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PubMed2026

Maternal immune activation perturbs the brain epitranscriptome.

Maternal immune activation (MIA) results in abnormal fetal neurodevelopment and an increased risk of neurodevelopmental disorders. Altered RNA translation has been implicated in the pathophysiology of MIA-associated neurodevelopmental deficits, but more precise mechanisms underlying disruption in RNA metabolism are lacking. Here, we characterize key components of the RNA epitranscriptomic machinery, which refers to the set of reversible chemical modifications on RNA molecules that influence RNA function, including translation, stability, splicing, and localization. Using spatial transcriptomics, we define cell type- and brain region-specific distribution of epitranscriptome regulators in the developing mouse brain. We also use direct RNA sequencing to define how MIA changes the brain epitranscriptome landscape. We identify the demethylase FTO as being notably perturbed in the context of MIA. Using pharmacological and genetic approaches, we target FTO to ameliorate behavioral phenotypes in MIA offspring. In total, this work expands upon mechanisms of translational misregulation in MIA and identifies new targets for therapeutic manipulation.

Animals↗

PubMed1995

Gene therapy and the brain.

In this article we describe the application of the emerging concepts of gene therapy to 4 different neurologic disorders. The first of these is Lesch-Nyhan disease, a genetically-determined neurodevelopmental disorder caused by a defect in the gene which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Two additional disorders, Parkinsonism and Alzheimer's disease, are both neurodegenerative diseases of unknown etiology which affect the elderly. The final disorder involves malignant brain tumors. In each of these disorders, basic research with in vitro systems and animal models has suggested that the tools of gene transfer may provide a novel and potentially effective treatment strategy.

Alzheimer Disease↗

PubMed1998

Neurodevelopmental Pathways in Schizophrenia.

We examined early-onset schizophrenia as a neurodevelopmental disorder. These data are from a 2-year longitudinal prospective study of youth with psychotic disorders. Standardized diagnostic and neuropsychological assessments include: Structured Clinical Interview for Diagnostic and Statistical Manual (DSM)-IV; Diagnostic Interview for Children and Adolescents, Revised; Premorbid Adjustment Scale; Wechsler Intelligence Scale for Children-III; the Wisconsin Card Sorting Test (WCST), and the California Verbal Learning Test. Pertinent family and developmental history are obtained via parent interviews and chart review. Forty-eight subjects have been recruited to date; 17 with schizophrenia, 13 with bipolar disorder, 10 with psychosis nos, seven with schizoaffective disorder, and one with an organic psychosis. Subjects with schizophrenia had higher ratings of premorbid social withdrawal and dysfunctional peer relationships. All groups had high rates of cognitive impairment, prenatal/perinatal complications, and comorbid psychiatric disorders. Homotypic family psychiatric history was associated with diagnosis in youth. Our data are consistent with a neurodevelopmental model, whereby specific genetic/neurological risk factors and nonspecific biologic/environmental modulating factors interact in the development of schizophrenia and other psychotic disorders.

Journal Article↗

PubMed2026

Recognizing genetic association between Lhermitte-Duclos Disease and Autism Spectrum Disorder in PTEN-related patients: a case report and literature comprehension.

