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Results for “Neurodevelopmental Disorders”

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PubMed1999

An infection-based model of neurodevelopmental damage.

Perinatal exposure to infectious agents and toxins is linked to the pathogenesis of neuropsychiatric disorders, but the mechanisms by which environmental triggers interact with developing immune and neural elements to create neurodevelopmental disturbances are poorly understood. We describe a model for investigating disorders of central nervous system development based on neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus. Infection results in abnormal righting reflexes, hyperactivity, inhibition of open-field exploration, and stereotypic behaviors. Architecture is markedly disrupted in hippocampus and cerebellum, with reduction in granule and Purkinje cell numbers. Neurons are lost predominantly by apoptosis, as supported by increased mRNA levels for pro-apoptotic products (Fas, caspase-1), decreased mRNA levels for the anti-apoptotic bcl-x, and in situ labeling of fragmented DNA. Although inflammatory infiltrates are observed transiently in frontal cortex, glial activation (microgliosis > astrocytosis) is prominent throughout the brain and persists for several weeks in concert with increased levels of proinflammatory cytokine mRNAs (interleukins 1alpha, 1beta, and 6 and tumor necrosis factor alpha) and progressive hippocampal and cerebellar damage. The resemblance of these functional and neuropathologic abnormalities to human neurodevelopmental disorders suggests the utility of this model for defining cellular, biochemical, histologic, and functional outcomes of interactions of environmental influences with the developing central nervous system.

Animals↗

PubMed2001

Association between maternal pre-existing or gestational diabetes and health problems in children.

UNLABELLED: There is general consensus that children of women with pre-existing diabetes mellitus (PDM) have an increased risk of malformations and neurodevelopmental problems. Whether this is also true for children of women with gestational diabetes mellitus (GDM) is a matter of debate. This study investigated inpatient hospital care up to 10 y of age of children born to GDM and PDM women as a rough estimate of child morbidity. Hospital care of children born to 82,684 GDM women, 3,874 PDM women and 1,213,957 controls was compared by linking the Swedish Medical Birth Registry with the Hospital Discharge Registry. Similar comparisons were performed in a local well-controlled group of 326 children born to GDM women in the Lund area. Children of PDM women and to a lesser degree children of GDM women had a statistically significant increase in hospitalizations, evident at least up to 10 y of age. Significantly increased risks of hospitalization were found for neurological/developmental disorders [odds ratio (OR) 2.30 and 1.36 for PDM and GDM, respectively)], malformations (OR 2.05 and 1.23), infections (OR 1.56 and 1.20) and accidents (OR 1.32 and 1.14). CONCLUSION: The high hospitalization rates of these children indicate an increased morbidity, including neurodevelopmental disorders.

Child↗

PubMedDate not supplied

Seizure disorder as a risk factor for gastroesophageal reflux in children with neurodevelopmental disabilities.

The proportion of children with severe neurodevelopmental disabilities, in whom symptoms of gastroesophageal reflux develop after gastrostomy placement, has not been well studied. The medical records of children who received a gastrostomy tube (with or without a simultaneous antireflux procedure) at our institution between 1987 and 1997 were reviewed to identify neurologically related diagnoses at the time of the gastrostomy, diagnostic tests ordered to detect reflux, and dates and reasons for re-admissions within 2 years of discharge. Of 102 patients studied, 37 received a gastrostomy tube alone. Complete follow-up data were available for 30 of these patients, 7 of whom (23%) required subsequent antireflux surgery within 2 years. Patients with a seizure disorder had greater than a 4-fold risk of re-admission for this operation compared with other patients (57% [4/7] vs. 13% [3/23]; P=0.03). In a child with severe neurodevelopmental disability, the existence of a seizure disorder at the time of a gastrostomy operation increases the risk of subsequently requiring an antireflux procedure by a factor of 4.

Adolescent↗

PubMed2026

Persistent tic disorders are associated with 17q12 duplications.

