Impact of Ocular Conditions and Improvements After Refractive Surgery in Quality of Life for Children With Neurodevelopmental Disorders.

PURPOSE: This study aims to characterize the eye-related quality of life of children with neurodevelopmental and ocular disorders at baseline and after refractive surgery. DESIGN: Prospective interventional case series. METHODS: We enrolled children and adolescents 5 to 18 of age with neurodevelopmental disorders undergoing refractive surgery (6 for pre-/postsurgical assessment and 14 for baseline analysis). Eye-related quality of life was measured using the Pediatric Eye Questionnaire (PedEyeQ). Baseline levels of adaptive functioning and social behaviors were measured using the Adaptive Behavioral Assessment System (ABAS-3) and Social Responsiveness Scale (SRS-2). We assessed the correlation between baseline PedEyeQ scores, number of ocular comorbidities, magnitude of refractive error, and ABAS-3 and SRS-2 scores. RESULTS: At baseline, 14 patients demonstrated decreased median eye-related quality of life (<60/100) in 5 of 9 PedEyeQ domains, moderate deficiencies in social behaviors (SRS-2 median 71, range 49-90), and low adaptive functioning (ABAS-3 median percentile for age of 0.100). Baseline PedEyeQ scores did not correlate with magnitude of refractive error or adaptive functioning scores but did correlate with number of ocular comorbidities and social behavior scores. Six patients have undergone refractive surgery without complication. Postoperatively, 11 of 11 eyes were within ±1.5 diopters spherical equivalent. Four of 6 patients exhibited clinically significant improvements in PedEyeQ scores after surgery. CONCLUSIONS: Even in the presence of significant social and adaptive impairments, quality of life in children with neurodevelopmental disorders is decreased by ocular disorders. Refractive surgery is associated with clinically significant improvements in eye-related quality of life.

Tibial Component Subsidence in a Total Ankle System Comparing Standard Technique Versus a Hybrid Technique.

Total ankle arthroplasty (TAA) is a viable treatment option for end-stage ankle arthritis. However, implant survivorship remains an important consideration. Concerns regarding early component loosening with the low-profile tibial tray utilized by fourth-generation TAA systems have been raised in the literature. We have previously described our preliminary outcomes of a hybrid technique combining a stemmed intramedullary tibial component with a chamfer-cut talar component for TAA. A retrospective study comparing short-term outcomes of the tibial component between a standard fourth-generation TAA system versus our hybrid technique was performed. 46 patients with a minimum of 1-year follow up were included in the analyses. There were 25 subjects in the standard implant cohort utilizing a low-profile tibial tray, and 21 subjects in the hybrid group utilizing a stemmed intramedullary tibial component. No statistically significant difference between the demographics of each group was found. The rate of tibial component subsidence was 8% (n = 2) in the standard implant group, and 0% (n = 0) in the hybrid group, though this did not meet statistical significance (p = .49). Mean time to subsidence was 6 months, and revision rate due to tibial component subsidence was 2.1% (n = 1). Periprosthetic lucency was present on most recent follow-up radiographs in 32% and 9.5% of ankles in the standard and hybrid groups, respectively (p = .08). Despite prior concerns for tibial component subsidence with the standard fourth-generation system, we demonstrated low rates in both implant groups. Additional studies are needed to further explore factors that may predispose patients to early tibial component subsidence and resulting implant failure.

Documenting Opportunity for Systematic Identification and Mitigation of Risk for Child Maltreatment.

This is a communication of preliminary data as a matter of priority in relation to Clinical Trials protocol ID 2018110118; NCT04438161. This protocol represents, to our knowledge, a first-ever attempt to convert an epidemiologic discovery on risk for child maltreatment (CM) into a readily deployable modification of obstetrical practice designed to offset risk for CM and its psychiatric sequelae. Before1 and during the coronavirus disease 2019 (COVID-19 pandemic),2,3 CM has incurred a burden of epidemic proportions to U.S. children, with confirmed incidents occurring on the order of 12% of the population. Wu et al.4 and Putnam-Hornstein and Needell5 previously established that profiles of risk ascertained exclusively from birth records identified specific groups of newborns at highly elevated risk for official-report CM. For example, infants with the joint characteristics of low birth weight, more than 2 siblings, and maternal characteristics of being unmarried, on Medicaid, and smoking during pregnancy (ascertained separately) were found to have a 7-fold risk for maltreatment compared with the population average.4 Putnam-Hornstein and Needell showed that newborns with 3 or more risk factors ascertained from birth records (including any of the above, delayed prenatal care, less than high school maternal education, and maternal age less than 24 years) comprised 15% of an epidemiologic birth cohort but accounted for more than half of all the children in the cohort who experienced substantiated official-report maltreatment by the age of 5 years. This study explored whether prospective implementation of birth records screening in an urban obstetrical service recapitulated the association with CM observed in an epidemiologic context and whether families in higher echelons of risk (ascertained in this manner through birth records) could be prospectively engaged in supportive interventions of demonstrated effect in reducing the occurrence of CM. This work follows on promising efforts elsewhere to use birth records information to prioritize support services for young families,6 though such innovations have yet to be systematically incorporated into obstetrical or newborn medical services of U.S. health systems.

