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PubMed2004

Neurobiology of dyslexia: a reinterpretation of the data.

Theories of developmental dyslexia differ on how to best interpret the great variety of symptoms (linguistic, sensory and motor) observed in dyslexic individuals. One approach views dyslexia as a specific phonological deficit, which sometimes co-occurs with a more general sensorimotor syndrome. This article on the neurobiology of dyslexia shows that neurobiological data are indeed consistent with this view, explaining both how a specific phonological deficit might arise, and why a sensorimotor syndrome should be significantly associated with it. This new conceptualisation of the aetiology of dyslexia could generalize to other neurodevelopmental disorders, and might further explain heterogeneity within each disorder and comorbidity between disorders.

Animals↗

PubMed2005

Stage-specific induction of DNA methyltransferases in olfactory receptor neuron development.

DNA methylation-dependent gene silencing, mediated by DNA methyltransferases (DNMTs), is essential for normal mammalian development and its dysregulation has been implicated in neurodevelopmental disorders. Despite this, little is known about DNMTs in the developing or mature nervous system. Here, we show that DNMT1, 3a and 3b are expressed at discrete developmental stages in the olfactory neuron lineage, coincident with key shifts in developmental gene expression. DNMT1 is induced in cycling progenitors and is retained in post-mitotic olfactory receptor neurons (ORNs). DNMT3b is restricted to mitotic olfactory progenitors, whereas DNMT3a is expressed only in post-mitotic immature neurons prior to ORN terminal maturation, coincident with histone deacetylase 2 (HDAC2), a key downstream effector of methylation-dependent chromatin condensation. Similar stage-specific expression of DNMT3b and 3a was also found in other developing sensory and CNS neurons. This suggests that progressive lineage restriction regulated by methylation-dependent silencing could be a highly conserved mechanism shared by multiple lineages in the developing nervous system.

Animals↗

PubMed2005

Microarray analysis of gene/transcript expression in Angelman syndrome: deletion versus UPD.

Angelman syndrome (AS) is a neurodevelopmental disorder due to a functional deficit, usually a deletion, of the UBE3A gene located in the 15q11-q13 chromosome region. We report the first microarray analysis of gene expression in AS using a custom cDNA microarray to compare expression patterns from lymphoblastoid cell lines from control males and AS subjects with a 15q deletion or uniparental paternal disomy 15. Expression patterns of genes known to be biallelically expressed or paternally or maternally expressed were consistent with expectations. We detected paternal or maternal allelic bias in the expression of several genes and transcripts (e.g., GABRA5, GABRB3, WI-14946). Additionally, mechanisms controlling paternal allele expression appear to be faithfully replicated in each paternal chromosome in individuals with paternal disomy. Our results indicate that interconnected mechanisms can produce subtle and unexpected changes in gene expression that may help explain the phenotypic differences observed among the genetic subtypes of AS.

Alleles↗

PubMed2026

DDX3X overexpression in mice can cause rapid tissue-specific toxicity and mortality.

DEAD-Box Helicase 3 X-Linked (DDX3X) is a ubiquitously expressed RNA helicase with diverse cellular roles implicated in a neurodevelopmental disorder called DDX3X syndrome. Although DDX3X is a leading genetic cause of intellectual disability in females, there is no treatment. While gene supplementation is a plausible therapeutic strategy, previous studies suggest DDX3X is carefully regulated and dose sensitive. To understand the consequences of overexpressing DDX3X with unregulated adeno-associated virus-mediated gene supplementation, we generated a vector driving strong ubiquitous DDX3X expression and administered it through a direct cerebrospinal fluid injection in newborn mice. Mice injected with a high dose died within 1 week from myocardial degeneration. Increased expression of stress response markers together with elevated apoptotic signaling in the heart suggested activation of stress-induced apoptotic pathways. Incidental findings included excess lipid accumulation, most prominent in the liver, and other liver injury. The innate immune system was also highly activated in the heart and liver. Interestingly, the brain was overall unaffected. The results suggest that DDX3X overexpression can cause rapid transgene-driven, tissue-specific toxicity, underscoring the need for tight DDX3X gene dosage control. These findings illustrate the possibility for improper transgene expression to drive severe toxicity including death within days following administration.

Animals↗

PubMed2005

Developmental abnormalities of neuronal structure and function in prenatal mice lacking the prader-willi syndrome gene necdin.