Tourette Syndrome (TS) and Persistent Tic Disorder (PTD) are childhood-onset neuropsychiatric conditions with high heritability. Due to current sample size limitations, identifying TS/PTD risk genes has been challenging. This study addressed this issue by conducting a meta-analysis of microarray copy number variant (CNV) studies from three TS/PTD genomics consortia, supplemented with new data from 3291 cases. This approach more than doubled the sample size of previous TS/PTD CNV studies, with CNV calls generated from 5725 TS/PTD cases and 10,982 matched controls. The results confirmed that TS/PTD cases 1) have a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes (OR = 1.68, P = 9.3×10-5) and 2) are more likely to carry established neurodevelopmental CNVs (OR = 1.42, P = 3.9×10-2) compared to controls. Additionally, a novel, genome-wide significant CNV locus for TS/PTD was discovered, involving duplications at 17q12 (hg19 chr17:34.8 - 36.2 Mb). This locus is associated with a known duplication syndrome associated with variable neuropsychiatric traits, but has not been previously linked to tic disorders. Eight cases and one control carried the canonical ~1.4 Mb duplication at chr17:34.8-36.2 Mb, while one additional case had a smaller 110 kb duplication within this known CNV that included only one gene, ACACA (acetyl-CoA carboxylase, OR = 26.7, P = 5.69×10-7). Overall, this study provides further evidence that rare, genic CNVs play a substantial role in the genetic architecture of TS/PTD and identifies a new genome-wide significant association with this neurodevelopmental disorder.

Journal Article↗

PubMed2000

The internal and external boundaries of obsessive-compulsive disorder.

OBJECTIVE: This study aims to explore the internal and external boundaries of obsessive-compulsive disorder (OCD). METHOD: Selected literature is reviewed. RESULTS: Prevalence and incidence estimates for OCD vary markedly according to diagnostic criteria applied. External boundaries of the disorder are permeable, with a large degree of overlap with other psychiatric disorders, and an association with certain neurological disorders. Some cases of OCD appear to have a neurodevelopmental origin. CONCLUSIONS: Further delineation of disorders characterised by obsessional and compulsive symptoms can inform models of aetiology, pathophysiology and treatment.

Humans↗

PubMed1998

Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan.

In Japan, urea cycle disorders (UCDs) are one of the most frequent inborn errors of metabolism, estimated to have a prevalence of 1 per 50,000 live births. In an attempt to develop more effective treatment and enhance the quality of life, we investigated the clinical manifestations and prognosis of 216 patients with UCDs diagnosed and treated between 1978 and 1995. These included 92 cases of neonatal-onset UCD and 116 of late-onset UCD. Two cases of ornithine transcarbamylase (OTC) deficiency in males and 2 cases of argininosuccinase (AL) deficiency were diagnosed prospectively. By far the most common disorder was OTC deficiency, accounting for 2/3 of all cases. At the end of 1995, the 5-year survival rate was 22% for the neonatal-onset type and 41% for the late-onset type. Among the 20 long-term survivors with neonatal-onset UCD, 18 (90%) had moderate to severe neurodevelopmental deficits; this contrasts with 13 of 47 (28%) survivors with the late-onset type. In analysing 108 UCD cases, peak blood ammonia level during the first hyperammonaemic attack was correlated with neurodevelopmental outcome. When the concentration of blood ammonia was less than 180 mumol/L (5 times normal), there was no severe neurological damage. When the concentration of blood ammonia exceeded 350 mumol/L (10 times normal) at the first hyperammonaemic attack, the patients died or had severe neurological deficits. Our data point to the importance of early diagnosis and aggressive treatment.

Age of Onset↗

PubMed1996

Minor physical anomalies and their relationship to the aetiology of schizophrenia.

BACKGROUND: Previous reports have suggested an increased prevalence of minor physical anomalies (MPAs) in schizophrenia. METHOD: A review of the literature was performed to examine the relationship between MPAs, schizophrenia and other disorders. RESULTS: Previous studies demonstrate a number of methodological shortcomings. Moreover, MPAs are found in several other psychiatric disorders. Proponents of the neurodevelopmental model of schizophrenia have focused on an environmental explanation for the increased prevalence of MPAs. We argue that this may be overly simplistic and propose various ways in which genetic factors may also be involved. CONCLUSIONS: Better studies should be performed to examine more precisely the nature of MPAs in schizophrenia and other disorders and also the relationship between MPAs and other developmental abnormalities. At present, it is unclear if MPAs are directly related to the pathogenesis of the disorder or even if they are related to the timing of critical events.

Adult↗

PubMed2004

Neurodevelopment and endocrine disruption.

