Childhood maltreatment is a significant risk factor for a host of psychiatric, developmental, medical, and neurocognitive conditions, often resulting in debilitating and long-term consequences. However, there is no available neuropsychological resource reviewing the literature on the associated neurocognitive deficits in children and adolescents. This review comprehensively examines the 23 prior studies that evaluated the intellectual, language, visual-spatial, memory, motor, and/or attention/executive functions in children and adolescents following an experience of childhood abuse and/or neglect. Neurocognitive impairments were frequently reported. Impairments in executive functions were the most frequent and severe reported impairments, although intelligence, language, visual-spatial skills, and memory are also at serious risk for compromised development following maltreatment. However, specific factors such as abuse/neglect duration, severity, type, and timing during development were all associated with neurocognition. This indicates that these factors are of greater importance than just the presence of abuse/neglect in identifying risk for neurocognitive compromise. Such neurocognitive deficits appear to be a consequence to the known neurobiological and brain development abnormalities of this population, suggesting traumatic stress can be a potential cause of neurodevelopmental disorders. These findings have critical implications for the clinical practice and research involving children following childhood maltreatment and other types of traumatic stress.

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Christianson syndrome (CS), an X-linked neurological disorder characterized by postnatal attenuation of brain growth (postnatal microcephaly), is caused by mutations in SLC9A6, the gene encoding endosomal Na+/H+ exchanger 6 (NHE6). To hasten treatment development, we established induced pluripotent stem cell (iPSC) lines from patients with CS representing a mutational spectrum, as well as biologically related and isogenic control lines. We demonstrated that pathogenic mutations lead to loss of protein function by a variety of mechanisms: The majority of mutations caused loss of mRNA due to nonsense-mediated mRNA decay; however, a recurrent, missense mutation (the G383D mutation) had both loss-of-function and dominant-negative activities. Regardless of mutation, all patient-derived neurons demonstrated reduced neurite growth and arborization, likely underlying diminished postnatal brain growth in patients. Phenotype rescue strategies showed mutation-specific responses: A gene transfer strategy was effective in nonsense mutations, but not in the G383D mutation, wherein residual protein appeared to interfere with rescue. In contrast, application of exogenous trophic factors (BDNF or IGF-1) rescued arborization phenotypes across all mutations. These results may guide treatment development in CS, including gene therapy strategies wherein our data suggest that response to treatment may be dictated by the class of mutation.

The objective of this study was to establish a large, densely sampled, U.S. population‐based cohort of people with autism spectrum disorder (ASD). The Rhode Island Consortium for Autism Research and Treatment (RI‐CART) represents a unique public‐private‐academic collaboration involving all major points of service for families in Rhode Island affected by ASD. Diagnosis was based on direct behavioral observation via the Autism Diagnostic Observation Schedule, Second Edition. For the first 1,000 participants, ages ranged from 21 months to 64 years. Using Geographic Information System and published prevalence rates, the overall cohort is estimated to represent between 20% and 49% of pediatric age persons in Rhode Island with ASD, with demographics representative of U.S. Census. We observed a high rate of co‐occurring medical and psychiatric conditions in affected individuals. Among the most prominent findings of immediate clinical importance, we found that females received a first diagnosis of ASD at a later age than males, potentially due to more advanced language abilities in females with ASD. In summary, this is the first analysis of a large, population‐based U.S. cohort with ASD. Given the depth of sampling, the RI‐CART study reflects an important new resource for studying ASD in a representative U.S. population. Psychiatric and medical comorbidities in ASD constitute a substantial burden and warrant adequate attention as part of overall treatment. Our study also suggests that new strategies for earlier diagnosis of ASD in females may be warranted. Autism Res 2020, 13: 474–488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary The Rhode Island Consortium for Autism Research and Treatment (RI‐CART) represents a unique public‐private‐academic collaboration involving all major points of service for families in Rhode Island affected by autism spectrum disorder (ASD). In this article, we provide results from the first 1,000 participants, estimated to represent >20% of affected families in the state. Importantly, we find a later age at first diagnosis of ASD in females, which potentially calls attention to the need for improved early diagnosis in girls. Also, we report a high rate of co‐occurring medical and psychiatric conditions in affected individuals.

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Aspartate-glutamate carrier 1 (AGC1) is one of two exchangers within the malateaspartate shuttle. AGC1 is encoded by the SLC25A12 gene. Three patients with pathogenic variants in SLC25A12 have been reported in the literature. These patients were clinically characterized by neurodevelopmental delay, epilepsy, hypotonia, cerebral atrophy, and hypomyelination; however, there has been discussion in the literature as to whether this hypomyelination is primary or secondary to a neuronal defect. Here we report a 12-year-old patient with variants in SLC25A12 and magnetic resonance imaging (MRI) at multiple ages. Novel compound heterozygous, recessive variants in SLC25A12 were identified: c.1295C>T (p.A432V) and c.1447-2_1447-1delAG. Clinical presentation is characterized by severe intellectual disability, nonambulatory, nonverbal status, hypotonia, epilepsy, spastic quadriplegia, and a happy disposition. The serial neuroimaging findings are notable for cerebral atrophy with white matter involvement, namely, early hypomyelination yet subsequent progression of myelination. The longitudinal MRI findings are most consistent with a leukodystrophy of the leuko-axonopathy category, that is, white matter abnormalities that are most suggestive of mechanisms that result from primary neuronal defects. We present here the first case of a patient with compound heterozygous variants in SLC25A12, including brain MRI findings, in the oldest individual reported to date with this neurogenetic condition.

Autism spectrum disorder (ASD) is among the most strongly genetic neuropsychiatric conditions, with an increased frequency of rare, deleterious copy number variants and single-nucleotide variants. Because of this, several medical professional societies have recommended offering chromosomal microarray (CMA) testing and Fragile X testing for people with ASD, 1 with growing support for exome sequencing as the first-tier genetic test. 2 To understand the implementation of genetic testing in a real-world population, we analyzed data from the Rhode Island Consortium for Autism Research and Treatment (RI-CART) study, a large, population-based study of people with ASD. 3 Methods | This study was approved by the institutional review board at Lifespan, and all participants provided written informed consent. We analyzed self-report data and medical records, when available, from 1280 participants in the RI-CART study, recruited between April 1, 2013, and April 30, 2019, with ASD diagnosis confirmed by assessment using the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). 3 Statistical analyses included Pearson correlations, χ 2 analyses, and analyses of variance. Statistical significance was set at a 2-sided P value less than .05.

The present study examined the intellectual and adaptive functioning in a sample of children and young adults with Sturge-Weber Syndrome. A total of 80 research participants from a SWS study database underwent full neurological evaluation as part of their participation or concurrent medical care. Twenty-nine of the participants received neuropsychological evaluations. Analyses indicated no significant demographic or neurological differences between those who did and did not receive neuropsychological evaluations. Overall, the neuropsychological evaluation sample displayed significantly lower functioning relative to published normative data across domains of intellectual and adaptive functioning. 32% of the sample displayed impaired performance (standard score ≤ 75) in intellectual functioning and 58% displayed impaired performance in adaptive functioning. Hemiparesis status independently predicted overall adaptive functioning while seizure frequency independently predicted overall intellectual functioning. Younger participants displayed significantly higher (more intact) ratings in adaptive functioning compared to older participants, specifically in overall adaptive functioning, motor skills, and community living skills. A composite measure of neurological status (SWS-NRS) incorporating seizure and hemiparesis status effectively distinguished between individuals with impaired or non-impaired adaptive and intellectual functioning, and showed promise as a screening method for identifying individuals with more involved intellectual and/or adaptive needs.