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare autosomal dominant disorder that increases the risk of various tumors and systemic malignancies, including Lhermitte-Duclos disease (LDD), known as dysplastic cerebellar gangliocytoma. Both conditions result from a PTEN gene mutation, which disrupts cellular growth and proliferation. Some children with such a mutation exhibit developmental delay or autism spectrum disorder (ASD), associated with PHTS. Herein, we report on a mother with LDD/PHTS and her child with ASD, discuss screening, genetic counseling, and management of PHTS-affected, PTEN-related, family-connected patients, and provide a narrative literature review. METHODS: Clinical and diagnostic evaluation and genetic analysis were performed on a female patient with LDD/PHTS and on her 14-year-old daughter, diagnosed with ASD. Genomic DNA was extracted from the peripheral blood of both, using a commercial DNA isolation kit to detect a PTEN mutation. RESULTS: Ten-year follow-up of the LDD/PHTS patient showed no evidence of tumor recurrence after partial tumor resection, resulting in full neurological recovery. Genetic testing of both the mother and her child confirmed the same genetic variant-PTEN c.370 T > C p.(Cys124Arg), NM_000314.8, in heterozygous status-classified as pathogenic for PHTS. CONCLUSIONS: This paper highlights the importance of timely diagnosis of PHTS in an ASD-affected child after identifying a parent with LDD/PHTS, a disorder with significant implications linked to a PTEN mutation. Given the risk of malignancy and neurodevelopmental disorders associated with PTEN mutation, patients suspected of having LDD/PHTS and children with ASD should undergo regular screening for PTEN-related diseases and receive appropriate genetic counseling.

Humans↗

PubMed2004

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues.

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation.

Animals↗

PubMed2006

White matter proton MR spectroscopy in children with isolated developmental delay: does it mean delayed myelination?

RATIONALE AND OBJECTIVES: Isolated developmental delay (IDD) is a common disorder in preschool and school-age children. Conventional magnetic resonance imaging (MRI) usually does not disclose abnormalities, but a myelination delay is suspected as causative or associated factor. N-acetyl-aspartate is a surrogate marker of neuronal integrity but also of axonal integrity. The goal of our study is to determine whether magnetic resonance spectroscopy (MRS) is able to detect alterations in the white matter supporting the hypothesis of delayed myelination in children with IDD and normal MRI. MATERIALS AND METHODS: In this cross-sectional study, we enrolled 12 consecutive children meeting the criteria if IDD and aged between 3 and 12 years (mean 7.25 years) and 11 healthy children as control group (mean age 7.18, range 3-12 years) on whom we performed conventional MRI and MRS. We did not include children with abnormal MRI. Single voxel (8 cm(3)) was placed in the white matter of the left centrum semiovale. The mode of acquisition was probe-p (PRESS technique) with a TR of 2500 milliseconds and a TE of 30 milliseconds. We measured the metabolite concentration of n-acetyl-aspartate (NAA), choline (Ch), creatine (Cr) y myo-inositol (mI), and ratios of NAA, Ch, and mI to creatine. RESULTS: In children with IDD, we found a significant decrease of the following ratios: NAA/Cr (P < .016), NAA/Ch (P < .026), and NAA/mI (P < .023) in relation to controls. The mean NAA/Cr ratio in IDD children was 1.92 (SD 0.14), and in controls it was 2.09 (SD 0.14); t = 2.62, fd (freedom degrees) = 21, P < .016. No differences were seen in the remaining ratios. CONCLUSIONS: The lower NAA/Cr ratio in children with IDD in relation to controls may be a promising marker of this disorder and supports the hypothesis of delayed myelination. MRS can provide important information in children with neurodevelopmental disorders.

Aspartic Acid↗

PubMed2001

Schizophrenia: a review, with emphasis on the neurodevelopmental hypothesis.

The neurodevelopmental hypothesis of schizophrenia has gained increasing acceptance. This hypothesis assumes a disruption in the normal development of the brain, secondary to genetic factors, environmental factors, or, most likely, a combination of both. After a brief review of the various aetiologic models since the first description of the disease, we review relevant aspects of normal brain development and then focus on the pathologic findings supporting the neurodevelopmental hypothesis. Although this hypothesis of schizophrenia appears to be valid in some cases, it is important to keep in mind that there are many cases of schizophrenia in which one finds no documented brain abnormality. It therefore seems wrong to speak of schizophrenia in general as a neurodevelopmental disorder. It appears that there is a group of patients with schizophrenia who fit into a neurodevelopmental model. There is a need to further investigate whether these patients can be identified clinically and what this may imply with regard to treatment and prognosis.