Familial aggregation of status epilepticus in generalized and focal epilepsies.

OBJECTIVE: To determine whether familial aggregation of status epilepticus (SE) occurs in a large cohort of familial common epilepsies. METHODS: We used the Epilepsy Phenome/Genome Project dataset, which consisted of 2,197 participants in 1,043 family units with ≥2 members having a common generalized or nonacquired focal epilepsy (NAFE). We identified participants with a history of traditionally defined SE (TSE) (seizures ≥30 minutes) and operationally defined SE (OSE) (seizures ≥10 minutes) by chart review. We assessed familial aggregation of TSE and OSE using χ2 analysis and generalized estimating equations (GEE). RESULTS: One hundred fifty-five (7%) participants in 1,043 families had ≥1 episodes of TSE. Two hundred fifty (11%) had ≥1 episodes of OSE. In a χ2 analysis, the number of family units with ≥2 members having TSE (odds ratio [OR] 4.79, 95% confidence interval [CI] 2.56-8.97) or OSE (OR 4.23, 95% CI 2.67-6.70) was greater than expected by chance. In GEE models adjusted for sex, broad epilepsy class (GE or NAFE), age at onset, and duration of epilepsy, TSE in a proband predicted TSE in a first-degree relative (OR 2.79, 95% CI 1.24-6.22), and OSE in a proband predicted OSE in a first-degree relative (OR 2.91, 95% CI 1.65-5.15). The results remained significant in models addressing epilepsy severity by incorporating the number of antiseizure medications used or epilepsy surgery. CONCLUSIONS: TSE and OSE showed robust familial aggregation in a cohort of familial epilepsy independently of epilepsy severity or class, suggesting that genetic factors contribute to SE independently of the genetic cause of these epilepsies. CLINICALTRIALSGOV IDENTIFIER: NCT00552045.

Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.

Psychiatry and developmental psychopathology: Unifying themes and future directions.

In the past 35 years, developmental psychopathology has grown into a flourishing discipline that shares a scientific agenda with contemporary psychiatry. In this editorial, which introduces the special issue, we describe the history of developmental psychopathology, including core principles that bridge allied disciplines. These include (1) emphasis on interdisciplinary research, (2) elucidation of multicausal pathways to seemingly single disorders (phenocopies), (3) description of divergent multifinal outcomes from common etiological start points (pathoplasticity), and (4) research conducted across multiple levels of analysis spanning genes to environments. Next, we discuss neurodevelopmental models of psychopathology, and provide selected examples. We emphasize differential neuromaturation of subcortical and cortical neural networks and connectivity, and how both acute and protracted environmental insults can compromise neural structure and function. To date, developmental psychopathology has placed greater emphasis than psychiatry on neuromaturational models of mental illness. However, this gap is closing rapidly as advances in technology render etiopathophysiologies of psychopathology more interrogable. We end with suggestions for future interdisciplinary research, including the need to evaluate measurement invariance across development, and to construct more valid assessment methods where indicated.

Characterization of a Mouse Model of Börjeson-Forssman-Lehmann Syndrome.

Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS), but the pathogenesis of BFLS remains poorly understood. Here, we report a mouse model of BFLS, generated using a CRISPR-Cas9 approach, in which cysteine 99 within the PHD domain of PHF6 is replaced with phenylalanine (C99F). Mice harboring the patient-specific C99F mutation display deficits in cognitive functions, emotionality, and social behavior, as well as reduced threshold to seizures. Electrophysiological studies reveal that the intrinsic excitability of entorhinal cortical stellate neurons is increased in PHF6 C99F mice. Transcriptomic analysis of the cerebral cortex in C99F knockin mice and PHF6 knockout mice show that PHF6 promotes the expression of neurogenic genes and represses synaptic genes. PHF6-regulated genes are also overrepresented in gene signatures and modules that are deregulated in neurodevelopmental disorders of cognition. Our findings advance our understanding of the mechanisms underlying BFLS pathogenesis.

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT).

IMPORTANCE: Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. OBJECTIVE: To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. DESIGN, SETTING, AND PARTICIPANTS: Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. MAIN OUTCOMES AND MEASURES: Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. RESULTS: Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples. CONCLUSIONS AND RELEVANCE: This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.

The social responsiveness scale in relation to DSM IV and DSM5 ASD in Korean children.

