Neurodevelopmental Disorders Research Articles

A life course perspective on mental disorders and psychopharmacologic drug use among persons living with cerebral palsy

In this study, we investigated the prevalence of mental disorders and the use of psychopharmacologic drugs among individuals with cerebral palsy (CP). We studied how the association between CP and mental illness develops over the life course (between ages 5 and 65 years), and how it varies across disability specific factors (intellectual disability, gross motor function and communicative ability). We used logistic regression models on a longitudinal matched case-control data material on all persons with CP in Sweden linked to several administrative registers including, the national patient registers and the pharmaceutical registers.Our results showed that the probability of being diagnosed with mental disorders and being dispensed psychopharmacologic drug was significantly higher among persons with CP compared to persons without CP across the different outcomes [OR=1.52–4.7]. For some mental and neurodevelopmental disorders including sleep disorders, autism, and ADHD, and for the use of anxiolytics and sedatives, there was a sizeable gap already in childhood. However, the excess burden of mental illness appeared to grow over the life course, indicating that adults with CP may be a particularly disadvantaged group. Diagnosis for mental disorders and dispensation for psychopharmacologic drugs were not consistent with respect to disability specific factors, especially communicative and intellectual function, which indicates the need for systematic approaches in the mental health care of individuals with CP.

Neurophysiological measures of covert semantic processing in neurotypical adolescents actively ignoring spoken sentence inputs: A high-density event-related potential (ERP) study

Language comprehension requires semantic processing of individual words and their context within a sentence. Well-characterized event-related potential (ERP) components (the N400 and late positivity component (LPC/P600)) provide neuromarkers of semantic processing, and are robustly evoked when semantic errors are introduced into sentences. These measures are useful for evaluating semantic processing in clinical populations, but it is not known whether they can be evoked in more severe neurodevelopmental disorders where explicit attention to the sentence inputs cannot be objectively assessed (i.e., when sentences are passively listened to). We evaluated whether N400 and LPC/P600 could be detected in adolescents who were explicitly ignoring sentence inputs. Specifically, it was asked whether explicit attention to spoken inputs was required for semantic processing, or if a degree of automatic processing occurs when the focus of attention is directed elsewhere? High-density ERPs were acquired from twenty-two adolescents (12–17 years), under two experimental conditions: 1. individuals actively determined whether the final word in a sentence was congruent or incongruent with sentence context, or 2. passively listened to background sentences while watching a video. When sentences were ignored, N400 and LPC/P600 were robustly evoked to semantic errors, albeit with reduced amplitudes and protracted/delayed latencies. Statistically distinct topographic distributions during passive versus active paradigms pointed to distinct generator configurations for semantic processing as a function of attention. Covert semantic processing continues in neurotypical adolescents when explicit attention is withdrawn from sentence inputs. As such, this approach could be used to objectively investigate semantic processing in populations with communication deficits.

Development and Validation of the Participation Questionnaire for Preschoolers with Autism Spectrum Disorder: Structural Validity, Internal Consistency, and Construct Validity

Aim This study aimed to develop the Participation Questionnaire for Preschoolers (PQP) and validate its psychometric properties as a disability-specific tool designed to assess participation in preschool-aged children with autism spectrum disorder (ASD). Methods This cross-sectional study recruited caregivers of 412 children, including those diagnosed with ASD and those at risk for neurodevelopmental disorders. Participants were recruited from child development facilities, medical institutions, and developmental support websites across Japan. Data from 287 children diagnosed with ASD were analyzed for item reduction, followed by exploratory factor analysis and the calculation of Cronbach’s alpha to evaluate internal consistency. Five hypotheses were tested to assess construct validity. Results Item reduction resulted in the removal of seven items and the identification of four factors: Friendship and Education, Family Satisfaction, Daily Living and Independence, and Leisure and Community Life. Cronbach’s alpha values for these factors ranged from 0.74 to 0.88, indicating acceptable internal consistency. Three of the five hypotheses related to construct validity were supported, aligning with expectations. Conclusion The PQP exhibited structural validity, internal consistency, and construct validity. However, further longitudinal studies are needed to validate its measurement properties over time.

