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PubMed2026

Analysis of 14q12 microdeletions reveals novel regulatory loci for the neurodevelopmental disorder-related gene FOXG1.

Up to 17% of neurodevelopmental disorders (NDDs) can be explained by pathogenic structural variants (SVs) that disrupt coding regions and elicit gene dosage defects. However, noncoding SVs which can perturb cis-regulatory elements (CREs) and downstream gene expression are understudied. In this study, we describe multiple 14q12 deletions downstream of NDD-related gene FOXG1 in individuals with overlapping phenotypes of FOXG1 haploinsufficiency. We show that deletion of a minimum region of overlap (MRO) reduced FOXG1 expression, disrupted CREs and altered FOXG1's native genomic interactions. Deleting the MRO did not fully eliminate FOXG1 expression, indicating that multiple CREs likely cooperate to regulate FOXG1 and would need to be deleted to completely prevent expression. The transcriptomic profiles of MRO loss overlap in part with FOXG1 loss, including direct FOXG1 targets, indicating converging molecular pathways. These findings expand the scope of FOXG1's complex regulatory region, and more broadly, of regulatory SVs in NDD susceptibility.

Forkhead Transcription Factors↗

PubMed2004

Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Although MECP2 is ubiquitously transcribed, MeCP2 expression is developmentally regulated and heterogeneous in neuronal subpopulations, defined as MeCP2(lo) and MeCP2(hi). To test the hypothesis that pathways affecting MeCP2 expression changes may be defective in RTT, autism and other neurodevelopmental disorders without MECP2 mutations, a high-throughput quantitation of MeCP2 expression was performed on a tissue microarray containing frontal cortex samples from 28 different patients with neurodevelopmental disorders and age-matched controls. Combined quantitative analyses of MeCP2 protein and alternatively polyadenylated transcript levels were performed by laser scanning cytometry and tested for significant differences from age-matched controls. Normal cerebral samples showed an increase in total MeCP2 expression and the percentage of MeCP2(hi) cells with age that could be explained by increased MECP2 transcription within the MeCP2(hi) population. A significant decrease in the relative usage of the long transcript in the MeCP2(lo) population was observed in postnatal compared to fetal brain, but alternate polyadenylation did not correlate with MeCP2 expression changes at the single cell level. Brain samples from several related neurodevelopmental disorders, including autism, pervasive developmental disorder, Prader-Willi and Angelman syndromes showed significant differences in MeCP2 expression from age-matched controls by apparently different transcriptional and post-transcriptional mechanisms. These results suggest that multiple pathways regulate the complex developmental expression of MeCP2 and are defective in autism-spectrum disorders in addition to RTT.

Adolescent↗

PubMed2026

Prominent Movement Disorders in RNU2-2-Related Spliceosomopathy.

Pediatric movement disorders often overlap with neurodevelopmental diseases, suggesting shared molecular mechanisms. Variants in small nuclear RNA (snRNA) genes encoding spliceosome components have recently been associated with neurodevelopmental disorders, termed "RNUopathies." We analyzed genome sequencing data from 14 patients with undiagnosed pediatric movement disorders for pathogenic variants in snRNA genes. We identified recurrent de novo RNU2-2 variants (n.35A > G and n.4G > A) in two patients with intellectual disability, epilepsy, and hyperkinetic movement disorders. RNA sequencing of fibroblasts in one patient showed no characteristic transcriptomic signature. Spliceosomopathies should be considered in neurodevelopmental disorders and developmental and epileptic encephalopathies with hyperkinetic features.

Humans↗

PubMed2023

De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities.

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.

Child↗

PubMed2000

The neurodevelopmental frontostriatal disorders: evolutionary adaptiveness and anomalous lateralization.