The Social Responsiveness Scale (SRS) is an autism rating scales in widespread use, with over 20 official foreign language translations. It has proven highly feasible for quantitative ascertainment of autistic social impairment in public health settings, however, little is known about the validity of the reinforcement in Asia populations or in references to DSM5. The current study aims to evaluate psychometric properties and cross-cultural aspects of the SRS-Korean version (K-SRS).The study subjects were ascertained from three samples: a general sample from 3 regular education elementary schools (n=790), a clinical sample (n=154) of 6-12-year-olds from four psychiatric clinics, and an epidemiological sample of children with ASD, diagnosed using both DSM IV PDD, DSM5 ASD and SCD criteria (n=151). Their parents completed the K-SRS and the Autism Spectrum Screening Questionnaire(ASSQ). Descriptive statistics, correlation analyses and principal components analysis (PCA) were performed on the total population. Mean total scores on the K-SRS differed significantly between the three samples. ASSQ scores were significantly correlated with the K-SRS T-scores. PCA suggested a one-factor solution for the total population.Our results indicate that the K-SRS exhibits adequate reliability and validity for measuring ASD symptoms in Korean children with DSM IV PDD and DSM5 ASD. Our findings further suggest that it is difficult to distinguish SCD from other child psychiatric conditions using the K-SRS.This is the first study to examine the relationship between the SRS subscales and DSM5-based clinical diagnoses. This study provides cross-cultural confirmation of the factor structure for ASD symptoms and traits measured by the SRS. Autism Res 2016, 9: 970-980. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Distribution and Within-Family Specificity of Quantitative Autistic Traits in Patients with Neurofibromatosis Type I.

OBJECTIVE: To examine the distribution of quantitative autistic traits (QATs) in an independent neurofibromatosis type I (NF1) sample, the relationships between QAT, sex, and attention deficit hyperactivity disorder (ADHD) symptomatology, and to explore evidence for QAT mutational specificity within families. STUDY DESIGN: Age-appropriate versions of the Social Responsiveness Scale, second edition and the Conners Adult ADHD Rating Scales were completed for 103 patients with NF1 from the Washington University Neurofibromatosis Center. RESULTS: Patients with NF1 exhibited a pathologically shifted unimodal distribution for QAT. Forty-four percent of the subjects exhibited a QAT burden at or above 1 SD from the population mean; 13% scored at or above the extreme first percentile of the general population distribution. Elevations in ADHD symptomatology exhibited a distinct bimodal distribution; however, mean ADHD index scores were equivalent in patients who had been diagnosed in the community with ADHD compared with those who had not. We observed striking within-family associations for QAT, reflected by an Social Responsiveness Scale, second edition intraclass correlation of 0.77 in pairings of first degree relatives with NF1. CONCLUSIONS: Impairments in reciprocal social behavior and attention affect a large proportion of patients with NF1 throughout life and are often clinically unrecognized. Further exploration of genotype-phenotype correlation is strongly warranted for the purpose of gaining insights into mechanisms by which specific mutational variations in the NF1 gene may influence autistic trait severity.

ADHD symptoms, autistic traits, and substance use and misuse in adult Australian twins.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder frequently co-occur. Several studies show increased risk of substance use disorders in ADHD, yet there is limited information related to how ADHD symptoms, autistic traits, and their combined effects are associated with nicotine, alcohol, and cannabis use and use disorders in the general population. METHOD: Cross-sectional interview and self-report questionnaire data from 3,080 young adult Australian twins (mean age 31.9 years) were used to assess ADHD symptoms, autistic traits, substance use, and substance use disorders. Substance use disorders-based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria-were assessed in the full sample as well as in those who reported substance use. Logistic regression analyses were used for comparing the associations between ADHD symptoms, autistic traits, substance use, and substance misuse after conduct disorder, sex, age, and zygosity were controlled for. RESULTS: Greater ADHD symptoms and autistic traits scores were associated with elevated levels of regular smoking; cannabis use; and nicotine, alcohol, and cannabis use disorders, even after conduct disorder was adjusted for. In contrast, for alcohol use, those with high autistic traits scores were less likely to report drinking to intoxication. However, upon initiation, and similar to the findings for nicotine and cannabis, they were at elevated risk for developing alcohol dependence. CONCLUSIONS: Increased liability to ADHD and elevated autistic traits scores were associated with substance use and misuse, with the exception of alcohol use. Given the social underpinnings of drinking, persons with autistic traits may be less likely to engage in it; however, upon engagement in drinking, their vulnerability to alcohol dependence is elevated.

Quantitative assessment of autistic symptomatology in preschoolers.

Given a growing emphasis on early intervention for children with autism, valid quantitative tools for measuring treatment response are needed. The Social Responsiveness Scale (SRS) is a brief (15-20 minute) quantitative measure of autistic traits in 4-to 18-year-olds, for which a version for 3-year-olds was recently developed. We obtained serial SRS measurements on 73 preschool children with (n = 51) and without (n = 22) autism spectrum conditions. Inter-rater reliability (mothers and teachers) and test-retest reliability were of the order of 0.75 (Pearson's r). There was substantial agreement between SRS scores and (1) the Vineland Adaptive Behavior Composite (Pearson's r = -0.86) and (2) scores for social impairment on the Autism Diagnostic Interview-Revised (r = 0.63). Overall, quantitative autistic trait scores tended to improve over time in preschoolers, irrespective of treatment conditions. We conclude that it is possible to obtain reliable quantitative measurements of autistic social impairment in preschoolers, suitable for assessing treatment response.