Necdin (Ndn) is one of a cluster of genes deleted in the neurodevelopmental disorder Prader-Willi syndrome (PWS). Ndntm2Stw mutant mice die shortly after birth because of abnormal respiratory rhythmogenesis generated by a key medullary nucleus, the pre-Bötzinger complex (preBötC). Here, we address two fundamental issues relevant to its pathogenesis. First, we performed a detailed anatomical study of the developing medulla to determine whether there were defects within the preBötC or synaptic inputs that regulate respiratory rhythmogenesis. Second, in vitro studies determined if the unstable respiratory rhythm in Ndntm2Stw mice could be normalized by neuromodulators. Anatomical defects in Ndntm2Stw mice included defasciculation and irregular projections of axonal tracts, aberrant neuronal migration, and a major defect in the cytoarchitecture of the cuneate/gracile nuclei, including dystrophic axons. Exogenous application of neuromodulators alleviated the long periods of slow respiratory rhythms and apnea, but some instability of rhythmogenesis persisted. We conclude that deficiencies in the neuromodulatory drive necessary for preBötC function contribute to respiratory dysfunction of Ndntm2Stw mice. These abnormalities are part of a more widespread deficit in neuronal migration and the extension, arborization, and fasciculation of axons during early stages of central nervous system development that may account for respiratory, sensory, motor, and behavioral problems associated with PWS.

Animals↗

PubMed2000

Towards the prevention of schizophrenia.

There is a growing emphasis on attempts to identify the early signs and symptoms of schizophrenia, largely because early detection and treatment of psychosis (i.e., secondary prevention) are associated with relatively favorable clinical outcomes. This raises the issue of whether prevention of psychosis itself is possible. The achievement of this goal will require the identification of a premorbid state that could serve as the foundation for treatment strategies aimed ultimately at the prevention of schizophrenia. Fortunately, evidence for such a state is emerging, in part because schizophrenia may result from a neurodevelopmental disorder that is associated with a variety of clinical, neurobiological, and neuropsychologic features occurring well before the onset of psychosis. These features may serve as both indicators of risk for subsequent deterioration and the foundation of treatment efforts. We reformulated Meehl's term schizotaxia to describe this liability and discuss here how its study could form the basis for future strategies of prevention. We also include a description of our initial attempts to devise treatment protocols for schizotaxia. It is concluded that schizotaxia is a feasible concept on which to base prevention efforts, and that treatment of adult schizotaxia may be among the next steps in the process.

Humans↗

PubMed2002

3D laser surface scanning and geometric morphometric analysis of craniofacial shape as an index of cerebro-craniofacial morphogenesis: initial application to sexual dimorphism.

BACKGROUND: Over early fetal life, when disturbances in schizophrenia have been posited and craniofacial dysmorphogenesis reported, cerebral morphogenesis proceeds in embryological intimacy with craniofacial morphogenesis. Digitization technologies now allow 3D recording of craniofacial surface landmarks and modeling of craniofacial shape differences using geometric morphometrics. METHODS: Using normal sexual dimorphism as an exemplar, facial surfaces of 131 Medical School employees [82 females, 49 males] were recorded in 3D using a portable, hand-held laser scanner; 3D coordinate data were then analyzed using geometric morphometrics. RESULTS: Males and females differed markedly on an omnibus test of craniofacial shape. Logistic regression analysis of 16 principal components of shape variability, explaining 84.9% of the overall sample variance, generated 8 principal components as significant and independent discriminators. On visualization, the female face is wider and flatter; the eyes are more lateral, anterior and are further apart, and nasal bridge is posterior; the nose is smaller; the lips are fuller and the chin more forward. These findings are complementary to sexual dimorphism in cerebral structures. CONCLUSIONS: This technique reliably discriminates geometric features of craniofacial morphology that are associated with aspects of cerebral morphology, and may inform on putative neurodevelopmental disorders characterised by dysmorphogenesis.

Adult↗

PubMed2002

Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical morphogenesis in rats.