In this article I explore the possibility that contaminants contribute to the increasing prevalence of attention deficit hyperactivity disorder, autism, and associated neurodevelopmental and behavioral problems in developed countries. I discuss the exquisite sensitivity of the embryo and fetus to thyroid disturbance and provide evidence of human in utero exposure to contaminants that can interfere with the thyroid. Because it may never be possible to link prenatal exposure to a specific chemical with neurodevelopmental damage in humans, I also present alternate models where associations have been made between exposure to specific chemicals or chemical classes and developmental difficulties in laboratory animals, wildlife, and humans.

Adult↗

PubMed2026

Untargeted metabolomics and proteomics reveals cocoa-mediated mitigation of valproic acid-induced dysregulation in a zebrafish model of autism: pilot study.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by behavioral impairments and limited therapeutic options. Emerging evidence suggests that plant-derived polyphenols may offer neuroprotective benefits. OBJECTIVES: This pilot study aimed to investigate the therapeutic potential of polyphenol-rich cocoa extract in a valproic acid (VPA)-induced zebrafish model of ASD. METHODS: Zebrafish were exposed to 3 μM VPA, cocoa powder providing 2.5 μM (-)-epicatechin, a combination of both, or left untreated. Behavioral phenotyping was conducted using DanioVision and gut morphology was assessed. Untargeted metabolomic and proteomic profiling was performed followed by univariate and multivariate analyses. RESULTS: VPA exposure induced ASD-like behavioral hyperactivity, and severe gastrointestinal abnormalities. Cocoa co-treatment ameliorated both behavioral performance and gut architecture. Metabolomic profiling revealed VPA-associated disruptions in neurotransmission, methylation, mitochondrial function and redox homeostasis. Proteomic profiling showed elevated levels of trafficking protein particle complex subunit 11, proteasomal ubiquitin receptor, betaine-homocysteine S-methyltransferase 1 (BHMT-1), and desmoplakin-A, consistent with genotoxic stress and impaired protein trafficking. Cocoa co-treatment normalized BHMT-1 and desmoplakin-A expression and mitigated broader metabolic dysregulation. CONCLUSION: Collectively, these results suggest that polyphenol-rich cocoa may represent a promising multi-targeted nutraceutical approach for mitigating ASD-related neurodevelopmental and metabolic disturbances.

Animals↗

PubMed1992

Abnormalities of cerebral structure in schizophrenia on magnetic resonance imaging: interpretation in relation to the neurodevelopmental hypothesis.

The nature of abnormalities of cerebral structure evident in schizophrenia on magnetic resonance imaging is considered in relation to the neurodevelopmental hypothesis of the disorder. While schizophrenic patients showed increased ventricular volume, the extent of increase with age was comparable with that evident in controls and was unrelated to duration of illness. Conversely, cortical atrophy was evident only in patients, and this increased markedly with age and duration of illness. Such findings could be suggestive of two distinct pathophysiological processes in schizophrenia, but a schema for their reconciliation with the neurodevelopmental hypothesis is elaborated.

Adult↗

PubMed2026

Beyond Rett syndrome: a case series expanding the neurological spectrum associated with pathogenic MECP2 variants.

BACKGROUND: Although pathogenic variants in MECP2 are classically associated with Rett syndrome (RTT), increasing evidence suggests that they can underlie a broader spectrum of neurological phenotypes. Clinical manifestations may vary according to sex, variant type, residual protein function, and pattern of X-chromosome inactivation. METHODS: We describe five unrelated individuals carrying pathogenic MECP2 variants identified through multiplex ligation-dependent probe amplification, chromosomal microarray analysis, and next-generation sequencing. Clinical, neuroradiological, neurophysiological, and molecular findings were retrospectively reviewed. RESULTS: Two unrelated girls carrying large de novo Xq28 deletions encompassing the entire MECP2 locus presented with mild neurodevelopmental impairment and epilepsy, but no developmental regression or classic RTT features. Both girls showed borderline cognitive functioning and normal brain MRI. A 9-year-old boy carrying a maternally inherited MECP2 frameshift variant presented with intellectual disability, autism spectrum disorder, and focal epilepsy, whereas carriers in his family exhibited milder neuropsychiatric manifestations. A 44-year-old man carrying a MECP2 missense variant presented with an early-onset spastic-ataxic syndrome, peripheral neuropathy, and cerebellar dysfunction, while a 16-year-old girl patient carrying a distinct de novo MECP2 missense variant displayed isolated mild motor incoordination and subtle cerebellar signs with preserved cognitive functioning. CONCLUSIONS: Our findings expand the evidence that pathogenic MECP2 variants can produce neurological phenotypes distinct from classic RTT, including mild neurodevelopmental impairment without regression, and predominantly cerebellar or spastic-ataxic manifestations associated with limited cognitive involvement. Allelic heterogeneity seems to correlate with clinical phenotypes, at least in our small cohort. In conjunction with established diagnostic criteria, these observations support testing MECP2 in a selection of atypical neurodevelopmental and movement disorder presentations.