A unique case of neurodevelopmental disorders and epilepsy linked to WDR45 variant inheritance and maternal mosaicism

This paper reports a case of a WDR45 variant inherited from an asymptomatic low-percentage mosaic mother. The proband boy was found to have significant psychomotor developmental delay, epilepsy, and abnormal liver function at four months of age, and a hemizygous variant WDR45 c.867_869dupGTA (p.Y290*) was detected by high throughput sequencing, which has an ACMG rating of likely pathogenic variant. The same variant was detected by high-throughput sequencing of the amniotic fluid of the fetus at his mother’s next pregnancy. Eventually, the same variant was detected in mosaic status in the unaffected mother by target capture-based deep sequencing of the asymptomatic mother, with a mutation load of 4.06 %.

FGF8-mediated gene regulation affects regional identity in human cerebral organoids.

The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic domains, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.

Exploring the effect of diet programs on the behavior of Sudanese children with autism and the prevalence and association of gastrointestinal symptoms: a multi-center cross-sectional study

Background and aims: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social difficulties, speech and nonverbal communication issues, and restricted behaviors. Nutritional issues, such as food allergies and intolerances, can affect children with ASD. This study aimed to evaluate the impact of diet programs on ASD behavior and gastrointestinal symptoms, which would be considered as a starting point to increase the family’s knowledge about how to practice healthy and suitable dieting for their children. Materials and methods: The study was a cross-sectional observational study on 45 children with an autism spectrum disorder in four centers aged 2–18 in Khartoum state. Data was collected through an interview questionnaire, which included sociodemographic, diet, gastrointestinal, and behavioral assessments. The data was analyzed using SPSS to find the correlation between the various variables. Independent t-test, Analysis of Variance, and Mann–Whitney test were used in univariant analysis to assess the association between study variables, while multiple linear regression was used in multivariant analysis for the same purpose Results: The study involved a large number of children with autism spectrum disorder (ASD), with 80% being male and 73.3% being school-aged. Most had parents as guardians and 71.1% were in intermediate financial status. About 20% were overweight or obese, and 57.8% did not have a specific diet program. Food selectivity was prevalent, with 22.7% having allergies to milk and wheat. ASD children experienced vomiting, gastric reflux, abdominal pain, and changes in stool characteristics. A significant link was found between financial status, behavioral status and gastrointestinal changes. High financial status was significantly different from intermediate and low statuses based on behavioral changes. However, no significant association was found in multivariant analysis. Conclusion: The study found that ASD children generally have good nutritional health, with a higher degree of dietary selection. The financial status of guardians significantly influenced behavioral and gastrointestinal changes in the children. Further interventional studies are recommended to assess the direct impact of diet programs on these symptoms.

Toward understanding autism heterogeneity: Identifying clinical subgroups and neuroanatomical deviations.

Autism spectrum disorder ("autism") is a neurodevelopmental condition characterized by substantial behavioral and neuroanatomical heterogeneity. This poses significant challenges to understanding its neurobiological mechanisms and developing effective interventions. Identifying phenotypically more homogeneous subgroups and shifting the focus from average group differences to individuals is a promising approach to addressing heterogeneity. In the present study, we aimed to parse clinical and neuroanatomical heterogeneity in autism by combining clustering of clinical features with normative modeling based on neuroanatomical measures (cortical thickness [CT] and subcortical volume) within the Autism Brain Imaging Data Exchange data sets (N autism = 861, N nonautistic individuals [N NAI] = 886, age range = 5-64). First, model-based clustering was applied to autistic symptoms as measured by the Autism Diagnostic Observation Schedule to identify clinical subgroups of autism (N autism = 499). Next, we ran normative modeling on CT and subcortical parcellations (N autism = 690, N NAI = 744) and examined whether clinical subgrouping resulted in increased neurobiological homogeneity within the subgroups compared to the entire autism group by comparing their spatial overlap of neuroanatomical deviations. We further investigated whether the identified subgroups improved the accuracy of autism classification based on the neuroanatomical deviations using supervised machine learning with cross-validation. Results yielded two clinical subgroups primarily differing in restrictive and repetitive behaviors (RRBs). Both subgroups showed increased homogeneity in localized deviations with the high-RRB subgroup showing increased volume deviations in the cerebellum and the low-RRB subgroup showing decreased CT deviations predominantly in the postcentral gyrus and fusiform cortex. Nevertheless, substantial within-group heterogeneity remained highlighted by the lack of improvement of the classifier's performance when distinguishing between the subgroups and NAI. Future research should aim to further reduce heterogeneity incorporating additional neuroanatomical clustering in even larger samples. This will eventually pave the way for more tailored behavioral interventions and improving clinical outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Expanding the phenotypic spectrum of CSNK2A1-associated Okur-Chung neurodevelopmental syndrome