We have shown previously that neonatal intraventricular injections of the selective cholinergic immunotoxin 192 IgG saporin on postnatal day 7 (pnd 7) induce marked cholinergic loss in hippocampus and neocortex and a learning impairment on pnd 15. In the present study, we analysed the behavioural, morphological and neurochemical effects of earlier intraventricular injection of the immunotoxin 192 IgG saporin (pnd 1 and 3). We hypothesised that these earlier lesions would interrupt a critical stage in neocortical maturation, and impair behavior more profoundly than the later lesions. Passive avoidance (PA) learning and locomotor activity during the PA test were assessed on pnd 15. Retention of the PA task was assessed on pnd 16. Reactivity to spatial and object novelty was assessed on pnd 180 in a spatial open field test with five objects. Choline acetyltransferase (ChAT) activity was measured in basal forebrain targets on pnd 20 and pnd 180. Neonatal administration of 192 IgG saporin resulted in a slower acquisition of the PA task in females; retention and locomotor activity were not affected. On pnd 180, reaction to spatial novelty was mildly impaired in lesioned rats of both sexes. There was a marked reduction of ChAT in the hippocampus and neocortex of lesioned rats of both sexes, at both ages. Morphological analysis of the somatosensory cortex of lesioned rats revealed alterations in cortical development with sex specific variations in total cortical thickness. These results suggest that interrupting cholinergic basal forebrain innervation of neocortex and hippocampus during the first postnatal days affects the development of cognitive behaviour, neurochemistry and cortical organisation in a sex specific manner. Furthermore, the alterations in cortical organization are more profound than those noted after a lesion later in postnatal development. These behavioural and morphological abnormalities could be considered a model for several neurodevelopmental disorders associated with mental retardation.

Animals↗

PubMed1997

Chronic postnatal hypoxia increases the numbers of cortical neurons.

Premature infants have been shown to undergo prolonged periods of sublethal hypoxia. There is considerable evidence to link these hypoxic events with neurodevelopmental disorders. As an animal model for this clinical problem, rats were raised from the third day of life in a chamber where the O2 level was 9.5%. After 30 days of hypoxia the rats were sacrificed and their brains processed for determination of the number of cortical neurons. This work was performed to test the hypothesis that chronic hypoxia would result in increased cortical cell death. The hypoxic rats had lower body and brain weights as well as decreased cortical volumes. However, hypoxic rats had increased neuronal density and significantly more cortical neurons than controls (P < 0.05). The results of this study suggest that chronic sublethal hypoxia may lead to reduction in the amount of programmed cell death in the developing neocortex.

Animals↗

PubMed2002

Controversies in urinary iodine determinations.

Iodine deficiency (ID) is associated with increased prevalence of goiter, increased risk for neurodevelopmental disorders, and is the world's leading cause of intellectual deficits. Iodine nutritional status of a population is assessed by measurements of urinary iodine concentrations which are also used to define, indicate, survey and monitor iodine deficiency and consequently its treatment. Several methods are available for urinary iodine determination. Discussed here are some of the limitations and controversies related to urinary iodine determinations, and recent findings with emphasis on measurements of urinary iodine concentrations in children and during pregnancy.

Child↗

PubMed2000

A componential view of theory of mind: evidence from Williams syndrome.

In this paper we argue that there are two distinct components of a theory of mind: a social-cognitive and a social-perceptual component. Evidence for this proposal is presented from various sources, including studies of children with Williams syndrome, a rare genetic neurodevelopmental disorder. Earlier work has demonstrated that people with Williams syndrome appear to be spared in the social-perceptual component of a theory of mind. In this paper we present evidence that they are not spared in the social-cognitive component of theory of mind. Three experiments with young children with Williams syndrome were conducted. In each experiment the children with Williams syndrome were compared to age-, IQ-, and language-matched children with Prader-Willi syndrome, and children with non-specific mental retardation. The experiments used different measures of theory of mind ability, including false belief (Experiment 1), explanation of action (Experiment 2), and recognition of emotional expressions (Experiment 3). In none of these experiments did the children with Williams syndrome evidence superior performance compared to the control groups. The results from this and other studies on Williams syndrome support the view that the social-cognitive and social-perceptual components of a theory of mind are dissociable. In Williams syndrome only the latter components, which are linked to distinct neurobiological substrates, are spared.

Child↗

PubMed1997

Do individuals with Williams syndrome have bizarre semantics? Evidence for lexical organization using an on-line task.

