J Neurodev Disord [JOURNAL]
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200 papers
The Brain Gene Registry: a data snapshot.
Baldridge D, Kaster L, Sancimino C … +17 more , Srivastava S, Molholm S, Gupta A, Oh I, Lanzotti V, Grewal D, Riggs ER, Savatt JM, Hauck R, Sveden A, Brain Gene Registry Consortium, Constantino JN, Piven J, Gurnett CA, Chopra M, Hazlett H, Payne PRO
J Neurodev Disord · 2024 Apr · PMID 38632549 · Full text
Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a par...
Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.
Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB.
McCullough KB, Titus A, Reardon K … +7 more , Conyers S, Dougherty JD, Ge X, Garbow JR, Dickson P, Yuede CM, Maloney SE
J Neurodev Disord · 2024 Apr · PMID 38632525 · Full text
BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models...
BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. METHODS: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. RESULTS: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. CONCLUSIONS: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.
Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions.
Neuhaus E, Rea H, Jones E … +9 more , Benavidez H, Miles C, Whiting A, Johansson M, Eayrs C, Kurtz-Nelson EC, Earl R, Bernier RA, Eichler EE
J Neurodev Disord · 2024 Apr · PMID 38622540 · Full text
BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and be...
BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes. METHODS: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features. RESULTS: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group. CONCLUSIONS: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.
Neurofeedback training of executive function in autism spectrum disorder: distinct effects on brain activity levels and compensatory connectivity changes.
Pereira DJ, Morais S, Sayal A … +6 more , Pereira J, Meneses S, Areias G, Direito B, Macedo A, Castelo-Branco M
J Neurodev Disord · 2024 Apr · PMID 38605323 · Full text
BACKGROUND: Deficits in executive function (EF) are consistently reported in autism spectrum disorders (ASD). Tailored cognitive training tools, such as neurofeedback, focused on executive function enhancement might have...
BACKGROUND: Deficits in executive function (EF) are consistently reported in autism spectrum disorders (ASD). Tailored cognitive training tools, such as neurofeedback, focused on executive function enhancement might have a significant impact on the daily life functioning of individuals with ASD. We report the first real-time fMRI neurofeedback (rt-fMRI NF) study targeting the left dorsolateral prefrontal cortex (DLPFC) in ASD. METHODS: Thirteen individuals with autism without intellectual disability and seventeen neurotypical individuals completed a rt-fMRI working memory NF paradigm, consisting of subvocal backward recitation of self-generated numeric sequences. We performed a region-of-interest analysis of the DLPFC, whole-brain comparisons between groups and, DLPFC-based functional connectivity. RESULTS: The ASD and control groups were able to modulate DLPFC activity in 84% and 98% of the runs. Activity in the target region was persistently lower in the ASD group, particularly in runs without neurofeedback. Moreover, the ASD group showed lower activity in premotor/motor areas during pre-neurofeedback run than controls, but not in transfer runs, where it was seemingly balanced by higher connectivity between the DLPFC and the motor cortex. Group comparison in the transfer run also showed significant differences in DLPFC-based connectivity between groups, including higher connectivity with areas integrated into the multidemand network (MDN) and the visual cortex. CONCLUSIONS: Neurofeedback seems to induce a higher between-group similarity of the whole-brain activity levels (including the target ROI) which might be promoted by changes in connectivity between the DLPFC and both high and low-level areas, including motor, visual and MDN regions.
Genetic determinants of global developmental delay and intellectual disability in Ukrainian children.
Shchubelka K, Turova L, Wolfsberger W … +8 more , Kalanquin K, Williston K, Kurutsa O, Makovetska A, Hasynets Y, Mirutenko V, Vakerych M, Oleksyk TK
J Neurodev Disord · 2024 Mar · PMID 38539105 · Full text
BACKGROUND: Global developmental delay or intellectual disability usually accompanies various genetic disorders as a part of the syndrome, which may include seizures, autism spectrum disorder and multiple congenital abno...
