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PubMedDate not supplied

Neurodevelopmental consequences of early exposure to phencyclidine and related drugs.

In the early development of the central nervous system, stimulation of N-methyl-D-aspartate (NMDA) receptors may be critical for neuronal cell survival and differentiation, as well as the establishment of neural networks resulting from "experience-dependent plasticity." The trophic influence of NMDA receptor stimulation may be present only during a certain critical period of development. There are, therefore, major concerns associated with the administration of noncompetitive NMDA receptor antagonists (such as MK-801 [dizocilpine]) as neuroprotective and anticonvulsant agents to pregnant women, neonates, infants, and young children. Several studies showing disruptive effects of noncompetitive NMDA receptor antagonists on normal neurobehavioral development are reviewed in this article. This research has important public health implications because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, is a frequently-abused drug that may disrupt brain development in utero when abused by pregnant women. The article also reviews studies of neonatal blockade of the NMDA receptor complex in animals; studies that may lead to useful models of human neurodevelopmental disorders. These models may even mimic the relevant neurodevelopmental aspects of at least some forms of schizophrenia, especially the early developmental disconnection of circuits between the hippocampus and frontal cortex.

Animals↗

PubMed1993

Some placental considerations related to neurodevelopmental and other disorders.

Many newborns who appear normal at birth later manifest substantial neurologic and other disease. Pathologists are able to explain some of that sad enigma. Placental pathology frequently reveals the pathogenesis of cerebral palsy, mental retardation, and other neurodevelopmental disorders. This requires recognition of gross placental abnormalities and insightful light microscopic examination. Chorioamnionitis is now proven to be the major cause of premature onset of labor and prematurity. There is important need for investigation of pathogenetic processes associated with ascending intrauterine infection. Major complications therein include bacterially mediated fetal hypoperfusion resulting from placental and umbilical vasocontraction. Placentas of 10% of newborns have villitis of unknown etiology. The importance of villitis is incompletely known. The fetus may discharge meconium on more than one occasion, particularly so when the fetus is postmature. Clinicians may not recognize that fetal discharge has occurred if the event occurred 4 days or more prior to delivery. Intra-amniotic meconium associated with oligohydramnios probably causes placental and umbilical vasocontraction. Meconium probably thus contributes to the pathogenesis of pulmonary vasoconstriction, persistent fetal circulation, necrotizing enterocolitis, and damage of the fetal brain, liver, and kidneys. Fetal hypoxia and asphyxia may be acutely or chronically acquired. Major placental lesions associated with neonatal asphyxia include chronic ischemic change, nucleated red blood cells, intravillous hemorrhages, intimal vascular fibrin cushions, meconium staining, and intervillous fibrin.

Brain Damage, Chronic↗

PubMed2005

Expressive and receptive vocabulary in children with Williams and Down syndromes.

BACKGROUND: Williams (WS) and Down syndromes (DS) are two genetic disorders that involve intellectual disability (ID) and have been extensively studied over the past decades because of the unique linguistic profiles they exhibit. Recent investigations seek to explore the fractionation of linguistic components within the cognitive system using genetically based neurodevelopmental disorders such as WS and DS and to identify different profiles of linguistic function in these two groups of individuals. METHOD: The 'expressive vocabulary', 'receptive vocabulary', 'word opposites' and 'word definitions' subtests (Level 1) of the Test of Word Knowledge (TOWK) were used to assess lexical skills in six children with WS and five children with DS. RESULTS: Our findings indicate that the two syndromes exhibit substantial differences on linguistic tasks with individuals with WS performing at a higher level compared to those with DS and producing atypical responses in word definitions. The pattern of errors for each syndrome is qualitatively different suggesting that their underlying linguistic mechanisms are distinctive even though ID is similar. CONCLUSIONS: This study supports the differential outcome of two chromosomal disorders with similar ID. It also argues in favour of the large within group variability of the two syndromes that is not related to mental age but rather to different underlying mechanisms supporting language. These findings are discussed in the light of the current evidence concerning linguistic knowledge of neurodevelopmental and genetic disorders.

Child↗

PubMed1998

Frontal lobe of children with schizophrenia spectrum disorders: a proton magnetic resonance spectroscopic study.

