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Results for “Neurodevelopmental Disorders”

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PubMed2001

Mechanisms of brain injury: L1 cell adhesion molecule as a target for ethanol-induced prenatal brain injury.

The magnitude of the problem of neurodevelopmental disorders is enormous. Frequently, the mechanism of injury is unknown. In this article, the function of one cell adhesion molecule, L1, will be reviewed. 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.

Adult↗

PubMedDate not supplied

Increased levels of cytosolic phospholipase A2 in dyslexics.

Research findings are increasingly reporting evidence of physiological abnormalities in dyslexia and sites for dyslexia have been identified on three chromosomes. It has been suggested that genetic inheritance may cause phospholipid abnormalities in dyslexia somewhat similar to those found in schizophrenia. A key enzyme in phospholipid metabolism, Type IV, or cytosolic, phospholipase A2 (cPLA2), releases arachidonic acid (AA), a 20-carbon fatty acid, which is the major source of production of prostaglandins and leukotrienes. An entirely new assay, which for the first time has enabled determination of the amount of the enzyme rather than its activity, was used to measure cPLA2 in dyslexic-type adults and controls and the two groups were found to differ significantly, the dyslexic-types having more of the enzyme. A report elsewhere of schizophrenics having even greater amounts of the enzyme suggests that dyslexia may be on a continuum with schizophrenia, as may be other neurodevelopmental disorders - which have also been described as phospholipid spectrum disorders.

Adult↗

PubMedDate not supplied

Visual function, fatty acids and dyslexia.

There is mounting evidence that developmental dyslexia is a neurodevelopmental disorder which involves abnormalities of fatty acid metabolism, particularly with respect to certain long-chain highly unsaturated fatty acids (HUFAs). Psychophysical evidence also strongly suggests that dyslexics may have visual deficits as well as phonological problems. Specifically, these visual deficits appear to be related to the magnocellular pathway, which is specialized for processing fast, rapidly-changing information about the visual scene. It remains unclear how these two aspects of dyslexia - fatty acid processing and visual magnocellular function - could be related. We propose some hypotheses - necessarily speculative, given the paucity of biochemical research in this field to date - which address this question.

Brain↗

PubMed1999

[Rett's syndrome: pathophysiology and anesthesiological implications].

Rett's syndrome is a neurodevelopmental disorder which is caused by a mutation on the x-chromosome; thus, it only affects the female sex. After seemingly normal postnatal development affected girls lose already acquired mental, motoric and social skills. The last stage of the syndrome is characterized by microcephaly, severe mental retardation, spastic paraparesis, epilepsia, respiratory dysrhythmia, neurogenic scoliosis, abnormal joint alignment and muscle contractures. Rett's syndrome is probably the leading cause for progressive mental retardation in girls, but still it is relatively unknown. This paper describes Rett syndrome and its pathophysiology. The following case report discusses special anesthesiological implications due to the immature cardiorespiratory system and describes a coagulation disorder following treatment with valproic acid.

Adult↗

PubMed2002

Influence of mutation type and location on phenotype in 123 patients with Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects girls. It is caused by mutations in the MECP2 gene that encodes the methyl-CpG-binding protein 2 (MeCP2). In this study we correlated mutation type and location with the severity of the phenotype in 123 girls with RTT. The ability to sit, walk, speak, hand function, head growth, occurrence of epilepsy and a combined severity score were assessed in all girls at 5 years of age and then statistically correlated with the results of the molecular genetic tests. We found that patients who carry either missense mutations or deletions located within the hotspot for deletions, an area between the base pairs (bp) 1030 and 1207 of the MECP2 gene, present with a milder phenotype than other patients. We correlated the location of the mutations with the phenotype and found that all mutations that lead to either a complete or partial truncation of the region coding for the nuclear localisation signal (NLS) are associated with a more severe phenotype than other truncating mutations (p = 0.001). We did not find a significant difference between the patients with mutations in the methyl-CpG-binding domain (MBD) and those with mutations in the transcriptional repression domain (TRD). We conclude that mutation type and location correlate with the phenotype in Rett syndrome. All mutations that impair the nuclear localisation signal (NLS) are associated with more severe phenotypes.