BACKGROUND: Global developmental delay or intellectual disability usually accompanies various genetic disorders as a part of the syndrome, which may include seizures, autism spectrum disorder and multiple congenital abnormalities. Next-generation sequencing (NGS) techniques have improved the identification of pathogenic variants and genes related to developmental delay. This study aimed to evaluate the yield of whole exome sequencing (WES) and neurodevelopmental disorder gene panel sequencing in a pediatric cohort from Ukraine. Additionally, the study computationally predicted the effect of variants of uncertain significance (VUS) based on recently published genetic data from the country's healthy population. METHODS: The study retrospectively analyzed WES or gene panel sequencing findings of 417 children with global developmental delay, intellectual disability, and/or other symptoms. Variants of uncertain significance were annotated using CADD-Phred and SIFT prediction scores, and their frequency in the healthy population of Ukraine was estimated. RESULTS: A definitive molecular diagnosis was established in 66 (15.8%) of the individuals. WES diagnosed 22 out of 37 cases (59.4%), while the neurodevelopmental gene panel identified 44 definitive diagnoses among the 380 tested patients (12.1%). Non-diagnostic findings (VUS and carrier) were reported in 350 (83.2%) individuals. The most frequently diagnosed conditions were developmental and epileptic encephalopathies associated with severe epilepsy and GDD/ID (associated genes ARX, CDKL5, STXBP1, KCNQ2, SCN2A, KCNT1, KCNA2). Additionally, we annotated 221 VUS classified as potentially damaging, AD or X-linked, potentially increasing the diagnostic yield by 30%, but 18 of these variants were present in the healthy population of Ukraine. CONCLUSIONS: This is the first comprehensive study on genetic causes of GDD/ID conducted in Ukraine. This study provides the first comprehensive investigation of the genetic causes of GDD/ID in Ukraine. It presents a substantial dataset of diagnosed genetic conditions associated with GDD/ID. The results support the utilization of NGS gene panels and WES as first-line diagnostic tools for GDD/ID cases, particularly in resource-limited settings. A comprehensive approach to resolving VUS, including computational effect prediction, population frequency analysis, and phenotype assessment, can aid in further reclassification of deleterious VUS and guide further testing in families.
Differential cognitive and behavioral development from 6 to 24 months in autism and fragile X syndrome.
Mullin LJ, Rutsohn J, Gross JL … +15 more , Caravella KE, Grzadzinski RL, Weisenfeld LA, Flake L, Botteron KN, Dager SR, Estes AM, Pandey J, Schultz RT, St John T, Wolff JJ, Shen MD, Piven J, Hazlett HC, Girault JB
J Neurodev Disord · 2024 Mar · PMID 38509470 · Full text
BACKGROUND: Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. R...
BACKGROUND: Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. Recent studies have uncovered important differences between infants with fragile X syndrome (FXS) and infants with familial history of autism spectrum disorder who go on to develop autism themselves (FH-ASD), including differences in brain development and behavior. Thus far, there have been no studies longitudinally investigating differential developmental skill profiles in FXS and FH-ASD infants. METHODS: The current study contrasted longitudinal trajectories of verbal (expressive and receptive language) and nonverbal (gross and fine motor, visual reception) skills in FXS and FH-ASD infants, compared to FH infants who did not develop ASD (FH-nonASD) and typically developing controls. RESULTS: Infants with FXS showed delays on a nonverbal composite compared to FH-ASD (as well as FH-nonASD and control) infants as early as 6 months of age. By 12 months an ordinal pattern of scores was established between groups on all domains tested, such that controls > FH-nonASD > FH-ASD > FXS. This pattern persisted through 24 months. Cognitive level differentially influenced developmental trajectories for FXS and FH-ASD. CONCLUSIONS: Our results demonstrate detectable group differences by 6 months between FXS and FH-ASD as well as differential trajectories on each domain throughout infancy. This work further highlights an earlier onset of global cognitive delays in FXS and, conversely, a protracted period of more slowly emerging delays in FH-ASD. Divergent neural and cognitive development in infancy between FXS and FH-ASD contributes to our understanding of important distinctions in the development and behavioral phenotype of these two groups.
Social skills in neurodevelopmental disorders: a study using role-plays to assess adolescents and young adults with 22q11.2 deletion syndrome and autism spectrum disorders.
Feller C, Ilen L, Eliez S … +1 more , Schneider M
J Neurodev Disord · 2024 Mar · PMID 38500028 · Full text
BACKGROUNDS: Social skills are frequently impaired in neurodevelopmental disorders and genetic conditions, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). Although often assessed with q...