The frontostriatal system (dorsolateral prefrontal cortex, lateral orbitofrontal cortex, anterior cingulate, supplementary motor area, and associated basal-ganglia structures) is subject to a range of neurodevelopmental disorders: Tourette's syndrome (TS), obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), autism, and probably depression. The system is responsible for our adaptive responses (initiation, execution, or withholding) to environmental situations, and the above disorders, involving effectively excessive release or withholding of various types of response, are all a consequence of changes in specific frontostriatal regions. The disorders all have a genetic component, and their persistence in the genome indicates that their clinical manifestations may also be associated, perhaps in low levels in close relatives, with certain adaptive advantages in given situations. Thus autism is associated with computational careers, depression with literary creativity, SCZ with lateral thinking and the Odyssean personality, ADHD with an Ice-Age readiness to respond, OCD with a focused range of interests, and TS with competitive sports and jazz improvisation. The disorders are all highly comorbid, and which one predominantly manifests may depend on how the frontostriatal system happens to be compromised as a result of inherited genetic predispositions and environmental contingency. We review the adaptive nature of the various subclinical manifestations and the evidence for concomitant phenomena (possibly epiphenomena): alterations in structural, functional, and behavioral lateralization in each syndrome. Indeed it is not clear that altered lateralization in frontostriatal disorders of a neurodevelopmental origin generally has any adaptive significance; it may often simply serve as a marker for altered regulatory function of the frontostriatal system, alterations which in low genetic dosage or penetrance continue to play an adaptive role in clinically unaffected close relatives of probands, but which, in high dosage or penetrance in the probands themselves, are generally deleterious.

Adaptation, Physiological↗

PubMed2003

Functional disability and school activity limitations in 41,300 school-age children: relationship to medical impairments.

OBJECTIVE: Our purpose was to examine the contribution of medical impairments to functional disability and school activity limitations in 41,300 school-age children participating in the 1994-1995 National Health Interview Survey. METHODS: The 1994 and 1995 National Health Interview Survey and Disability Interview Supplement samples provide International Classification of Diseases, Ninth Revision medical impairment codes for children with functional limitations or school activity limitations in a nationally representative US sample. Functional limitations were distributed as follows: mobility 12.4/1000 (95% confidence interval [CI]: 11.1-13.6), self-care 8.8/1000 (95% CI: 7.7-9.8), communication 52.9/1000 (95% CI: 50.2-55.5), and learning 104.6/1000 (95% CI: 100.7-108.4). Functional disability status was classified as 4.1% mild, 5.9% major, and 1.9% multiple. School activity limitations included 4.1% needing or receiving special education, 0.7% unable to attend, and 0.9% limited attendance. We categorized International Classification of Diseases, Ninth Revision impairment codes reported in conjunction with medical usage as physical disorders (n = 1251; eg, leukemia, diabetes), asthma (n = 916), neurodevelopmental disorders (n = 802; eg, cerebral palsy, epilepsy, mental retardation, autism, blindness, deafness), and learning-behavior disorders (n = 806; eg, attention-deficit/hyperactivity disorder, learning disability, anxiety) for children with functional or school activity limitations. Of children with multiple functional disabilities, 29.9% had neurodevelopmental disorders, 27.1% had learning-behavior disorders, 18.1% had physical disorders, 4.2% had asthma, and 20.8% did not have an identified medical impairment because they had not received medical services in the past year. Among children requiring special education, physical disorders accounted for 9.4%, neurodevelopmental disorders for 16.7%, learning and behavior disorders for 17%, asthma for 3.4%, and 53.4% did not have an identified medical impairment because they had not received medical services in the past year. CONCLUSIONS: Chronic health impairments, neurodevelopmental disorders, learning-behavior disorders, and functional limitations in essential activities are required to understand the complexity of disability in school-age children. A large number of children with functional disability or school activity limitations have not received ongoing medical services.

Activities of Daily Living↗

PubMed2005

Rett syndrome.