Binding Sites↗

PubMed2002

Altered methylation pattern of the G6 PD promoter in Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects girls. Recently mutations in MECP2, that encodes the methyl CpG binding protein 2 (MeCP2), have been found to cause RTT. MeCP2 has a role in gene silencing. It binds to methylated cytosine in the DNA and recruits histone deacetylases. We studied the methylation pattern of the promoters of two X chromosomal genes, G6 PD and SYBL1, in patients with RTT and in a control group. Both genes undergo X inactivation which correlates with promoter methylation. A 1 : 1 ratio of methylated versus non-methylated alleles was expected. In the control group a median ratio of 47 : 53 of methylated to non-methylated alleles was found at the G6 PD promoter locus. In 22 patients with RTT the median ratio was significantly different, 33 : 67 (p < 0.0001). Analysis of the SYBL1 promoter revealed an almost identical median ratio of methylated versus non-methylated alleles (RTT 47 : 53; control 49 : 51), however, the range was wider in the RTT group (RTT 23 : 77 to 56 : 44; control 43 : 57 to 55 : 45). There was no apparent correlation between G6 PD promoter methylation status and mutations in the MeCP2 gene or the severity of the clinical phenotype in our patient group. The finding of reduced methylation at the G6 PD promoter is an interesting finding and suggests that there could be widespread dysregulation of X chromosomal genes in Rett syndrome.

Chromosomal Proteins, Non-Histone↗

PubMed1999

Altered cholinergic function in the basal forebrain of girls with Rett syndrome.

Rett syndrome (RS) is a neurodevelopmental disorder that is predominant in females and is associated with cortical atrophy, stereotyped hand movements and severe mental deficiency. Previous studies have demonstrated a significant decline in number of choline acetyltransferase (ChAT)-containing neurons throughout the forebrain of RS girls. The loss of these ChAT-positive cells may be caused by a lack of nerve growth factor (NGF). In the current study, cortical levels of NGF were normal in RS girls as compared to age-and sex-matched controls. The number of neurons within the basal forebrain that express the 75 kDa (p75) low-affinity receptor for NGF was unchanged. In contrast, the number of ChAT-positive neurons was significantly decreased. The results suggest that normal amounts of NGF are available for binding to the p75 receptor and for retrograde transport to forebrain cholinergic cells, however, these neurons do not respond by producing the ChAT protein that is necessary for the production of the neurotransmitter acetylcholine.

Acetylcholine↗

PubMed1985

Prognostic value of neonatal CT scans in asphyxiated term babies: low density score compared with neonatal neurological signs.

Twenty-five asphyxiated term babies were investigated in order to evaluate the prediction of their neurodevelopmental outcome by means of computerized tomography (CT) as compared to neurological symptoms during the neonatal period. Low density (LD) areas, thought to represent hypoxicischaemic lesions, were assessed quantitatively by means of a LD score based on the extent and degree of LD, the total score ranging from 0-36. Neonatal scans were defined according to the time span elapsed between asphyxia and CT as (1) early CT (day 1-7, n = 15), and (2) intermediate CT (day 9-23: n = 14; day 29: n = 1). The newborns were classified according to the neonatal neurological findings as having mild (n = 8, 32%), moderate (n = 9, 36%), and severe (n = 8, 32%) encephalopathy, following the definition of Sarnat and Sarnat (1976). Among the twenty-two survivors, the follow-up (mean age 19.2 +/- 6.0 mts) revealed fourteen (56%) with normal outcome, two (8%) with transient neurodevelopmental anomalies during the first year, and nine (36%) with permanent abnormalities such as cerebral palsy and/or retardation (mainly global) and/or epilepsy. Early CT scans had no predictive value. Intermediate CT, however, showed distinct variations of LD areas which resulted in an LD score well correlated with the later outcome. In particular, a LD score below 14 characterized every baby who developed normally; a prediction not possible in a reliable way be means of neonatal neurological signs. For all abnormal children, the score correlated with the severity of the later neurodevelopmental disorder, except for one with the latest intermediate CT (day 29).