BACKGROUNDS: Social skills are frequently impaired in neurodevelopmental disorders and genetic conditions, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). Although often assessed with questionnaires, direct assessment provides a more valid estimate of the constructs. Role-plays (i.e., simulates situational settings) therefore appear to be an appropriate indicator of social skills in daily life. METHODS: This co-registered study involved 53 individuals with 22q11DS, 34 individuals with ASD, and 64 typically developing (TD) peers aged 12-30 years. All participants were assessed with role-plays as well as parent-reported questionnaires and clinical interviews focusing on social skills, functioning and anxiety. RESULTS: Both clinical groups showed impaired social skills compared to TD, but distinct social profiles emerged between the groups. Individuals with 22q11DS displayed higher social appropriateness and clarity of speech but weaker general argumentation and negotiation skills, with the opposite pattern observed in participants with ASD. No association was found between social skills measured by direct observation and caregiver reports. Social anxiety, although higher in clinical groups than in TD, was not associated with role-plays. CONCLUSIONS: This study highlights the need to train social skills through tailored interventions to target the specific difficulties of each clinical population. It also highlights the importance of combining measures as they do not necessarily provide the same outcome.
Using team-based precision medicine to advance understanding of rare genetic brain disorders.
Walkley SU, Molholm S, Jordan B … +2 more , Marion RW, Wasserstein M
J Neurodev Disord · 2024 Mar · PMID 38491427 · Full text
We describe a multidisciplinary teamwork approach known as "Operation IDD Gene Team" developed by the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) at the Albert Einstein College...
We describe a multidisciplinary teamwork approach known as "Operation IDD Gene Team" developed by the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) at the Albert Einstein College of Medicine. This initiative brings families affected by rare genetic diseases that cause intellectual and developmental disability together with physicians, basic scientists, and their trainees. At team meetings, family members share their child's medical and personal history, physicians describe the broader clinical consequences of the condition, and scientists provide accessible tutorials focused on the fundamental biology of relevant genes. When appropriate, possible treatment approaches are also discussed. The outcomes of team meetings have been overwhelmingly positive, with families not only expressing deep gratitude, but also becoming empowered to establish foundations dedicated to their child's specific condition. Physicians, and in particular the scientists and their trainees, have gained a deeper understanding of challenges faced by affected families, broadening their perspective on how their research can extend beyond the laboratory. Remarkably, research by the scientists following the Gene Team meetings have often included focus on the actual gene variants exhibited by the participating children. As these investigations progress and newly created foundations expand their efforts, national as well as international collaborations are forged. These developments emphasize the importance of rare diseases as windows into previously unexplored molecular and cellular processes, which can offer fresh insights into both normal function as well as more common diseases. Elucidating the mechanisms of and treatments for rare and ultra-rare diseases thus has benefits for all involved-families, physicians, and scientists and their trainees, as well as the broader medical community. While the RFK IDDRC's Operation IDD Gene Team program has focused on intellectual disabilities affecting children, we believe it has the potential to be applied to rare genetic diseases impacting individuals of any age and encompassing a wide variety of developmental disorders affecting multiple organ systems.
Protein Kinase A in neurological disorders.
Glebov-McCloud AGP, Saide WS, Gaine ME … +1 more , Strack S
J Neurodev Disord · 2024 Mar · PMID 38481146 · Full text
Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolis...
Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction.
Etiologic heterogeneity, pleiotropy, and polygenicity in behaviorally defined intellectual and developmental disabilities.
Girault JB, Veatch OJ, Won H
J Neurodev Disord · 2024 Mar · PMID 38481128 · Full text
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Conducting head-mounted eye-tracking research with young children with autism and children with increased likelihood of later autism diagnosis.
Perkovich E, Laakman A, Mire S … +1 more , Yoshida H
J Neurodev Disord · 2024 Mar · PMID 38438975 · Full text
BACKGROUND: Over the past years, researchers have been using head-mounted eye-tracking systems to study young children's gaze behaviors in everyday activities through which children learn about the world. This method has...