PURPOSE OF REVIEW: Nearly 70 reports on Rett syndrome were published in 2004. We have selected 51 articles, including clinical reports, on pathophysiology, genotype-phenotype correlation, and clinical and basic molecular biology studies. These articles explain how mutation of the gene (MECP2) for methyl-CpG-binding protein 2 causes the particular disorders of Rett syndrome, and also induces other neurodevelopmental disorders, clarifying the situation for future studies. RECENT FINDINGS: The role of X-chromosome inactivation has been clarified in animal experiments. New isoforms of MeCP2 have been discovered and its functional characteristics are under research. Understanding of the influence of the MECP2 mutation on other neurodevelopmental disorders has increased. However, there is no apparent progress in neurophysiological studies. SUMMARY: Clinical studies included the pathophysiology of stereotyped movement, and cardiac and respiratory disturbances, and there were four therapeutic trials including one for epilepsy. For genotype-phenotype correlation the role of X-chromosome inactivation was looked at and its basic mechanisms were studied extensively in animals. Characteristics of mutations in the C-terminus and the biological function of the new isoform, exon 1, were introduced. In studies on related neurodevelopmental disorders, a relationship is suggested between the MECP2 gene and autism-related gene, with overlapping pathways, but this is not common to other neurodevelopmental disorders. Developmental studies suggest an important role for MeCP2 in the formation and/or maintenance of synapses, and clarify the molecular biological aspects of Rett syndrome. However, early involvement of the aminergic neurons, suggested as the basic, pathognomonic lesion of Rett syndrome, has unfortunately not been investigated with the MECP2 mutation.

Animals↗

PubMed2001

Developmental disorders of activity dependent neuronal plasticity.

A number of neurodevelopmental disorders are caused by defects in activity dependent neuronal plasticity, the process by which neuronal activity shapes developing neuronal circuits. These disorders are caused by genetic mutations or other factors that disrupt intracellular signaling pathways that link the cell surface with the nuclear machinery for gene expression. The signaling pathways disrupted by these disorders are involved in learning, memory and behavior as well as in the synaptic proliferation and pruning that occurs during normal development. Examples of neurodevelopmental disorders that target plasticity include X-linked disorders such as Rett, Fragile-X and Coffin-Lowry Syndromes as well as acquired disorders such as cretinism. Several other X-linked mental retardation syndromes as well as autosomal disorders including neurofibromatosis type 1 and tuberous sclerosis also involve signaling pathways involved in neuronal plasticity. Disruption of neuronal plasticity is a mechanism that may underlie a diverse group of neurodevelopmental disorders.

Brain Diseases↗

PubMed2002

The dynamic approach to neurodevelopmental psychiatric disorders: use of fMRI combined with neuropsychology to elucidate the dynamics of psychiatric disorders, exemplified in ADHD and schizophrenia.

The paper discusses the application of fMRI in combination with neuropsychology to neurodevelopmental psychiatric disorders, exemplified on the case of attention deficit hyperactivity disorder (ADHD) in comparison with schizophrenia. The view is presented that ADHD, rather than being a compound of unrelated co-existing deficits, is a pervasive disorder of impulsiveness, which manifests at the motor, emotional, social and cognitive domain. Neuropsychology needs to refine the psychological measurements of these impulsivity symptoms and, in combination with fMRI, provide new insights into the interrelationship between brain and dysfunction and its bi-directional causalities. The suitability of the dynamic technique of functional MRI to assess the dynamic nature of developmental neuropsychiatric disorders is discussed. Brain activation can inform about strategy and compensatory mechanisms at a neuroanatomical level, which are not observable at a psychological level, providing insight into the underlying neurocognitive mechanisms of psychiatric disorders. Data are presented and discussed on opposing neurocognitive activation patterns for patients with ADHD and those with schizophrenia while performing a stop task. Comparisons between patient groups will be essential to address the specificity of neurocognitive mechanisms corresponding to specific neurodevelopmental psychiatric disorders.

Aging↗

PubMed2002

Amygdala or ventral hippocampal lesions at two early stages of life differentially affect open field behaviour later in life; an animal model of neurodevelopmental psychopathological disorders.

Psychiatric disorders like schizophrenia or autism are thought to result from disruption of the normal pattern of brain development. Abnormalities in the amygdaloid complex and hippocampus have been reported in these disorders. In the present study rats were lesioned in the amygdala or ventral hippocampus on day 7 of life (immature brain) or day 21 of life (almost mature brain) and open field behaviour was determined later in life before and after puberty. Lesioning on day 7 resulted in behavioural changes, interpreted as locomotor stereotypy and decreased anxiety in case of amygdala or hippocampus, respectively. These effects were more profoundly present after puberty. Lesioning on day 21 did not result in these behavioural changes, which subscribes to the importance of the stage of brain maturation on functional development. The results suggest that the behavioural changes in rats lesioned on day 7 may due to a malfunctioning of structures connected to the amygdala or ventral hippocampus. Brain lesions made on day 7 of life may serve as a potential model of psychopathological neurodevelopmental disorders.

