Neuroimaging effects of prenatal alcohol exposure on the developing human brain: a magnetic resonance imaging review.

OBJECTIVE: This paper reviews the magnetic resonance imaging (MRI) literature on the effects of prenatal alcohol exposure on the developing human brain. METHOD: A literature search was conducted through the following databases: PubMed, PsycINFO and Google Scholar. Combinations of the following search terms and keywords were used to identify relevant studies: 'alcohol', 'fetal alcohol spectrum disorders', 'fetal alcohol syndrome', 'FAS', 'FASD', 'MRI', 'DTI', 'MRS', 'neuroimaging', 'children' and 'infants'. RESULTS: A total of 64 relevant articles were identified across all modalities. Overall, studies reported smaller total brain volume as well as smaller volume of both the white and grey matter in specific cortical regions. The most consistently reported structural MRI findings were alterations in the shape and volume of the corpus callosum, as well as smaller volume in the basal ganglia and hippocampi. The most consistent finding from diffusion tensor imaging studies was lower fractional anisotropy in the corpus callosum. Proton magnetic resonance spectroscopy studies are few to date, but showed altered neurometabolic profiles in the frontal and parietal cortex, thalamus and dentate nuclei. Resting-state functional MRI studies reported reduced functional connectivity between cortical and deep grey matter structures. Discussion There is a critical gap in the literature of MRI studies in alcohol-exposed children under 5 years of age across all MRI modalities. The dynamic nature of brain maturation and appreciation of the effects of alcohol exposure on the developing trajectory of the structural and functional network argue for the prioritisation of studies that include a longitudinal approach to understanding this spectrum of effects and potential therapeutic time points.

Parental Perspectives Regarding the Return of Genomic Research Results in Neurodevelopmental Disorders in South Africa: Anticipated Impact and Preferences.

Few policies and little research exist regarding the disclosure of genomic results to research participants in Africa. As understanding participant preferences would be pivotal to the success of the feedback process, this study set out to address this issue by engaging with enrolled participants from an ongoing genomics research project on neurodevelopmental disorders with the aim to assess the anticipated impact of receiving pertinent results and explore the preferences for feedback in a South-African context. Twelve semi-structured interviews were conducted with 17 parents of children participating in the research study. Transcribed interview data and observational notes were analysed using thematic analysis and framework matrices. Participants linked their own meaning to the impact of receiving a pertinent result and perceived the information as useful for reasons other than only clinical utility. These included closure, improved management of their child's condition and information regarding recurrence risks. In terms of preferences for feedback, an in-person result delivery session, conducted by a member of the study team or medical professional familiar with their child was preferred. In addition, participants felt a sense of ownership over their blood or their contribution to the research study, finding meaning even in non-pertinent (secondary findings) or negative results. These findings provide insight into the type of discussions that may be valuable in enabling the development of best practices and guidelines for the return of individual genetic research results, in a culturally appropriate manner, within South-African communities.

Validity of the SNAP-IV For ADHD Assessment in South African Children With Neurodevelopmental Disorders.

This study investigated the psychometric properties of the Swanson, Nolan, and Pelham ADHD Rating Scale (SNAP-IV) in a sample of South African children with neurodevelopmental disorders (n = 201), primarily Autism Spectrum Disorder and Intellectual Disability. We conducted a confirmatory factor analysis to inspect the two-factor structure of the SNAP-IV. We also calculated ordinal coefficient alpha to estimate internal consistency. Fit statistics for the two-factor model approached acceptable levels. The model fit improved slightly after removing an item related to spoken language. The subscales had acceptable internal consistencies. Findings partially support the use of the SNAP-IV in this group of children. However, there are limitations to its performance in this population likely related to the presence of neurodevelopmental disorders.

Phenotype and genetic analysis of data collected within the first year of NeuroDev.

Genetic association studies have made significant contributions to our understanding of the etiology of neurodevelopmental disorders (NDDs). However, these studies rarely focused on the African continent. The NeuroDev Project aims to address this diversity gap through detailed phenotypic and genetic characterization of children with NDDs from Kenya and South Africa. We present results from NeuroDev's first year of data collection, including phenotype data from 206 cases and clinical genetic analyses of 99 parent-child trios. Most cases met criteria for global developmental delay/intellectual disability (GDD/ID, 80.3%). Approximately half of the children with GDD/ID also met criteria for autism. Analysis of exome-sequencing data identified a pathogenic or likely pathogenic variant in 13 (17%) of the 75 cases from South Africa and 9 (38%) of the 24 cases from Kenya. Data from the trio pilot are publicly available, and the NeuroDev Project will continue to develop resources for the global genetics community.

De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.

BACKGROUND: De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. METHODS: Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. RESULTS: We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. LIMITATIONS: The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. CONCLUSIONS: Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

The NeuroDev Study: Phenotypic and Genetic Characterization of Neurodevelopmental Disorders in Kenya and South Africa.

The NeuroDev study will deeply phenotype cognition, behavior, dysmorphias, and neuromedical traits on an expected cohort of 5,600 Africans (1,800 child cases, 1,800 child controls, and 1,900 parents) and will collect whole blood for exome sequencing and biobanking.

The Early Developmental Outcomes of Prenatal Alcohol Exposure: A Review.

Aim: This paper systematically reviews the literature on the effects of prenatal alcohol exposure on early child development from birth to 5 years with the aim to synthesize the developmental outcomes associated with prenatal alcohol exposure, and inform further research to improve our knowledge of the manifestations of prenatal alcohol exposure. Methods: Electronic databases (MEDLINE, Psych INFO, and Psych ARTICLES) were searched to find papers on the developmental outcomes of prenatal alcohol exposure in neonates, infants and toddlers and pre-school aged children. Studies were selected based on participants self-reporting alcohol consumption during pregnancy (either prospectively or retrospectively) and/or children being diagnosed with FASD based on a standardized assessment that includes a dysmorphology examination. The search was limited to peer-reviewed, English language studies involving human subjects, up to 5.5 years old. Results: Out of the 1,684 titles screened, a total of 71 papers were identified as relevant and included in this review. The majority of studies were prospective longitudinal studies. A range of assessment modalities (or tools) was used to determine neurodevelopmental outcomes of prenatal exposure to alcohol in the age group under review, the most frequently described being the Bayley Scales of Infant and Toddler Development (BSID) (n = 19). Studies varied in terms of the dose, frequency, and timing of alcohol consumption during pregnancy and methodology used to assess alcohol consumption. Findings demonstrate extensive evidence for poor global developmental outcomes in children prenatally exposed to alcohol, particularly with moderate to severe levels of prenatal alcohol exposure. Conclusion: The outcomes related to lower levels of prenatal alcohol exposure as well as outcomes in specific developmental domains, are poorly understood. Further research should aim to clarify the more subtle or less easily measurable manifestations of prenatal alcohol exposure on early development when the potential for greatest impact of interventions is highest.