Brain↗

PubMedDate not supplied

Pharmacotherapeutic trials in adolescent alcohol use disorders: opportunities and challenges.

Medications as adjuncts to psychosocial treatments for adolescent alcohol use disorders hold the promise of improved efficacy over psychosocial treatments alone. Specific components should be included in the design and implementation of these medication studies. Included should be assessment of the developmental risks of the chosen medication, consideration of short-term effects on the clinical disorder, factors affecting compliance and retention, age-specific pharmacokinetics, and systematic safety monitoring. A risk-benefit analysis should be conducted on the potential benefits of the medication to decrease alcohol use versus the potential long-term effects of medication use on brain development. To select clinically meaningful subtypes of adolescents with alcohol use disorders for medication trials, classification systems should be derived from multi-factorial models of complex neurodevelopmental disorders. Multi-factorial models will be required to select samples wherein specific gene-gene and gene-environment interactions predict medication treatment response. In samples of adolescents with alcohol use disorders, clinically meaningful subtypes are likely to have differential medication treatment response as a function of age of onset, family history of disorder, and comorbid psychopathology. Findings from preclinical and treatment studies in adults, along with pilot treatment findings in adolescents, suggest that particular serotonergic agents, opioid antagonists, and agents that modulate excitatory amino acids and GABAergic transmission might be effective. Future medication trials for adolescents with alcohol use disorders should use specific combinations of medications, based on specific hypotheses involving key neurotransmitter systems that putatively modulate treatment response. Combinations of medications may have additive effects on particular neurotransmitter systems or synergistic effects across two or more neurotransmitter systems, to further decrease alcohol consumption when compared with single-agent treatment.

Alcoholism↗

PubMed2004

Gene-environment interactions in mental disorders.

Research clearly shows that both nature and nurture play important roles in the genesis of psychopathology. In this paper, we focus on 'gene-environment interaction' in mental disorders, using genetic control of sensitivity to the environment as our definition of that term. We begin with an examination of methodological issues involving gene-environment interactions, with examples concerning psychiatric and neurological conditions. Then we review the interactions in psychiatric disorders using twin, adoption and association designs. Finally, we consider gene-environment interactions in selected neurodevelopmental disorders (autism and schizophrenia).

Journal Article↗

PubMed2000

Outcome measures in pediatric neurology: why do we need them?

Outcome measures should include the patient's values and preferences (from the patient's perspective) in addition to performance ratings and physiologic states. Outcome measures can assess relationships between services and interventions and their end results, can clarify which therapies are worth providing and which therapies need more evidence about their effectiveness, and can measure the burdens of different disorders and interventions. Researchers recently have shown the feasibility of creating and using outcome measures for children with neurodevelopmental disorders. Clinicians may wish to familiarize themselves with the concepts of outcome measures and health-related quality of life in order to understand the rationale, utility, properties, and various types of outcome measures in order to select the most appropriate instruments that will best serve their patient populations. Ongoing research efforts are currently using such measures in children with central nervous system tumors, with neural tube defects, and of extremely low birthweight; in childhood and adolescent epilepsy; and in adolescents with headaches.

Brain Neoplasms↗

PubMed2006

Attention deficit hyperactivity disorder, tics and Tourette's syndrome: the relationship and treatment implications. A commentary.

Tourette's Syndrome (TS) is now recognised to be a common childhood onset neurodevelopmental disorder. Attention deficit hyperactivity disorder (ADHD) is also a common childhood disorder. There are many cases in which the two disorders are comorbid. The reasons for this are unclear, but the comorbidity does not necessarily point to one genetic cause. Sleep is also often disturbed in individuals with TS and ADHD. The treatment implications of ADHD in the setting of tics or TS are important. Clonidine is suggested as a first line treatment. It was once thought that stimulants were contraindicated in the treatment of ADHD in the setting of TS, whereas it is suggested that they may be safe, but should be used judiciously. In addition, it was once thought that the combination of stimulants and clonidine was contraindicated, but from a large study the combination does appear to be safe. A relatively new medication for ADHD is atomoxetine, and although not documented widely in the setting of tics and TS, it may prove useful in this setting; further research is required. This commentary briefly discusses the comorbidity between TS and ADHD and offers treatment suggestions.