BACKGROUND: Schizophrenia is commonly considered a neurodevelopmental disorder. Our aim was to determine whether the proton magnetic resonance spectroscopic (1H-MRS) changes seen in adults with schizophrenia are displayed in children at risk for developing schizophrenia. METHODS: Children with symptoms of schizophrenia-spectrum disorders (n = 16; mean age = 132 months) and a comparison group (n = 12; mean age 130 months) took part in a 1H-MRS study of the left frontal lobe. Areas of peaks from N-acetylaspartate (NAA), choline (Cho), and creatine (Cre) were determined and ratios of NAA/Cre and Cho/Cre calculated and compared between groups. RESULTS: The mean ratio of NAA/Cre was significantly lower in schizophrenia-spectrum subjects than the comparison group (1.67 vs. 1.92; p < .05). Medication status did not affect results in schizophrenia-spectrum subjects. CONCLUSIONS: Our findings suggest that the metabolic changes associated with adult schizophrenia are observed in children with some or all of the symptoms of schizophrenia, supporting a neurodevelopmental theory for schizophrenia.

Antipsychotic Agents↗

PubMed2004

An analogue assessment of repetitive hand behaviours in girls and young women with Rett syndrome.

BACKGROUND: Rett syndrome is a neurodevelopmental disorder that almost exclusively affects females. In addition to neurodevelopmental regression and loss of hand skills, apraxia, deceleration of head growth, and increasing spasticity and scoliosis, a number of behavioural features are also seen, including stereotypic hand movements, hyperventilation and breath holding. The aim of the study was to investigate the extent to which analogue environmental conditions affected the frequency of repetitive hand behaviour in eight girls and young women with Rett syndrome. METHOD: The frequency of repetitive hand movements was observed every 10 s for four 4-min sessions under the following conditions: Continuous Adult Attention, Adult Demands, Stimulation and No Stimulation. RESULTS: The frequency of repetitive hand movements was high -- they occurred in above 60% of all intervals in all conditions for all participants and at nearly 100% for some participants in some conditions. For one participant the frequency of repetitive hand movements was somewhat reduced in the Stimulation condition; for another it was relatively increased in the No Stimulation condition. CONCLUSIONS: Overall, environmental manipulations had relatively limited effects on repetitive hand behaviours. Repetitive hand behaviour in Rett syndrome may be maintained by automatic reinforcement or neurochemical processes and may not be primarily influenced by contingent reinforcement.

Adolescent↗

PubMed2025

Discovery of a DNA methylation episignature as a molecular biomarker for fetal alcohol syndrome.

PURPOSE: Fetal alcohol spectrum disorder (FASD) encompasses a range of clinical features and neurodevelopmental disorders in children exposed to alcohol in utero. Despite its global public health significance, FASD diagnosis remains challenging because of nonspecific clinical findings and the lack of an accurate molecular diagnostic biomarker. This study aimed to evaluate peripheral blood DNA methylation (DNAm) profiles as a potential diagnostic biomarker for fetal alcohol syndrome. METHODS: Genomic DNAm profiles from 93 individuals with suspected or confirmed FAS, including a clinically diagnosed FAS subgroup, were analyzed and compared with a large database of control and patient cohorts with previously reported DNAm episignatures. Functional analysis of these DNAm profiles was performed to identify episignatures and assess their potential diagnostic utility. RESULTS: A relatively sensitive and specific DNAm episignature for FAS was identified. Comparative epigenomic analysis revealed functional correlations between FAS and other rare genetic disorders, supporting the robustness of the identified DNAm profiles as a diagnostic tool. CONCLUSION: This study demonstrates that unique DNAm profiles provide a robust episignature biomarker for FAS. These findings contribute to the molecular understanding of FAS and hold promise for improving diagnostic accuracy for this complex disorder.

Humans↗

PubMed2006

The immune response in autism: a new frontier for autism research.

Autism spectrum disorders (ASD) are part of a broad spectrum of neurodevelopmental disorders known as pervasive developmental disorders, which occur in childhood. They are characterized by impairments in social interaction, verbal and nonverbal communication and the presence of restricted and repetitive stereotyped behaviors. At the present time, the etiology of ASD is largely unknown, but genetic, environmental, immunological, and neurological factors are thought to play a role in the development of ASD. Recently, increasing research has focused on the connections between the immune system and the nervous system, including its possible role in the development of ASD. These neuroimmune interactions begin early during embryogenesis and persist throughout an individual's lifetime, with successful neurodevelopment contingent upon a normal balanced immune response. Immune aberrations consistent with a dysregulated immune response, which so far, have been reported in autistic children, include abnormal or skewed T helper cell type 1 (T(H)1)/T(H)2 cytokine profiles, decreased lymphocyte numbers, decreased T cell mitogen response, and the imbalance of serum immunoglobulin levels. In addition, autism has been linked with autoimmunity and an association with immune-based genes including human leukocyte antigen (HLA)-DRB1 and complement C4 alleles described. There is potential that such aberrant immune activity during vulnerable and critical periods of neurodevelopment could participate in the generation of neurological dysfunction characteristic of ASD. This review will examine the status of the research linking the immune response with ASD.