De novo variants in CSNK2A1 cause autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS has an evolving clinical phenotype predominantly characterized by intellectual disability, global delays, dysmorphic features, and immunological manifestations. Microcephaly, defined as a small head circumference, is not widely recognized as a classical clinical presentation. Here, we describe four individuals from three unrelated families who shared several clinical features characteristic of an underlying syndromic neurodevelopmental condition. Trio clinical exome and research genome sequencing revealed that all affected individuals had heterozygous pathogenic missense variants in CSNK2A1. Two variants (c.468T>A p.Asp156Glu and c.149A>G p.Tyr50Cys) were de novo and previously reported , but the third variant (c.137G>T p.Gly46Val) is novel, and segregated in two affected individuals in a family. This adds to growing evidence of inherited disease-causing variants in CSNK2A1, an observation reported only twice previously. A detailed phenotypic analysis of our cohort together with those individuals reported in the literature revealed that OCNDS individuals, on average, have a smaller head circumference with 1/3rd presenting with microcephaly. We also show that the incidence of microcephaly is significantly correlated with the location of the variant in the encoded protein. Our findings suggest that small head circumference is a common but under-recognized feature of OCNDS which may not be apparent at birth.

Voluntary Attention Assessing Tests in Children with Neurodevelopmental Disorders Using Eye Tracking

Background/Objectives: The development of techniques for assessing cognitive functions using eye tracking is particularly important for children with developmental disabilities. In this paper, we present pilot results from the validation of two methods for assessing voluntary attention based on eye tracking. Methods: The study involved 80 children aged 3 to 8 years with neurodevelopmental disorders. Children performed two eye-tracking tests in which they had to ‘catch’ a stimulus by looking at it. They also completed the Attention Sustained subtest of the Leiter-3 International Performance Scale. In the first test, the stimuli were presented at different locations on the screen in subtests with stimuli onset asynchrony of 2 s and 1 s. A translucent blue marker marked the position of the gaze on the screen. The number of trials in which the gaze marker approached the stimulus was determined. In the second test, the location of the stimuli on the screen was changed based on gaze fixation in the ROI area. The time taken to complete the task was evaluated. Results: The results of both eye-tracking tests showed significant correlations with scores on the Attention Sustained Leiter-3 subtest and significant test–retest reliability. Conclusions: The results indicate that the present eye-tracking tests can be used for assessing voluntary attention in children with some neurodevelopmental disorders, and further research is warranted to assess the feasibility of these tests for a broader range of developmental disorders. Our findings could have practical implications for the early intervention and ongoing monitoring of attention-related issues.

Tocolysis and Neurodevelopment of Children Born Very Preterm

Neurodevelopmental outcomes of very preterm children exposed to tocolytics are not well described. To investigate whether tocolysis administered after spontaneous preterm labor is associated with neurodevelopmental outcomes at 5.5 years and to assess whether the type of tocolytic drug is associated with neurodevelopmental outcomes among infants exposed. This prospective, national, population-based cohort study used data from the French Etude Épidémiologique sur les Petits Âges Gestationnels-2 cohort. Children who were alive and participated in an assessment at 5.5 years and whose mothers experienced spontaneous preterm labor without an infectious context and delivered at 24 to 31 weeks were eligible for this study. Recruitment occurred from March to December 2011. Follow-up at age 5.5 years was conducted from September 2016 to December 2017. Data analysis was performed from July 2023 through April 2024. The primary analysis examined tocolytics (yes vs no), and the secondary analysis examined the type of tocolytic (atosiban vs calcium channel blockers [CCBs]). The composite outcome neurodevelopmental disabilities included cerebral palsy; visual, hearing, and cognitive deficiencies; developmental coordination disorders; or behavioral problems. A total of 1055 mothers (mean [SD] age, 29.2 [5.7] years) had preterm labor without fever and gave birth to 1320 children (704 male [weighted percentage, 53.3%; 95% CI, 50.6%-56.1%]; mean [SD] gestational age, 28.8 [2.0] weeks). Overall, 776 mothers (weighted percentage, 73.5%; 95% CI, 70.8%-76.2%) received tocolytics; 136 mothers (weighted percentage, 17.9%; 95% CI, 15.3%-20.8%) received only a CCB, and 295 mothers (weighted percentage, 37.6%; 95% CI, 34.2%-41.0%) received only atosiban. From modified Poisson regression with propensity score matching, the risk of overall neurodevelopmental disabilities (mild, moderate, or severe) at 5.5 years did not differ between preterm children exposed and not exposed to tocolytics (relative risk [RR], 1.11; 95% CI, 0.85-1.45; P = .44) or in preterm infants exposed to atosiban compared with those exposed to CCBs (RR, 0.94; 95% CI, 0.67-1.32; P = .71). In this study, tocolytics were not associated with neurodevelopmental disabilities among very preterm children surviving at 5.5 years.

