained to be equal in a subset of equate groups, linking instruments to a common scale, the D-score, a continuous metric with interval-scale properties. D-score-for-age z-scores (DAZ) were evaluated for discriminant, concurrent and predictive validity to outcomes in middle childhood to adolescence. RESULTS: Concurrent validity of DAZ with original instruments was strong (average r=0.71), with few exceptions. In approximately 70% of data rounds collected across studies, DAZ discriminated between children above/below cut-points for low birth weight (<2500 g) and stunting (-2 SD below median height-for-age). DAZ increased significantly with maternal education in 55% of data rounds. Predictive correlations of DAZ with outcomes obtained 2-16 years later were generally between 0.20 and 0.40. Correlations equalled or exceeded those obtained with original instruments despite using an average of 55% fewer items to estimate the D-score. CONCLUSION: The D-score metric enables quantitative comparisons of early childhood development across ages and sets the stage for creating simple, low-cost, global-use instruments to facilitate valid cross-national comparisons of early childhood development.

Intellectual Disability in a Birth Cohort: Prevalence, Etiology, and Determinants at the Age of 4 Years.

BACKGROUND: Intellectual disability (ID), characterized by impairments in intellectual function and adaptive behavior, affects 1-3% of the population. Many studies investigated its etiology, but few are cohort studies in middle-income countries. AIMS: To estimate prevalence, etiology, and factors related to ID among children prospectively followed since birth in a Southern Brazilian city (Pelotas). METHODS: In 2004, maternity hospitals were visited daily and births were identified. Live-born infants (n = 4,231) whose family lived in the urban area have been followed for several years. At the age of 2 and 4 years, performances in development and intelligence tests were evaluated using the Battelle Developmental Inventory and Wechsler Intelligence Scale, respectively. Children considered as having developmental delay were invited to attend a genetic evaluation. RESULTS: At 4 years of age, the prevalence of ID was 4.5%, and the etiology was classified into 5 groups: environmental (44.4%), genetic (20.5%), idiopathic (12.6%), neonatal sequelae (13.2%), other diseases (9.3%). Most children presented impairment in two or more areas of adaptive behavior. There was no difference in prenatal care attendance or maternal schooling among the groups. CONCLUSION: For about 40% of children, ID was attributed to nonbiological factors, suggesting that the rate may be reduced with appropriate interventions early in life.

Genetic causes of intellectual disability in a birth cohort: a population-based study.

Intellectual disability affects approximately 1-3% of the population and can be caused by genetic and environmental factors. Although many studies have investigated the etiology of intellectual disability in different populations, few studies have been performed in middle-income countries. The present study estimated the prevalence of genetic causes related to intellectual disability in a cohort of children from a city in south Brazil who were followed from birth. Children who showed poor performance in development and intelligence tests at the ages of 2 and 4 were included. Out of 4,231 liveborns enrolled in the cohort, 214 children fulfilled the inclusion criteria. A diagnosis was established in approximately 90% of the children evaluated. Genetic causes were determined in 31 of the children and 19 cases remained unexplained even after extensive investigation. The overall prevalence of intellectual disability in this cohort due to genetic causes was 0.82%. Because this study was nested in a cohort, there were a large number of variables related to early childhood and the likelihood of information bias was minimized by collecting information with a short recall time. This study was not influenced by selection bias, allowing identification of intellectual disability and estimation of the prevalence of genetic causes in this population, thereby increasing the possibility of providing appropriate management and/or genetic counseling.

Clinical and biochemical findings in 7 patients with X-linked adrenoleukodystrophy treated with Lorenzo's Oil