Adrenergic Uptake Inhibitors↗

PubMed2001

Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology.

BACKGROUND: Twin studies demonstrate the importance of genes and environment in the aetiology of childhood psychiatric and neurodevelopmental disorders. Advances in molecular genetics enable the identification of genes involved in complex disorders and enable the study of molecular mechanisms and gene--environment interactions. AIMS: To review the role of molecular genetics studies in childhood behavioural and developmental traits. METHOD: Molecular approaches to complex disorders are reviewed, with examples from autism, reading disability and attention-deficit hyperactivity disorder (ADHD). RESULTS: The most robust finding in ADHD is the association of a variable number tandem repeat polymorphism in exon 3 of the DRD4 gene. Other replicated associations with ADHD are outlined in the text. In autism, there is a replicated linkage finding on chromosome 7. Linkage studies in reading disability have confirmed a locus on chromosome 6 and strongly suggest one on chromosome 15. CONCLUSIONS: In the next 5--0 years susceptibility genes for these disorders will be established. Describing their relationship to biological and behavioural function will be a far greater challenge.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at approximately 2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and approximately 30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.

Animals↗

PubMed2002

Effects of genetic background on neonatal Borna disease virus infection-induced neurodevelopmental damage. I. Brain pathology and behavioral deficits.

The pathogenic mechanisms of gene-environment interactions determining variability of human neurodevelopmental disorders remain unclear. In the two consecutive papers, we used the neonatal Borna disease virus (BDV) infection rat model of neurodevelopmental damage to evaluate brain pathology, monoamine alterations, behavioral deficits, and responses to pharmacological treatments in two inbred rat strains, Lewis and Fisher344. The first paper reports that despite comparable virus replication and distribution in the brain of both rat strains, neonatal BDV infection produced significantly greater thinning of the neocortex in BDV-infected Fisher344 rats compared to BDV-infected Lewis rats, while no strain-related differences were found in BDV-induced granule cell loss in the dentate gyrus of the hippocampus and cerebellar hypoplasia. Unlike BDV-infected Lewis rats, more severe BDV-induced brain pathology in Fisher344 rats was associated with (1) greater locomotor activity to novelty and (2) impairment of habituation and prepulse inhibition of the acoustic startle response. The present data demonstrate that the same environmental insult can produce differential neuroanatomical and behavioral abnormalities in genetically different inbred rat strains.

Acoustic Stimulation↗

PubMed1991

Pre-morbid adjustment and personality in psychosis. Effects of sex and diagnosis.

Pre-morbid schizoid and schizotypal traits and social adjustment were assessed blind to diagnosis by interviewing the mothers of 73 consecutively admitted patients with DSM-III schizophrenia or affective psychosis. Analysis of factors associated with pre-morbid deficits showed a highly significant interaction of diagnosis with sex, such that schizophrenic men showed much greater pre-morbid impairment than either schizophrenic women or men with affective disorder. Poor pre-morbid adjustment predicted an early age at first admission. The results can be explained by a neurodevelopmental disorder in some schizophrenic males.

Adolescent↗

PubMed2006

Development of multi-agency referral pathways for attention-deficit hyperactivity disorder, developmental coordination disorder and autistic spectrum disorders: reflections on the process and suggestions for new ways of working.