BACKGROUND: Over the past years, researchers have been using head-mounted eye-tracking systems to study young children's gaze behaviors in everyday activities through which children learn about the world. This method has great potential to further our understanding of how millisecond-level gaze behaviors create multisensory experiences and fluctuate around social environments. While this line of work can yield insight into early perceptual experiences and potential learning mechanisms, the majority of the work is exclusively conducted with typically-developing children. Sensory sensitivities, social-communication difficulties, and challenging behaviors (e.g., disruption, elopement) are common among children with developmental disorders, and they may represent potential methodological challenges for collecting high-quality data. RESULTS: In this paper, we describe our research practices of using head-mounted eye trackers with 41 autistic children and 17 children with increased likelihood of later autism diagnosis without auditory or visual impairments, including those who are minimally or nonspeaking and/or have intellectual disabilities. The success rate in gathering data among children with autism was 92.68%. 3 of 41 children failed to complete the play-session, resulting in an 86.36% success rate among 1-4-year-olds and a 100.00% success rate among 5-8-year-olds. 1 of 17 children with increased likelihood of later autism diagnosis failed to complete the play-session, resulting in a success rate of 94.11%. There were numerous "challenging" behaviors relevant to the method. The most common challenging behaviors included taking the eye-tracking device off, elopement, and becoming distressed. Overall, among children with autism, 88.8% of 1-4-year-olds and 29.4% of 5-8-year-olds exhibited at least one challenging behavior. CONCLUSIONS: Research capitalizing on this methodology has the potential to reveal early, socially-mediated gaze behaviors that are relevant for autism screening, diagnosis, and intervention purposes. We hope that our efforts in documenting our study methodology will help researchers and clinicians effectively study early naturally-occuring gaze behaviors of children during non-experimental contexts across the spectrum and other developmental disabilities using head-mounted eye-tracking. Ultimately, such applications may increase the generalizability of results, better reflect the diversity of individual characteristics, and offer new ways in which this method can contribute to the field.
Outcome measures in Angelman syndrome.
Hagenaar DA, Bindels-de Heus KGCB, van Gils MM … +10 more , van den Berg L, Ten Hoopen LW, Affourtit P, Pel JJM, Joosten KFM, Hillegers MHJ, Moll HA, de Wit MY, Dieleman GC, Mous SE
J Neurodev Disord · 2024 Mar · PMID 38429713 · Full text
BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a...
BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. AIM: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. METHODS: The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. RESULTS: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). CONCLUSIONS: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. TRIAL REGISTRATION: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.
Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities.
Martinez D, Jiang E, Zhou Z
J Neurodev Disord · 2024 Feb · PMID 38424476 · Full text
X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous expression of X-linked genes in females. This is becaus...
X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous expression of X-linked genes in females. This is because most genes on the X chromosome are subject to random X chromosome inactivation (XCI) during early embryonic development, which results in a mosaic pattern of gene expression for a given X-linked mutant allele. This mosaic expression produces substantial complexity, especially when attempting to study the already complicated neural circuits that underly behavior, thus impeding the understanding of disease-related pathophysiology and the development of therapeutics. Here, we review a few selected X-linked forms of ID that predominantly affect heterozygous females and the current obstacles for developing effective therapies for such disorders. We also propose a genetic strategy to overcome the complexity presented by mosaicism in heterozygous females and highlight specific tools for studying synaptic and circuit mechanisms, many of which could be shared across multiple forms of intellectual disability.
Correction: Endophenotype trait domains for advancing gene discovery in autism spectrum disorder.
Mosconi MW, Stevens CJ, Unruh KE … +2 more , Shafer R, Elison JT
J Neurodev Disord · 2024 Feb · PMID 38418939 · Full text
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Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN).
Brima T, Freedman EG, Prinsloo KD … +7 more , Augustine EF, Adams HR, Wang KH, Mink JW, Shaw LH, Mantel EP, Foxe JJ
J Neurodev Disord · 2024 Jan · PMID 38183037 · Full text
BACKGROUND: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in audi...
BACKGROUND: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. METHODS: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. RESULTS: Data from individuals with CLN3 disease (N = 21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6-26 years). CONCLUSIONS: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.
White matter microstructure of children with sensory over-responsivity is associated with affective behavior.
Wren-Jarvis J, Powers R, Lazerwitz MC … +11 more , Xiao J, Cai LT, Choi HL, Brandes-Aitken A, Chu R, Trimarchi KJ, Garcia RD, Rowe MA, Steele MC, Marco EJ, Mukherjee P
J Neurodev Disord · 2024 Jan · PMID 38166648 · Full text
BACKGROUND: Sensory processing dysfunction (SPD) is linked to altered white matter (WM) microstructure in school-age children. Sensory over-responsivity (SOR), a form of SPD, affects at least 2.5% of all children and has...