Humans↗

PubMed1994

Two-year infant neurodevelopmental outcome after expectant management and indicated preterm delivery in hypertensive pregnancies.

BACKGROUND: To evaluate the impact of the expectant management of hypertensive disorders of pregnancy on infant neurodevelopmental outcome. METHODS: The two-year neurodevelopmental outcome of infants delivered prematurely because of complications of maternal hypertension after expectant management was compared with that of infants of uncomplicated age-matched pregnancies delivered after spontaneous preterm labor or premature rupture of membranes. RESULTS: The rate of cerebral palsy was similar between the two groups. Conditional logistic regression analysis of the matched sets showed an increased risk of minor neurodevelopmental impairment among infants delivered after severe hypertension (odds ratio (OR) = 4.0, 95% confidence interval (CI) 1.34-12.1) or preeclampsia (OR = 4.0, 95% CI = 1.61-10.2). Fetal growth retardation was not associated with increasing infant neurodevelopmental morbidity. CONCLUSIONS: Infants delivered prematurely because of preeclampsia or severe hypertension are at increased risk of later minor neurodevelopmental problems.

Cerebral Palsy↗

PubMed2002

The neurodevelopmental impact of childhood onset temporal lobe epilepsy on brain structure and function and the risk of progressive cognitive effects.

The purpose of this study is to explore the possibility of progressive neuropsychological decline in chronic temporal lobe epilepsy (TLE) and determine how this vulnerability may be associated with the neurodevelopmental impact of the disorder. 53 patients with TLE and 62 healthy controls underwent quantitative MRI volumetric imaging of total brain tissue and hippocampal volumes as well as assessment of intelligence and memory function. In addition to reduced hippocampal volume, childhood onset (< 14 years) but not adult onset TLE was associated with significantly reduced total brain tissue that was generalized in nature and extended into extratemporal regions. In addition to this adverse impact on brain structure, there was significantly reduced intellectual status as well as memory function in childhood onset TLE patients, consistent with the generalized nature of the MRI volumetric abnormalities. Finally, cross-sectional correlational analyses indicated that increasing duration of epilepsy in childhood onset patients was associated with declining performance across both intellectual and memory measures, suggestive of progressive cognitive effects. We propose that childhood onset TLE is associated with an adverse neurodevelopmental impact on brain structure and function which represents an early acquired vulnerability, effectively reducing cerebral reserve, placing patients at risk for progressive cognitive decline in the context of chronic and unremitting epilepsy.

Age of Onset↗

PubMed2005

Developing predictive animal models and establishing a preclinical trials network for assessing treatment effects on cognition in schizophrenia.

Animal models are an essential initial phase in the discovery of novel drugs to treat psychiatric disorders. At the sixth Measurement and Treatment Research to Improve Cognition in Schizophrenia conference, "New Approaches to Assessing and Improving Cognition in Schizophrenia," a discussion group was formed to address issues related to the development of predictive animal models of cognition that may be used as preclinical assays for putative cognitive enhancers. We identified 2 complementary approaches used to model cognitive impairments in animals. First, basic lesion/pharmacological models provide information about the particular neural substrates that may underlie different types of cognitive deficits found in schizophrenia. Findings from these studies can be mapped onto the second, more elaborate and etiologically relevant neurodevelopmental models of the disorder to ascertain which cognitive systems may be altered by early developmental insults. Particular attention must be given to the types of animal tasks used, in order to relate directly to the cognitive domains that are affected in schizophrenia patients. Importantly, the validation and standardization of the methodologies used in these preclinical assays would require the establishment of a preclinical trials network, serving as a counterpart to the recently established Treatment Units for Research on Neurocognition and Schizophrenia. The need to validate specific approaches to assess cognitive functions relevant to schizophrenia could be satisfied by a concerted effort enabled by a new funding directive from the National Institute of Mental Health with the explicit purpose of facilitating research on these models and assessing novel drug therapies that may be used to ameliorate the cognitive deficits in schizophrenia.

Animals↗

PubMed2026

Mendelian disorders of the epigenetic machinery: a decade of insights into the molecular basis.