Williams syndrome, a neurodevelopmental disorder, has attracted a great deal of debate concerning the purported intactness of language in the face of other serious cognitive deficits. As more in-depth studies of specific aspects of WS language have emerged, the notion of a preserved language module has been seriously challenged. Although WS vocabulary scores are often impressive, several investigators have claimed the WS semantics are aberrant. All studies hitherto have been based on off-line experiments which necessarily involve metalinguistic processes. This clearly affects the performance of individuals with cognitive deficits. We report here an on-line study probing the semantic structure of the WS lexicon, using a task-semantic priming-which minimises metalinguistic demands. We show that WS subjects display the same taxonomic/category and thematic/functional priming effects as normal controls. The results are discussed in terms of the differences between receptive and expressive language, as well as the fact that although semantic memory and the automatic access to semantic information for individual words is normal in WS, the integration of semantic information into sentence comprehension may be abnormal. The importance of online tasks to highlight such differences is stressed.

Adolescent↗

PubMed1983

Follow-up of infants screened by auditory brainstem response in the neonatal intensive care unit.

Auditory brainstem response screening at 40 and 60 dB was conducted in 100 infants in the neonatal intensive care unit to determine initial failure rate and prevalence of abnormality on follow-up. Of our NICU population, 20% failed one or both of the screening levels: 9% failed at 60 dB in both ears, and 11% failed at 40 dB in one or both ears. On follow-up, half of the 60 dB failure group were found to have sensorineural or conductive impairment and represent the 2% to 4% prevalence of serious otologic-audiologic problems generally found in an NICU population. Subsequent improvement (reversal) of the retest ABR records of the remaining infants in the 60 dB failure group was thought to be related to neural changes in the brainstem associated with recovery from hypoxic episodes. A transient or reversible conductive deficit appeared to account for the majority of failures at 40 dB. We recommend the screening protocol be expanded to include threshold and latency measures in infants who fail the initial screening. The transient nature of many ABR abnormalities makes postdischarge ABR, otologic, audiologic, and neurologic examinations mandatory before any inferences are made about hearing loss or neurodevelopmental disorders.

Brain Stem↗

PubMedDate not supplied

Which characteristics of schizophrenia predate psychosis?

Neuropsychological and brain structural abnormalities are present in first onset schizophrenia; the balance of evidence is that in the majority of cases these are developmental in origin. A proportion of first degree relatives also show lateral ventricular enlargement, cortical volume decrease and possibly loss of the normal cerebral asymmetry; these findings suggest that certain families transmit a genetic defect in the control of neurodevelopment. On the contrary, decrement in left hippocampal volume appears to be secondary to perinatal hypoxia. High risk, follow-back and cohort studies all demonstrate that preschizophrenics as a group show deviant development; delayed milestones, lower IQ, solitary play, excessive anxiety, and minor neurological problems are all common. It seems likely, but not proven, that these are a manifestation of underlying neurodevelopmental disorder.

Adolescent↗

PubMed1998

Linguistic dissociations in Williams syndrome: evaluating receptive syntax in on-line and off-line tasks.

Williams syndrome (WS) is a neurodevelopmental disorder of genetic origin which results in relatively spared language in the face of serious non-verbal deficits. There is controversy, however, about how intact WS language abilities are. The discussion has focused on impairments of lexico-semantics and of morphological feature analysis, with the presumption that WS syntax is intact. We challenged this view and assessed WS receptive syntax by using two tasks testing various syntactic structures: an on-line word monitoring task and an off-line picture-pointing task. WS performance on the off-line task was generally poor. By contrast, their performance on the on-line task was far better and allowed us to ascertain precisely which aspects of WS receptive syntax are preserved and which are impaired. WS participants were sensitive to the violation of auxiliary markers and phrase structure rules but, unlike both the normal young and elderly controls, they did not show sensitivity to violations of subcategory constraints. The present study suggests that there exist dissociations within WS language which are not restricted to lexico-semantics or to morphological feature analysis, but which also invade their processing of certain syntactic structures. We conclude by arguing that WS syntax is not intact and that their language might turn out to be more like second language learning than normal acquisition.

Adolescent↗

PubMed2001

Developmental neurotoxicity. Illustration of principles.

The magnitude of the problem of neurodevelopmental disorders is enormous. Frequently, the mechanism of injury is unknown. In this article, several common developmental neurotoxins are discussed, and the function of one cell adhesion molecule, L1, will be reviewed to illustrate the principles of developmental neurotoxicology. L1 is critical for proper central nervous system development. Similarities between patients with fetal alcohol syndrome and with L1 mutations suggest that the mechanism of developmental neurotoxicity of ethanol is partly due to effects on L1 cell adhesion molecule.