Aging↗

PubMed2001

Schizophrenia, a neurodegenerative disorder with neurodevelopmental antecedents.

Schizophrenia is a devastating disorder that has been referred to as youth's greatest disabler. Although a number of hypotheses have been proposed in an attempt to explain the pathophysiology of schizophrenia no single theory seems to account for all facets of the disease. Each hypothesis explains some of the phenomena associated with schizophrenia and it is probable that many variables described in these hypotheses interact to produce a disorder characterized by heterogeneous symptomatology, progression and prognosis. Compelling evidence suggests that the primary disturbance is a neurodevelopmental abnormality, possibly resulting from a genetic defect(s), resulting in a predisposition to schizophrenia. Events later in life may then lead to the presentation of symptoms and a subsequent progression of the disease. Recent evidence suggests that the progressive course of schizophrenia is associated with ongoing neurodegenerative processes. Changes in brain derived neurotrophic factor (BDNF) may explain the various changes observed in schizophrenia.

Animals↗

PubMed2004

Chronic pain in individuals with previously undiagnosed autistic spectrum disorders.

UNLABELLED: The aim of this article is to heighten clinician awareness by describing 2 patients with signs and symptoms of a possible autistic disorder. Autistic spectrum disorders are neurodevelopmental disorders characterized by impairment in reciprocal social interaction skills or communication skills and/or by the presence of stereotyped behavior, interests, and activities. Pain can be the initial presenting symptom for individuals with a previously undiagnosed autistic spectrum disorder. Two case presentations show indicators, such as reported sensory abnormalities, impaired social behaviors, and unusual interests, that should lead the physician to consider a referral for further evaluation. An accurate diagnosis of autism or related disorder can lead to a greater understanding of the nature of the patient's pain, as well as to more appropriate and effective treatment strategies. In addition, such patients might benefit from therapeutic interventions to improve overall functioning and decrease distress and, consequently, to decrease pain and other symptoms. Finally, autism research might inform pain researchers on topics such as neurobiology, development, and treatment of chronic pain disorders. PERSPECTIVE: Pain experts might be underrecognizing signs and symptoms of autistic spectrum disorders (ASDs) in their patients. Clinical evaluation for ASDs should be considered in patients with specific unusual characteristics. Research on the topic of ASDs and pain is encouraged.

Adolescent↗

PubMed2005

Neuropsychiatric disorders at the presentation of type 2 diabetes mellitus in children.

OBJECTIVES: To estimate the frequency of neuropsychiatric disease (NPD) in an urban pediatric type 2 diabetes mellitus (T2DM) population, to compare demographic characteristics of affected patients with those unaffected with NPD, and to determine the frequency of psychotropic medication treatment. STUDY DESIGN: Retrospective chart review of patients with T2DM at the Children's Hospital of Philadelphia. RESULTS: Of 237 patients with T2DM, 46 (19.4%) were found to have NPD at the presentation of diabetes. Diagnoses by report included depression, attention-deficit hyperactivity disorder (ADHD), neurodevelopmental disorders, schizophrenia, and bipolar disorder. Those affected were 63% females and 37% males, with a mean age of 14.6 yr and body mass index (BMI) of 34.3 kg/m(2) at diagnosis of T2DM. Patients were 79% African American, 13% Caucasian, 4.3% Hispanic, and 4.3% Asian. There were no statistically significant differences in demographic characteristics or BMI between those affected and unaffected with NPD. Twenty-nine patients (63%) were on psychotropic medication and were prescribed 58 medications, most commonly mood stabilizers (n = 20) and atypical antipsychotics (n = 17). CONCLUSIONS: Our data reveal a high frequency of NPD among pediatric patients with T2DM at presentation to a tertiary care, urban medical center. Many affected patients are receiving psychotropic medication. These data have implications for screening regimens for pediatric populations at high risk for T2DM and for therapeutic interventions, including lifestyle measures.