Asphyxia Neonatorum↗

PubMed2004

Temporal and regional differences in the olfactory proteome as a consequence of MeCP2 deficiency.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the gene encoding MeCP2. By binding to methylated CpG dinucleotide promoter regions, MeCP2 acts as a transcriptional repressor, predicting that its absence might result in widespread aberrant gene transcription, leading to the RTT phenotype. Considering this potentially broad action of MeCP2 on expression and the complexity of the brain, especially during development, we approached the consequences of MeCP2 deficiency in a mouse model by using a temporal and regional proteomic strategy. We used the olfactory system (olfactory epithelium and bulb) because its attributes make it an excellent developmental model system. We find evidence of temporal and regional proteomic pattern differences between WT and MeCP2-deficient mice. It was possible to segregate these changes in protein expression into five biological function groups: cytoskeleton arrangement, chromatin modeling, energy metabolism, cell signaling, and neuroprotection. By combining the proteomic results with the RNA levels of the identified proteins, we show that protein expression changes are the consequence of differences in mRNA level or posttranslational modifications. We conclude that brain regions and ages must be carefully considered when investigating MeCP2 deficiency, and that not only transcription should be taken into account as a source for these changes, but posttranslational protein modifications as well.

Animals↗

PubMed2004

Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice.

Mutations in MECP2 are the cause of Rett syndrome (RTT) in humans, a neurodevelopmental disorder that affects mainly girls. MeCP2 is a protein that binds CpG dinucleotides and is thought to act as a global transcriptional repressor. It is highly expressed in neurons, but not in glia, of the postnatal brain. The timing of MeCP2 activation correlates with the maturation of the central nervous system, and recent reports suggest that MeCP2 may be involved in the formation of synaptic contacts and may function in activity-dependent neuronal gene expression. Deletion or targeted mutation of Mecp2 in mice leads to a Rett-like phenotype. Selective mutation of Mecp2 in postnatal neurons leads to a similar, although delayed, phenotype, suggesting that MeCP2 plays a role in postmitotic neurons. Here we test the hypothesis that the symptoms of RTT are exclusively caused by a neuronal MeCP2 deficiency by placing Mecp2 expression under the control of a neuron-specific promoter. Expression of the Mecp2 transgene in postmitotic neurons resulted in symptoms of severe motor dysfunction. Transgene expression in Mecp2 mutant mice, however, rescued the RTT phenotype.

Animals↗

PubMed2004

Dynamic mapping of human cortical development during childhood through early adulthood.

We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4-21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8-10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse "movies" reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism.

Adolescent↗

PubMed2006

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling.

Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. Using expression microarrays and a unique method for comparative expression analysis called L2L, we sought to define this defect in cells lacking a functional CS group B (CSB) protein, the SWI/SNF-like ATPase responsible for most cases of CS. Remarkably, many of the genes regulated by CSB are also affected by inhibitors of histone deacetylase and DNA methylation, as well as by defects in poly(ADP-ribose)-polymerase function and RNA polymerase II elongation. Moreover, consistent with these microarray expression data, CSB-null cells are sensitive to inhibitors of histone deacetylase or poly(ADP-ribose)-polymerase. Our data indicate a general role for CSB protein in maintenance and remodeling of chromatin structure and suggest that CS is a disease of transcriptional deregulation caused by misexpression of growth-suppressive, inflammatory, and proapoptotic pathways.

Cell Line↗

PubMed2006

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia.

Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33-35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.

Adult↗

PubMed2006

Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome.