Comparing methods for risk prediction of multicategory outcomes: dichotomized logistic regression vs. multinomial logit regression

BackgroundMedical outcomes of interest to clinicians may have multiple categories. Researchers face several options for risk prediction of such outcomes, including dichotomized logistic regression and multinomial logit regression modeling. We aimed to compare these methods and provide guidance needed for practice.MethodsWe described dichotomized logistic regression, multinomial continuation-ratio logit regression, which is an alternative to standard multinomial logit regression for ordinal outcomes, and logistic competing risks regression. We then applied these methods to develop prediction models of survival and neurodevelopmental outcomes based on the NICHD Extremely Preterm Birth Outcome Tool model. The statistical and practical advantages and flaws of these methods were examined. Both discrimination and calibration of the estimated logistic models of dichotomized outcomes and continuation-ratio logit model were assessed.ResultsThe dichotomized logistic models and multinomial continuation-ratio logit model had similar discrimination and calibration in predicting death and survival without neurodevelopmental impairment. But the continuation-ratio logit model had better discrimination and calibration in predicting neurodevelopmental impairment. The sum of predicted probabilities of outcome categories from the dichotomized logistic models could deviate from 100% substantially, ranging from 87.7 to 124.0%, and the dichotomized logistic model of neurodevelopmental impairment greatly overpredicted low risks and underpredicted high risks.ConclusionsEstimating multiple logistic regression models of dichotomized outcomes may result in poorly calibrated predictions for an outcome with multiple ordinal categories. Multinomial continuation-ratio logit regression produces better calibrated predictions, constrains the sum of predicted probabilities to 100%, and has the advantages of simplicity in model interpretation, flexibility to include outcome category-specific predictors and random-effect terms for patient heterogeneity by hospital. It also accounts for mutual dependence among multiple categories and accommodates competing risks.

The neurocognitive correlates of DTI indicators of white matter disorganization in pediatric moderate-to-severe traumatic brain injury

IntroductionNeuroimaging has expanded our understanding of pediatric brain disorders in which white matter organization and connectivity are crucial to functioning. Paralleling the known pathobiology of many neurodevelopmental disorders, traumatic brain injury (TBI) in childhood can alter trajectories of brain development. Specifically, diffusion tensor imaging (DTI) studies in TBI have demonstrated white matter (WM) abnormalities that suggest microstructural disruptions that may underlie atypical neurodevelopment. The neurocognitive correlates of these previous findings will be explored in this study.MethodsIndicators of WM organization were collected in 44 pediatric patients with moderate/severe TBI and 76 controls over two post-injury time points: T1 (8–20 weeks) and T2 (54–96 weeks). Our previous work identified two TBI subgroups based on information processing differences: one with slower interhemispheric transfer times (IHTT) of visual information than controls and another with comparable IHTT. We extend this prior work by evaluating neurocognitive trajectories associated with divergent WM structure post-injury in slow and normal IHTT TBI subgroups.ResultsAt T1, both TBI subgroups performed significantly worse than controls on a norm-referenced working memory index (WMI), but only the Normal IHTT TBI subgroup significantly improved over the 12-month follow-up period (p = 0.014) to match controls (p = 0.119). In contrast, the Slow IHTT TBI subgroup did not show any recovery in working memory performance over time and performed more poorly than the control group (p < 0.001) at T2. Improvement in one of the two WMI subtests was associated with DTI indicators of WM disorganization in CC tracts to the precentral, postcentral, frontal, and parietal cortices. IHTT and WM mean diffusivity predicted 79% of the variance in cognitive recovery from T1 to T2 when also accounting for other known predictors of TBI recovery.DiscussionIn the year following TBI, some pediatric patients experienced persisting working memory disturbance while others exhibited recovery; stratification was based on an event-related potential marker. More or less improvement in neurocognition was also associated with the degree of WM disorganization. IHTT, measured post-acutely after TBI, and progression of WM disorganization over time predicted neurocognitive trajectories at the chronic timeframe - potentially representing a prognostic biomarker.