This article summarizes the rationale for multi-agency working when assessing children and young people with suspected neurodevelopmental disorders such as attention-deficit hyperactivity disorder, developmental coordination disorder and autistic spectrum disorders. Details of referral pathways that have been drawn up for each separate disorder are given and the process through which multi-agency agreement was reached is described. Key features thought to be common to all three pathways are discussed and factors thought to have contributed to successful multi-agency working highlighted. The work is described in the context of existing national policy documents in the UK.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Neuropsychological impairment and its neurological correlates in adult offspring with heightened risk for schizophrenia and affective psychosis.

OBJECTIVE: Schizophrenia is generally considered to be a neurodevelopmental disorder reflected in findings of neuropsychological impairments and neurological abnormality in patients and their relatives. The authors investigated whether neuropsychological impairments are related to neurological abnormality and whether such deficits also characterize risk for affective psychosis. METHOD: In a longitudinal study with a 93% rate of effective follow-up, the authors investigated neuropsychological impairment and its relation to neurological abnormality at a mean age of 22.3 years in 74 offspring of mothers with a history of psychotic disorders (38 offspring with heightened risk for schizophrenia and 36 with risk for affective psychosis) and 88 normal-risk offspring born to mothers with no history of psychosis. RESULTS: Offspring with genetically heightened risk for schizophrenia showed significantly impaired verbal memory, selective attention, and grammatical reasoning, compared with normal-risk offspring. Having impaired verbal memory, attention, and grammatical reasoning functions identified a significantly larger subgroup (16%) among offspring with heightened risk for schizophrenia than among offspring with heightened risk for affective psychosis (0%) and among normal-risk offspring (3%). Multiple neuropsychological functions were significantly related to neurological abnormality in offspring with heightened risk for schizophrenia and in normal-risk offspring but not among offspring with heightened risk for affective psychosis. The extension of schizophrenia and affective psychosis risk groups to include additional offspring of mothers with psychosis-spectrum disorders yielded results similar to those for the core risk groups. CONCLUSIONS: The neurocognitive dysfunction attending heightened risk for schizophrenia is likely based on genetically mediated neurodevelopmental factors, with schizophrenia and affective psychosis belonging to different biological spheres.

Adult↗

PubMed2006

Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications.

Two members of the family of low-density lipoprotein receptors (i.e., very low-density lipoprotein [VLDL] receptor and apolipoprotein E [apoE] type 2 receptor) are expressed in brain, where they bind and transduce reelin, a secreted glycoprotein that shares structural analogies with extracellular matrix proteins. In the developing fetal brain, reelin-signal transduction is critical for the correct positioning of neurons and the formation of appropriate synaptic connections, whereas in the mature brain, reelin participates in the mediation of experience-dependent synaptic plasticity. An important "downstream" consequence of the reelin-signal transduction cascade is inhibition of the phosphorylation of tau, a protein that regulates microtubule assembly and stability. Importantly, hyperphosphorylated tau comprises the paired helical filament, whose pathological deposition as neurofibrillary tangles is implicated in Alzheimer's disease; hyperphosphorylated tau is also implicated in the pathogenesis of other neurodegenerative disorders. Isoforms of apoE may affect the binding of reelin to its cell surface receptors and, thereby, influence tau phosphorylation, whereas insulin, insulin-like growth factor-1, and the lithium ion have actions within the cell at the level of the specific tyrosine kinases involved in the phosphorylation of tau. These data support the exploration of pharmacotherapeutic interventions designed to prevent or reduce the burden of hyperphosphorylated tau. Impaired reelin-signal transduction due to an actual deficiency of reelin expression may occur in at least some patients with psychotic disorders, especially schizophrenia; conceivably, hyperphosphorylation of tau would result from deficient transduction of reelin in schizophrenia. Schizophrenia has been conceptualized as a neurodevelopmental disorder of impaired synaptic "connectivity", whose consequence does not become fully apparent until late adolescence or early adulthood. In summary, hyperphosphorylation of tau may be an underlying point of pathological convergence for several neuropsychiatric disorders, and prevention of tau hyperphosphorylation may be an important therapeutic target.

Aging↗