A adrenoleucodistrofia ligada ao X (X-ALD) é uma desordem hereditária do metabolismo peroxissomal, bioquimicamente caracterizada pelo acúmulo de ácidos graxos de cadeia muito longa ("very long chain fatty acids"- VLCFA) em diferentes tecidos e em fluidos biológicos, sendo os principais ácidos acumulados o hexacosanóico (C26:0) e o tetracosanóico (C24:0). O acúmulo destes ácidos graxos está associado com esmielinizaçäo cerebral e insuficiência adrenal. A incidência desta condiçäo é estimada em 1 para 25.000 em homens. Pelo menos seis fenótipos podem ser distinguidos, sendo a adrenoleucodistrofia (ALD) cerebral infantil e a adrenomieloneuropatia (AMN) os mais comuns. O tratamento preconizado consiste na utilização da mistura gliceroltrioleato/gliceroltrierucato (GTO/GTE), conhecida como Óleo de Lorenzo, combinada com dieta pobre em VLCFA. Existem ainda, terapias alternativas como transplante de medula óssea e imunossupressäo, além da utilizaçäo de lovastatina e fenilacetato de sódio. Neste trabalho fez-se uma avaliaçäo do tratamento com Óleo de Lorenzo associado à dieta restrita em VLCFA de 7 pacientes homens com X-ALD analisando a evoluçäo clínica e bioquímica. Os pacientes apresentaram uma reduçäo média de 50 por cento nos valores de C26:0 e de 42,8 por cento na razäo C26:0/C22:0 após o início do tratamento. A maioria dos pacientes permaneceu clinicamente bem e aproximadamente 30 por cento dos pacientes apresentaram uma progressäo rápida no curso clínico da doença. Parece näo haver uma clara correlaçäo bioquímico-clínica do tratamento. Os resultados nos mostram que novas terapias mais eficazes para X-ALD säo necessárias para que se possa obter um melhor prognóstico da doença com progressäo mais lenta dos sintomas apresentados ou mesmo reversäo dos sintomas já presentes nos pacientes.

Cockayne syndrome: report of a Brazilian family with confirmation of impaired RNA synthesis after UV-irradiation

A síndrome de Cockayne (CS) é uma desordem autossômica recessiva caracterizada por nanismo, déficit de crescimento, deterioraçäo neurológica, fotossensibilidade e uma progressiva aparência facial característica. Neste artigo relatamos a primeira família brasileira com CS, cujo diagnóstico foi confirmado pela demonstraçäo de uma síntese diminuída de RNA na cultura de fibroblastos expostos à radiaçäo ultravioleta. Apesar do curso progressivo da doença e da inexistência de um tratamento efetivo, o diagnóstico faz-se muito importante, pois a família pode se beneficiar do aconselhamento genético e/ou do diagnóstico pré-natal.

Desenvolvimento e Comportamento Infantil: Uma Visão dos Pediatras / Child development and behavior: a pediatric perception

Resumo: Foram entrevistados os pediatras que exerciam clínica na cidade de Pelotas, RS. Em 1994, o conhecimento sobre questões relativas ao desenvolvimento e comportamento infantil e promoção da saúde foi avaliado através de um questionário estruturado. Dos 102 pediatras contactados, 75 retornaram o questionário. Os pediatras concordam na sua maioria que depressão materna e dificuldade no relacionamento influencia o desenvolvimento infantil. Somente 53% concordam que o tabagismo materno é causa de desmame precoce; 71% referem os fatores perinatais como o principal causador de atrasos no desenvolvi menta da criança. Embora concordem (84%) que a triagem para atrasos no desenvolvimento deva ser incluída na rotina pediátrica, somente 59% fazem algum tipo de avaliação informal do desenvolvimento. Embora quase metade dos pediatras exerçam algum tipo de função docente, não houve diferença significativa entre os docentes e não-docentes em relação às respostas encontradas. A maioria dos pediatras (77%) referem que a escola médica não proporciona conhecimento suficiente sobre o assunto, e 50% deles têm a mesma opinião sobre a residência de pediatria. Os resultados mostraram que ainda existem controvérsias a respeito de algumas importantes questões relativas ao desenvolvimento infantil, e apontam para a importância ele serem feitas modificações no ensino de pediatria tanto nas escolas médicas como nos programas de residência.

Summary: In 1994 the pediatricians who practice in Pelotas, RS were interviewed. Questions concerning child development behavior and health promotion were assessed through a structured questionnaire. Of 102 pediatricians 75 answered the self-administered questionnaire. The results show that almost the totality of pediatricians agree that maternal depression and family dysfunction can cause developmental delays. Only 53% agree that maternal smoking cause early weaning. 71% refer perinatal factors as the main cause of developmental delays. 84% agree that developmental screening should be included in the routine pediatric practice, but only 59% perform an informal developmental evaluation in their practice. Almost half of the pediatricians have a teaching position, but there is no significant difference between this group and the one who don't have teaching obligations. They refers that medical school provide no enough knowledge about child development, and 50% have the same opinion about the pediatric residence. The survey show that there are important controversies about child development and behavior and modifications should be made in the pediatrics programs in the medical schools and residence programs.