Consanguinity

Objective: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with genetic and environmental factors. Although consanguinity is a common practice in the Middle Eastern population, the association between consanguinity and ASD severity is not clear. Methods: This retrospective study analyzed the records of 139 children (1.5-14 years) diagnosed with ASD from June 2011 to May 2024. The study analyzed the correlation between consanguinity, homozygosity, and ASD severity. Results: Of 139 cases, 74.1% were male, with an average age of diagnosis of 4.5 years (SD+- 2). Most ASD cases were at severity levels 2 (63.3%) and 3 (35.3%). Consanguinity was reported in 59% of cases, with a mean homozygosity rate of 4.6%. No significant correlation was found between consanguinity or homozygosity rates and ASD severity. Conclusion: No significant association was found between consanguinity or homozygosity rates and ASD severity. Further research is needed to explore the genetic mechanisms of ASD in consanguineous populations.

Ortholog of autism candidate gene RBM27 regulates mitoribosomal assembly factor MALS-1 to protect against mitochondrial dysfunction and axon degeneration during neurodevelopment.

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and attention-deficit hyperactivity disorder (ADHD). However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation of rbm-26, the Caenorhabditis elegans ortholog of the RBM27 autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against axonal defects by negatively regulating expression of the MALS-1 (MALSU1) mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with defects in axon overlap and axon degeneration that occurs during larval development. Using a biochemical screen, we identified the mRNA for the MALS-1 mitoribosomal assembly factor as a binding partner for RBM-26. Loss of RBM-26 function causes a dramatic overexpression of mals-1 mRNA and MALS-1 protein. Moreover, genetic analysis indicates that this overexpression of MALS-1 is responsible for the mitochondrial and axon degeneration defects in rbm-26 mutants. These observations reveal a mechanism that regulates expression of a mitoribosomal assembly factor to protect against axon degeneration during neurodevelopment.

Endocrine disorders in Rett syndrome: a systematic review of the literature

BackgroundRett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder that involves mainly girls and is the second most frequent cause of genetic intellectual disability. RTT leads to neurological regression between 6 and 18 months of life and could be associated with a variable neurological impairment. However, RTT affects not only neurological function but also wide aspects of non-neurological organs. Recent data showed that the endocrine system is often involved in RTT patients, including disorders of growth, bone health, thyroid, puberty onset, and weight abnormalities However, systematic data on endocrinopathies in RTT are scarce and limited.ObjectiveThis review aims to analyze the prevalence and type of endocrine comorbidities in RTT population, to allow a precocious diagnosis and appropriate endocrinological management.MethodsSystematic research was carried out from January 2000 to March 2024 through MEDLINE via PubMed, Scopus, and the Cochrane Library.ResultsAfter the selection phase, a total of 22 studies (1090 screened) met the inclusion criteria and were reported in the present review. Five studies were observational-retrospective, four were cross-sectional and case report or series, three were survey, prospective, and case-control, and finally one study for descriptive-transversal and longitudinal population-based study. The sample population consisted of multiethnic groups or single ethnic groups. The main endocrinopathies reported were malnutrition, bone alterations, and alterations of puberty onset.ConclusionsOur analysis shows that endocrinopathies are not rare in RTT patients. Therefore, in the context of a multidisciplinary approach, accurate screening and monitoring for endocrinopathies should be recommended in all RTT patients, to improve clinical practice, healthcare management, and, finally, patients’ quality of life.

Gambaran Penerapan Pola Asuh Orang Tua dengan Anak Attention Deficit/Hyperactivity Disorder

This research study delves into the parenting styles employed by parents of children with Attention Deficit Hyperactivity Disorder (ADHD). ADHD is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, potentially impacting a child's social, academic, and professional functioning. The research method used is qualitative. The study involved three pairs of parents cohabiting with their children aged 6-11 years old who have been diagnosed with ADHD by a specialist. The Parenting Styles and Dimensions Questionnaire (PSDQ) was employed to categorize the parenting styles of each couple. Screening results were further analyzed qualitatively, and semi-structured interviews were conducted to gather qualitative data. The findings revealed that parents do not adhere to a single parenting style, exhibiting varied responses and employing different styles depending on the situation and specific conditions. Mothers tend to be more involved in their child's daily activities, actively implementing strategies to manage ADHD symptoms, while fathers are more involved in disciplining their children through punishments aimed at promoting discipline.