BACKGROUND: Sensory processing dysfunction (SPD) is linked to altered white matter (WM) microstructure in school-age children. Sensory over-responsivity (SOR), a form of SPD, affects at least 2.5% of all children and has substantial deleterious impact on learning and mental health. However, SOR has not been well studied using microstructural imaging such as diffusion MRI (dMRI). Since SOR involves hypersensitivity to external stimuli, we test the hypothesis that children with SOR require compensatory neuroplasticity in the form of superior WM microstructural integrity to protect against internalizing behavior, leaving those with impaired WM microstructure vulnerable to somatization and depression. METHODS: Children ages 8-12 years old with neurodevelopmental concerns were assessed for SOR using a comprehensive structured clinical evaluation, the Sensory Processing 3 Dimensions Assessment, and underwent 3 Tesla MRI with multishell multiband dMRI. Tract-based spatial statistics was used to measure diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics from global WM and nineteen selected WM tracts. Correlations of DTI and NODDI measures with measures of somatization and emotional disturbance from the Behavioral Assessment System for Children, 3rd edition (BASC-3), were computed in the SOR group and in matched children with neurodevelopmental concerns but not SOR. RESULTS: Global WM fractional anisotropy (FA) is negatively correlated with somatization and with emotional disturbance in the SOR group but not the non-SOR group. Also observed in children with SOR are positive correlations of radial diffusivity (RD) and free water fraction (FISO) with somatization and, in most cases, emotional disturbance. These effects are significant in boys with SOR, whereas the study is underpowered for girls. The most affected white matter are medial lemniscus and internal capsule sensory tracts, although effects of SOR are observed in many cerebral, cerebellar, and brainstem tracts. CONCLUSION: White matter microstructure is related to affective behavior in children with SOR.
Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats.
Tamaoki Y, Pasapula V, Chandler C … +4 more , Borland MS, Olajubutu OI, Tharakan LS, Engineer CT
J Neurodev Disord · 2024 Jan · PMID 38166599 · Full text
BACKGROUND: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs...
BACKGROUND: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. METHODS: In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. RESULTS: Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. CONCLUSIONS: These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.
Assessing receptive verb knowledge in late talkers and autistic children: advances and cautionary tales.
Horvath S, Arunachalam S
J Neurodev Disord · 2023 Dec · PMID 38087233 · Full text
PURPOSE: Using eye-tracking, we assessed the receptive verb vocabularies of age-matched late talkers and typically developing children (experiment 1) and autistic preschoolers (experiment 2). We evaluated how many verbs...
PURPOSE: Using eye-tracking, we assessed the receptive verb vocabularies of age-matched late talkers and typically developing children (experiment 1) and autistic preschoolers (experiment 2). We evaluated how many verbs participants knew and how quickly they processed the linguistic prompt. Our goal is to explore how these eye-gaze measures can be operationalized to capture verb knowledge in late talkers and autistic children. METHOD: Participants previewed two dynamic scenes side-by-side (e.g., "stretching" and "clapping") and were then prompted to find the target verb's referent. Children's eye-gaze behaviors were operationalized using established approaches in the field with modifications in consideration for the type of stimuli (dynamic scenes versus static images) and the populations included. Accuracy was calculated as a proportion of time spent looking to the target, and linguistic processing was operationalized as latency of children's first look to the target. RESULTS: In experiment 1, there were no group differences in the proportion of verbs known, but late talkers required longer to demonstrate their knowledge than typically developing children. Latency was predicted by age but not language abilities. In experiment 2, autistic children's accuracy and latency were both predicted by receptive language abilities. CONCLUSION: Eye gaze can be used to assess receptive verb vocabulary in a variety of populations, but in operationalizing gaze behavior, we must account for between- and within-group differences. Bootstrapped cluster-permutation analysis is one way to create individualized measures of children's gaze behavior, but more research is warranted using an individual differences approach with this type of analysis.
The association between cardiovascular health and cognition in adults with Down syndrome.
Frank L, Helsel B, Dodd D … +8 more , Bodde AE, Danon JC, Sherman JR, Forsha DE, Szabo-Reed A, Washburn RA, Donnelly JE, Ptomey LT
J Neurodev Disord · 2023 Dec · PMID 38057709 · Full text
INTRODUCTION: Evidence in the general population suggests that predictors of cardiovascular health such as moderate to vigorous physical activity (MVPA), cardiorespiratory fitness, and systolic blood pressure are associa...