Adolescent↗

PubMed1998

Clinical applications of neuroimaging in psychiatry.

New techniques are dramatically expanding current clinical applications of neuroimaging in neuropsychiatry. Neuroimaging research that examines brain structure and function relationships in neuropsychiatric disorders is also enhancing our understanding of the pathophysiology of neuropsychiatric illnesses such as dementia, focal CNS insult, schizophrenia, affective disorders, and neurodevelopmental disorders.

Brain↗

PubMed2003

Microbiology and immunology of autism spectrum disorders.

Both generic and environmental factors are likely to contribute to the pathogenesis of neurodevelopmental disorders. Even in heritable disorders of high penetrance, variability in timing of onset or severity of disease indicate a role for modifying principles. Investigation in animal models of the consequences of interactions between host response genes and microbes, toxins, and other environmental agents in a temporal context may elucidate the pathophysiology of a wide spectrum of chronic diseases. Here we review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline plans for translational research in animal models and prospective human birth cohorts.

Animals↗

PubMed1991

Growth increments in preterm low risk infants.

Thirty five surviving low risk vaginally born preterm infants were followed for four years. Weekly increments for weight, length and head circumference were obtained. The implications relating to growth velocity from gestational age, fetal acidosis and neurodevelopmental disorders as well as sex, feeding habits and mothers' educational level were studied. A significant difference for weight was found between infants with and without a neurodevelopmental disorder during the first 7 months. Infants with fetal acidosis (scalp pH less than 7.2) or a neurodevelopmental disorder have lower increments for weight and head circumference during the first 3 months than infants without fetal acidosis or a neurodevelopmental disorder, but they demonstrated the highest increments for weight between 3-7 months of age. Mean growth increments were high for infants of well educated mothers, but the growth increments for infants of less educated mothers did not differ from the total preterm group. Breastfed infants between birth and 3 months of age show high increments for weight. Boys have a better mean increment for weight than girls between birth and 3 months of age. The opposite was found for length. The group differences are not significant and too small for a definite statement, but they do reveal small differences during early infancy that may prove helpful in the management of infants at risk.

Body Weight↗

PubMedDate not supplied

Attention-deficit/hyperactivity disorder: a neurodevelopmental approach.

TOPIC: Attention-deficit/hyperactivity disorder is frequently overdiagnosed when a complete evaluation by a knowledgeable clinician is not undertaken. Because of the recent negative media campaign regarding psychostimulant medication, it becomes more imperative that a thorough and accurate evaluation be completed before starting children and adolescents on psychostimulant medications. PURPOSE: To describe the neurodevelopmental perspective in the assessment and treatment of ADHD. SOURCES: Published literature and clinical experience. CONCLUSION: It is useful in practice to conceptualize the developmental path of children with ADHD not as disordered but as delayed, and to build on each child's strengths. The neurodevelopmental approach provides the child psychiatric nurse a child-focused framework for assessment and development of individualized interventions.

Attention Deficit Disorder with Hyperactivity↗

PubMed2003

Attenuated stress responsiveness in an animal model for neurodevelopmental psychopathological disorders.

Day 7 amygdala-lesioned (D7 AMX) rats have been proposed as a model for neurodevelopmental psychopathological disorders such as schizophrenia. Patients with schizophrenia are sensitive to stress and show an impaired hypothalamic-pituitary-adrenal response to certain stressful stimuli. Therefore, we investigated neuroendocrine and behavioral stress responses in the D7 AMX lesion model. Plasma concentrations of ACTH, corticosterone, and catecholamines were measured in response to foot shock and novelty in D7 and D21 lesioned (AMX) and non-lesioned (SHAM) animals. Behavior was recorded and analyzed afterwards. D7 AMX rats, unlike other rats, had a reduced ACTH response to foot shock and showed less active behavior in response to novelty. Neurodevelopmental dysfunction of target structures of the amygdala is associated with disturbed endocrine and behavioral responses to stress. These data accord with the notion that the D7 amygdala-lesioned rat can function as a neurodevelopmental model with relevance to schizophrenia.

Adrenocorticotropic Hormone↗