Animals↗

PubMed1990

The effects of cisapride on gastro-oesophageal reflux in children with and without neurological disorders.

Cisapride was used to treat gastro-oesophageal reflux in seven children with neurodevelopmental disorders and in 15 children who were neurologically normal. 24-hour lower-oesophageal pH monitoring was carried out before and after treatment. The neurologically normal group had a statistically significant decrease after treatment in percentage time pH less than 4, but children with neurological abnormalities did not have a comparable improvement in reflux scores.

Acetylcholine↗

PubMed2024

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Humans↗

PubMed2005

Leucodysplasia, microcephaly, cerebral malformation (LMC): a novel recessive disorder linked to 2p16.

We report three related and one unrelated child with an apparently novel neurodevelopmental disorder. The clinical course was very similar in all the four patients: congenital microcephaly with severe failure of post-natal brain growth, neonatal onset of intractable seizures associated with lack of developmental progression and death within the first 3 years of life. The appearance on cerebral neuroimaging was almost identical, with simplified gyration associated with a non-thickened cortex, severe hypoplasia of the corpus callosum, a small flattened brain stem, and specific cystic lesions in the white matter around the temporal and occipital horns. To our knowledge these patients represent a previously unreported, autosomal recessive syndrome. Homozygosity mapping in the consanguineous family has identified a candidate region on the chromosome 2p16.

Abnormalities, Multiple↗

PubMed2026

Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.

15q11-q13↗

PubMed2006

Migration abnormality in the left cingulate gyrus presenting with autistic disorder.

Autism, characterized by an impairment in communication, including language, narrowly focused interests, and poor sociability, is a neurodevelopmental disorder of still largely unknown pathogenesis. In children with autistic symptomatology, the most consistent functional or anatomic abnormalities are found in the cingulate gyrus, particularly in the anterior regions. Neuronal migration malformations caused by incomplete neuronal migration and characterized by loss of the normal gyral patterns in the cerebral hemispheres and prominent disorganization of the cerebral cortical cytoarchitecture are generally associated with profound neurologic deficits, epilepsy, and autism. In this report, we present a case with an isolated migration abnormality located in the anterior part of the left cingulate gyrus who was admitted with the complaints of epileptic seizures and autism. In addition, the role of the localization of the migration abnormality in the appearance of autistic symptomatology is discussed.

Autistic Disorder↗

PubMed1998

The Dutch famine and schizophrenia spectrum disorders.

In the Dutch Hunger Winter at the end of World War II a combination of circumstances created the conditions of a natural experiment. Unlike other famines, the Dutch famine struck at a precisely circumscribed time and place, and in a society able to document the timing and severity of the nutritional deprivation as well as the effects on fertility and health. Because the Dutch maintained comprehensive military and health records, it was possible to compare the incidence of neurodevelopmental disorders in adulthood for birth cohorts exposed versus those unexposed to prenatal famine. We have conducted several studies guided by the hypothesis that prenatal micronutrient deficiencies can cause neurodevelopmental schizophrenia or related personality disorders. In this paper we shall summarize our previous work and combine the outcome data of the different studies. Early prenatal famine was found to be specifically and robustly associated with each of three conditions: (1) congenital anomalies of the central nervous system, (2) schizophrenia, and (3) schizophrenia spectrum personality disorders. We found that the greatest increase in the risk of schizophrenia spectrum disorder- schizophrenia plus spectrum personality disorder- occurred among males born in the famine cities in December 1945 (relative risk = 2.7; 95% confidence interval = 1.5-5.1). Persons born in December 1945 were generally conceived at the absolute peak of the famine (March-April 1945). In the hope that the associations we have found may offer clues to the aetiology of schizophrenia, we are currently tracing and examining the cases of schizophrenia after prenatal exposure to famine.

Adult↗

PubMedDate not supplied

Rett syndrome.