Cell Adhesion Molecules↗

PubMed2005

Immunological findings in autism.

The immunopathogenesis of autism is presented schematically in Fig. 1. Two main immune dysfunctions in autism are immune regulation involving pro-inflammatory cytokines and autoimmunity. Mercury and an infectious agent like the measles virus are currently two main candidate environmental triggers for immune dysfunction in autism. Genetically immune dysfunction in autism involves the MHC region, as this is an immunologic gene cluster whose gene products are Class I, II, and III molecules. Class I and II molecules are associated with antigen presentation. The antigen in virus infection initiated by the virus particle itself while the cytokine production and inflammatory mediators are due to the response to the putative antigen in question. The cell-mediated immunity is impaired as evidenced by low numbers of CD4 cells and a concomitant T-cell polarity with an imbalance of Th1/Th2 subsets toward Th2. Impaired humoral immunity on the other hand is evidenced by decreased IgA causing poor gut protection. Studies showing elevated brain specific antibodies in autism support an autoimmune mechanism. Viruses may initiate the process but the subsequent activation of cytokines is the damaging factor associated with autism. Virus specific antibodies associated with measles virus have been demonstrated in autistic subjects. Environmental exposure to mercury is believed to harm human health possibly through modulation of immune homeostasis. A mercury link with the immune system has been postulated due to the involvement of postnatal exposure to thimerosal, a preservative added in the MMR vaccines. The occupational hazard exposure to mercury causes edema in astrocytes and, at the molecular level, the CD95/Fas apoptotic signaling pathway is disrupted by Hg2+. Inflammatory mediators in autism usually involve activation of astrocytes and microglial cells. Proinflammatory chemokines (MCP-1 and TARC), and an anti-inflammatory and modulatory cytokine, TGF-beta1, are consistently elevated in autistic brains. In measles virus infection, it has been postulated that there is immune suppression by inhibiting T-cell proliferation and maturation and downregulation MHC class II expression. Cytokine alteration of TNF-alpha is increased in autistic populations. Toll-like-receptors are also involved in autistic development. High NO levels are associated with autism. Maternal antibodies may trigger autism as a mechanism of autoimmunity. MMR vaccination may increase risk for autism via an autoimmune mechanism in autism. MMR antibodies are significantly higher in autistic children as compared to normal children, supporting a role of MMR in autism. Autoantibodies (IgG isotype) to neuron-axon filament protein (NAFP) and glial fibrillary acidic protein (GFAP) are significantly increased in autistic patients (Singh et al., 1997). Increase in Th2 may explain the increased autoimmunity, such as the findings of antibodies to MBP and neuronal axonal filaments in the brain. There is further evidence that there are other participants in the autoimmune phenomenon. (Kozlovskaia et al., 2000). The possibility of its involvement in autism cannot be ruled out. Further investigations at immunological, cellular, molecular, and genetic levels will allow researchers to continue to unravel the immunopathogenic mechanisms' associated with autistic processes in the developing brain. This may open up new avenues for prevention and/or cure of this devastating neurodevelopmental disorder.

Antibody Formation↗

PubMed2006

Are autistic and catatonic regression related? A few working hypotheses involving gaba, Purkinje cell survival, neurogenesis, and ECT.

Autistic regression seems to occur in about a quarter of children with autism. Its cause is unknown. Late-onset autistic regression, that is, after 2 years of age, shares some features with catatonic regression. A working hypothesis is developed that some children with autistic regression suffer from early-onset catatonic regression. This hypothesis cannot be answered from current data and is difficult to address in clinical studies in the absence of definite markers of autistic and catatonic regression. Treatment implications are theoretical and involve the potential use of anticatatonic treatments for autistic regression. Focus is on electroconvulsive therapy (ECT)--an established but controversial treatment that is viewed by many, but not all, as the most effective treatment for severe, life-threatening catatonic regression. Clinical trials of ECT in early- or late-onset autistic regression in children have not been done yet. The effects of electroconvulsive seizures--the experimental analogue of ECT--should also be tested in gamma-aminobutyric acid-ergic animal models of autistic regression, autism, catatonia, and other neurodevelopmental disorders. Purkinje cell survival and neurogenesis are putative outcome measures in these models.

Adolescent↗