INTRODUCTION: Evidence in the general population suggests that predictors of cardiovascular health such as moderate to vigorous physical activity (MVPA), cardiorespiratory fitness, and systolic blood pressure are associated with cognitive function. Studies supporting these associations in adults with Down syndrome (DS) are limited. The purpose of this study was to examine the associations between systolic blood pressure, cardiorespiratory fitness, and MVPA on cognition in adults with DS. METHODS: This is a cross-sectional analysis using baseline data from a trial in adults with DS. Participants attended a laboratory visit where resting blood pressure, cardiorespiratory fitness (VO), and cognitive function (CANTAB® DS Battery) were obtained. The cognitive battery included tests measuring multitasking, episodic memory, and reaction time. Physical activity (accelerometer) was collected over the week following the laboratory visit. Pearson correlations and linear regressions were used to measure the impact of systolic blood pressure, cardiorespiratory fitness, and MVPA on cognitive outcomes. RESULTS: Complete data was available for 72 adults with DS (26.8 ± 9.3 years of age, 57% female). At baseline, VO (21.1 ± 4.2 ml/kg/min) and MVPA were low (14.4 ± 14.4 min/day), and systolic blood pressure was 118.3 ± 13.3 mmHg. VO was correlated with simple movement time (rho = - 0.28, p = 0.03) but was not significant using a linear regression controlling for age and sex. Systolic blood pressure was significantly associated with episodic memory (first attempt memory score: β = - 0.11, p = 0.002; total errors: β = 0.58, p = 0.001) and reaction time (five-choice movement time: β = 4.11, p = 0.03; simple movement time: β = 6.14, p = 0.005) using age- and sex-adjusted linear regressions. No associations were observed between MVPA and multitasking, episodic memory, or reaction time. CONCLUSION: Predictors of cardiovascular health, including cardiorespiratory fitness and systolic blood pressure, were associated with some aspects of cognition in adults with DS. While future research should examine the role of improved cardiovascular health on delaying decreases in cognitive function and dementia in adults with DS, we recommend that health care providers convey the importance of exercise and cardiovascular health to their patients with DS. TRIAL REGISTRATION: NCT04048759, registered on August 7, 2019.
The use of eye-tracking technology as a tool to evaluate social cognition in people with an intellectual disability: a systematic review and meta-analysis.
Jenner LA, Farran EK, Welham A … +2 more , Jones C, Moss J
J Neurodev Disord · 2023 Dec · PMID 38044457 · Full text
BACKGROUND: Relatively little is known about social cognition in people with intellectual disability (ID), and how this may support understanding of co-occurring autism. A limitation of previous research is that traditio...
BACKGROUND: Relatively little is known about social cognition in people with intellectual disability (ID), and how this may support understanding of co-occurring autism. A limitation of previous research is that traditional social-cognitive tasks place a demand on domain-general cognition and language abilities. These tasks are not suitable for people with ID and lack the sensitivity to detect subtle social-cognitive processes. In autism research, eye-tracking technology has offered an effective method of evaluating social cognition-indicating associations between visual social attention and autism characteristics. The present systematic review synthesised research which has used eye-tracking technology to study social cognition in ID. A meta-analysis was used to explore whether visual attention on socially salient regions (SSRs) of stimuli during these tasks correlated with degree of autism characteristics presented on clinical assessment tools. METHOD: Searches were conducted using four databases, research mailing lists, and citation tracking. Following in-depth screening and exclusion of studies with low methodological quality, 49 articles were included in the review. A correlational meta-analysis was run on Pearson's r values obtained from twelve studies, reporting the relationship between visual attention on SSRs and autism characteristics. RESULTS AND CONCLUSIONS: Eye-tracking technology was used to measure different social-cognitive abilities across a range of syndromic and non-syndromic ID groups. Restricted scan paths and eye-region avoidance appeared to impact people's ability to make explicit inferences about mental states and social cues. Readiness to attend to social stimuli also varied depending on social content and degree of familiarity. A meta-analysis using a random effects model revealed a significant negative correlation (r = -.28, [95% CI -.47, -.08]) between visual attention on SSRs and autism characteristics across ID groups. Together, these findings highlight how eye-tracking can be used as an accessible tool to measure more subtle social-cognitive processes, which appear to reflect variability in observable behaviour. Further research is needed to be able to explore additional covariates (e.g. ID severity, ADHD, anxiety) which may be related to visual attention on SSRs, to different degrees within syndromic and non-syndromic ID groups, in order to determine the specificity of the association with autism characteristics.
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