The Mendelian disorders of the Epigenetic Machinery (MDEMs), or Chromatinopathies, are now understood to be a collectively common cause of childhood neurodevelopmental delays and intellectual disability. In the past decade, the chromatin and gene expression consequences of heterozygous chromatin regulator disruption have been investigated in various disease models, yielding insights into the molecular pathogenesis of MDEMs. In this review, we highlight some of these results - drawing upon studies of representative MDEMs - together with potential unifying concepts. We propose that MDEMs are characterized by distributed, often subtle chromatin and gene expression perturbations, which impact diverse cellular pathways and processes and are frequently shared between distinct disorders. In this sense, they occupy an intermediate space between classical monogenic disorders and complex traits. We propose potential explanations for the variable expressivity in MDEMs and conclude by considering how technological advances can now enable a deeper and more precise mechanistic characterization of this important Mendelian disease group.

Humans↗

PubMed2002

Does schizophrenia result from developmental or degenerative processes?

The debate as to whether schizophrenia is a neurodevelopmental or a neurodegenerative disorder has its roots in the latter part of the 19th century when authorities such as Clouston (1891) posited that at least some insanities were "developmental" in origin. These views were soon eclipsed by Kraepelin's (1896) concept of dementia praecox as a degenerative disease, and the latter view carried not only the day but also much of the 20th century. Then, in the 1980s several research groups again began to speculate that schizophrenia might have a significant developmental component (Feinberg, 1982-1983; Schulsinger et al., 1984; Murray et al., 1985; Murray and Lewis, 1987; Weinberger et al., 1987). What became known as the "neurodevelopmental hypothesis" received support from neuropathological studies implicating anomalies in early brain development such as aberrant migration of neurons. Unfortunately, these studies proved difficult, if not impossible, to replicate (Harrison, 1999). The pendulum, therefore, began to swing again, and in the latter part of the 1990s came renewed claims that the clinical progression of the illness was accompanied by continued cerebral ventricular enlargement and reduction in the volumes of certain brain structures. Nevertheless, since few doubt that there is a developmental component to schizophrenia, the question which we will address in this paper is whether schizophrenia is a) simply the final consequence of a cascade of increasing developmental deviance (Bramon et al., 2001), or b) whether there is an additional brain degeneration following onset of psychosis which is superimposed on the developmental impairment (Lieberman, 1999).

Brain↗

PubMed2002

Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2).

BACKGROUND: This study evaluated differences in caudate volumes in subjects with velo-cardio-facial syndrome due to a 22q11.2 (22qDS) deletion. Because psychosis is observed in 30% of adult subjects with 22qDS, this neurogenetic disorder could represent a putative model for a genetically mediated subtype of schizophrenia. METHODS: Caudate volumes were measured on high-resolution magnetic resonance images in 30 children and adolescents with 22qDS and 30 gender- and age-matched normal comparison subjects. RESULTS: Caudate head volumes were increased in the 22qDS group independent of neuroleptic medications. Subjects with 22qDS also displayed an abnormal pattern of asymmetry in the anterior caudate, with left side greater than right. CONCLUSIONS: Alterations in the basal ganglia circuitry have been implicated in learning, cognitive, and behavioral problems in children and therefore could be involved in the expression of the neurobehavioral phenotype expressed by subjects with 22qDS. Abnormal caudate volume is a neurodevelopmental feature shared with schizophrenia, further establishing 22qDS as a potential neurodevelopmental model for this disorder.

Adolescent↗

PubMedDate not supplied

[Is the developmental model accurate for all psychiatric disorders?].

In the 1980's a neurodevelopmental hypothesis of schizophrenia was proposed. Since that time, the role of early developmental age as a risk period for action of etiological factors in psychosis was confirmed. Additionally, many disturbances of pre-schizophrenic persons in the developmental age were demonstrated. Recently published longitudinal cohort studies indicate that majority of the psychiatric disorders other than schizophrenia are preceded by occurrence of psychiatric disorders in childhood and early adolescence. Moreover, in numerous studies of adult anxiety and mood disorders, the role of early risk factors was observed and temperament, neurophysiological and psychopathological disturbances in early age were reported. The resulting developmental model of psychiatric disorders may help in the understanding of their pathogenesis. Subsequently, detection and treatment of early life disturbances may hypothetically prevent severe psychopathological symptoms in adulthood.

Adult↗