Role of adenosine in the pathophysiology and treatment of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental condition characterized by persistent inattention, hyperactivity, and impulsivity. Although its precise etiology remains unclear, current evidence suggests that dysregulation within the neurotransmitter system plays a key role in the pathogenesis of ADHD. Adenosine, an endogenous nucleoside widely distributed throughout the body, modulates various physiological processes, including neurotransmitter release, sleep regulation, and cognitive functions through its receptors. This review critically examines the role of the adenosine system in ADHD, focusing on the links between adenosine receptor function and ADHD-related symptoms. Additionally, it explores how adenosine interacts with dopamine and other neurotransmitter pathways, shedding light on its involvement in ADHD pathophysiology. This review aims to provide insights into the potential therapeutic implications of targeting the adenosine system for ADHD management.

Beyond anosmia: olfactory dysfunction as a common denominator in neurodegenerative and neurodevelopmental disorders

Olfactory dysfunction has emerged as a hallmark feature shared among several neurological conditions, including both neurodevelopmental and neurodegenerative disorders. While diseases of both categories have been extensively studied for decades, their association with olfaction has only recently gained attention. Olfactory deficits often manifest already during prodromal stages of these diseases, yet it remains unclear whether common pathophysiological changes along olfactory pathways cause such impairments. Here we probe into the intricate relationship between olfactory dysfunction and neurodegenerative and neurodevelopmental disorders, shedding light on their commonalities and underlying mechanisms. We begin by providing a brief overview of the olfactory circuit and its connections to higher-associated brain areas. Additionally, we discuss olfactory deficits in these disorders, focusing on potential common mechanisms that may contribute to olfactory dysfunction across both types of disorders. We further debate whether olfactory deficits contribute to the disease propagation or are simply an epiphenomenon. We conclude by emphasizing the significance of olfactory function as a potential pre-clinical diagnostic tool to identify individuals with neurological disorders that offers the opportunity for preventive intervention before other symptoms manifest.

Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans.

Theories of amygdala function are central to our understanding of psychiatric and neurodevelopmental disorders. However, limited knowledge of the molecular and cellular composition of the amygdala impedes translational research aimed at developing new treatments and interventions. The aim of this study was to characterize and compare the composition of amygdala cells to help bridge the gap between preclinical models and human psychiatric and neurodevelopmental disorders. Tissue was dissected from multiple amygdala subnuclei in both humans (N=3, male) and rhesus macaques (N=3, male). Single-nucleus RNA sequencing was performed to characterize the transcriptomes of individual nuclei. The results reveal substantial heterogeneity between regions, even when restricted to inhibitory or excitatory neurons. Consistent with previous work, the data highlight the complexities of individual marker genes for uniquely targeting specific cell types. Cross-species analyses suggest that the rhesus monkey model is well-suited to understanding the human amygdala, but also identify limitations. For example, a cell cluster in the ventral lateral nucleus of the amygdala (vLa) is enriched in humans relative to rhesus macaques. Additionally, the data describe specific cell clusters with relative enrichment of disorder-related genes. These analyses point to the human-enriched vLa cell cluster as relevant to autism spectrum disorder, potentially highlighting a vulnerability to neurodevelopmental disorders that has emerged in recent primate evolution. Further, a cluster of cells expressing markers for intercalated cells is enriched for genes reported in human genome-wide association studies of neuroticism, anxiety disorders, and depressive disorders. Together, these findings shed light on the composition of the amygdala and identify specific cell types that can be prioritized in basic science research to better understand human psychopathology and guide the development of potential treatments.

Basic helix-loop-helix transcription factor BHLHE22 monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, tone and movement abnormalities.

BHLHE22 encodes a Class II basic helix-loop-helix transcription factor (bHLH). It is expressed exclusively in the retina and central nervous system (CNS), and functions as an important regulator of retinogenesis and neuronal differentiation. Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum. Here we report eleven individuals from nine unrelated families with BHLHE22 variants, with a neurodevelopmental disorder presenting with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals have partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms. Four individuals carry de novo missense variants within the highly conserved helix-loop-helix domain while seven individuals from five unrelated families carry a recurrent homozygous frameshift variant, p.(Gly74Alafs*18). Our findings implicate BHLHE22 variants in causing a previously unidentified autosomal dominant and recessive neurodevelopmental disorder associated with ACC, severe motor, language, and cognitive delays, abnormal tone, and involuntary movements. To our knowledge, this is the first report of Class II bHLH variants in humans shown to significantly disrupt brain development, cognition, and movement.