Rett syndrome (RS) is a neurological disorder that mainly, and possibly exclusively, affects girls. After its description in 1966 by Andreas Rett in the Wiener Klinische Wochenschrift, awareness and interest in RS were enhanced by the 1983 report of Hagberg et al. in the Annals of Neurology. Diagnosis, and indeed the hypothesis that it exists, continue to be based upon a consistent constellation of clinical features observed in thousands of female patients world-wide. A diagnostic marker has not been identified. Notwithstanding this serious limitation, it is generally agreed that RS is a distinct entity and that it is genetically determined. Although it is associated with devastating loss of function between infancy and the fifth year of life, its course becomes relatively static thereafter, setting it apart from most of the genetic neurodegenerative disorders of childhood. Neuropathological and neurochemical studies call attention to RS as a neurodevelopmental disorder. Clarification of its pathogenesis may provide new insight into normal brain development. This report summarizes existing information and concepts about RS, and presents recent advances.

Age Distribution↗

PubMed1994

Programmed cell death: implications for neuropsychiatric disorders.

Programmed cell death, sometimes referred to as apoptosis, occurs through an active process requiring new gene transcription, in contrast to the passive cell death produced by metabolic toxins. Programmed cell death is an essential part of normal development, particularly in the nervous system. Spatial, temporal, or quantitative errors in the stimuli that initiate programmed cell death, or errors within the programmed cell death pathway itself, can result in an abnormal number of neurons and pathological neural development. Excesses and deficits in neuronal numbers have now been observed not only in typical neurodegenerative disorders such as Alzheimer's and Huntington's diseases, but also in several neurodevelopmental disorders, including schizophrenia and autism. Recent investigations into the mechanisms of cell death during C. elegans neurodevelopment thymocyte negative selection, and withdrawal of sympathetic ganglion cells trophic support provides intriguing clues to the etiology and pathophysiology of these neuropsychiatric disorders.

Apoptosis↗

PubMed1999

Supravalvular aortic stenosis, Williams syndrome and sudden death. A case report.

Supravalvular aortic stenosis (SVAS) is an uncommon but well characterized congenital narrowing of the ascending aorta above the level of the coronary arteries. It can be a familial disorder, can occur sporadically, or associated with Williams syndrome (WS) which is a neurodevelopmental disorder affecting connective tissue and the central nervous system. Sudden death is a well-known complication of non-syndromic SVAS but few cases have been reported associated with WS. We present a case of sudden death in a woman with the diagnosis of SVAS and WS since the age of 3 years who refused surgical correction and died at the age of 27 years. At autopsy, the aorta and pulmonary trunk were narrowed and the walls showed peculiar microscopical characteristics. In the cardiac conduction system the His bundle was small and intramyocardial. The incidence, pathology, pathogenesis and prognosis of both conditions (SVAS and WS) are reviewed.

Adult↗

PubMed2001

Case series: amantadine open-label treatment of impulsive and aggressive behavior in hospitalized children with developmental disabilities.

OBJECTIVE: A growing body of literature implicates interactions between glutamatergic and neostriatal dopaminergic neurotransmitter systems in the development and expression of impulsivity, hyperactivity, and stereotypy. Amantadine hydrochloride, a drug used in young children for influenza prophylaxis, acts both as an indirect dopamine agonist as well as an N-methyl-D-aspartate (NMDA) receptor antagonist. Thus an open clinical trial of this medication for the treatment of symptoms of impulse control disorders in children was performed. METHOD: A total of eight children (seven with neurodevelopmental disorders and all inpatients) with target behaviors refractory to other treatments were selected after parental informed consent. All patients were male and ranged in age from 4 to 12 years. Outcome was based on subjective consensus clinical ratings by the multidisciplinary treatment team. RESULTS: For four of the children, amantadine was associated with marked clinical improvement. In the remainder, improvement was also observed. Amantadine was well tolerated. CONCLUSIONS: On the basis of this experience, it appears that amantadine hydrochloride or related NMDA antagonists may warrant additional study in this and related populations.

Aggression↗

PubMed1997

Rett syndrome: natural history and underlying disease mechanisms.

Rett syndrome (RS) is a neurological disorder that mainly, and possibly exclusively, affects girls. Diagnosis continues to be based upon a consistent constellation of clinical features observed in all of the patients worldwide. A biological marker has not been identified. In spite of this serious limitation, it is generally agreed that RS is a distinct entity and that it is genetically determined. Although it is associated with loss of function between infancy and the fifth year of life, its course becomes relatively static thereafter, setting it apart from most of the genetic neurodegenerative disorders of childhood. Neuropathological and neurochemical studies call attention to RS as a neurodevelopmental disorder of infancy resulting in failed brain growth. Clarification of its pathogenesis may provide new insight into normal brain development.

Adolescent↗