Rett syndrome (RTT), a postnatal neurodevelopmental disorder, is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Children with RTT display cognitive and motor abnormalities as well as autistic features. We studied mice bearing a truncated Mecp2 allele (Mecp2(308/Y) mice) and found evidence of increased anxiety-like behavior and an abnormal stress response as evidenced by elevated serum corticosterone levels. We found increased corticotropin-releasing hormone (Crh) gene expression in the paraventricular nucleus of the hypothalamus, the central amygdala, and the bed nucleus of the stria terminalis. Finally, we discovered that MeCP2 binds the Crh promoter, which is enriched for methylated CpG dinucleotides. In contrast, the MeCP2(308) protein was not detected at the Crh promoter. This study identifies Crh as a target of MeCP2 and implicates Crh overexpression in the development of specific features of the Mecp2(308/Y) mouse, thereby providing opportunities for clinical investigation and therapeutic intervention in RTT.

Animals↗

PubMed2026

Loss of function of the chromatin remodeling gene INO80D leads to neurogenic features of schizophrenia.

Schizophrenia has been linked to severely damaging de novo mutations in synaptic junction proteins, neurotransmitter receptors, transcription factors, and chromatin remodeling proteins. In a patient with schizophrenia in the absence of a family history of severe mental illness, we identified de novo nonsense mutation, INO80D p.Q568X, associated with both a truncated protein and partial nonsense-mediated decay. Three experiments were undertaken to evaluate the consequences of the mutation. 1) In neural stem cells (iNSCs) differentiated from WTC11 iPSCs, CRISPRi knockdown of INO80D led to downregulation of three subunits of the AMPA-glutamate receptor, of multiple genes mutant in schizophrenia, and of genes of synaptic function. 2) INO80D p.Q568X iNSCs and neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) had significantly lower expression of neurogenesis genes compared to patient-derived cells with the mutation corrected by CRISPR-Cas9 gene editing. Patient-derived INO80D p.Q568X neurons had significantly higher expression of cell division genes compared to lines with the mutation corrected, consistent with the possibility that some of these cells may be undergoing mitosis, which is not normal for neurons. 3) Finally, on microelectrode array (MEA) plates, WTC11-derived glutamatergic neurons with reduced expression of INO80D had more rapid firing rate and increased average network burst duration, both features of neurons derived from patients with neurodevelopmental disorders. Overall, these findings suggest that partial loss of INO80D function due to de novo mutation may have disrupted normal neurodevelopment and contributed to the schizophrenia of this patient.

Humans↗

PubMed2026

A complex of MAST1 and 14-3-3η regulates Tau phosphorylation in the developing cortex.

The MAST family of serine/threonine kinases has been implicated in a spectrum of human neurodevelopmental disorders. However, little is known about their biological function or regulation. Seeking to fill these gaps in our knowledge, we have identified upstream and downstream partners of MAST1. 14-3-3η, a neuronal 14-3-3 paralog, specifically interacts with MAST1 at two regulatory serines, S90 and S161. p21-activated kinase (PAK), a neuronal regulator of the actin cytoskeleton, phosphorylates MAST1 to regulate its interaction with 14-3-3η. Exploiting mouse models of human Mega-Corpus-Callosum Syndrome (MCC) and whole brain phosphoproteomics, we identify the microtubule-associated protein Tau as a candidate substrate of MAST1. We show that pathogenic MAST1 mutations perturb protein function either through misfolding or attenuation of kinase activity. Our data are consistent with a model in which the MAST kinases couple PAK, a neuronal regulator of the actin cytoskeleton, to microtubule remodeling during the differentiation and specification of cortical neurons.

Animals↗

PubMed1999

Ethanol inhibits L1-mediated neurite outgrowth in postnatal rat cerebellar granule cells.

The neuropathology of the effects of ethanol on the developing central nervous system are similar to those of patients with mutations in L1, a neural cell adhesion molecule. This observation suggests that inhibition of L1 plays a role in the pathogenesis of alcohol-related neurodevelopmental disorders. Here we examine the effects of ethanol on L1 homophilic binding and on L1-mediated neurite outgrowth. Ethanol had no effect on cell adhesion or aggregation in a myeloma cell line expressing full-length human L1. In contrast, the rate of L1-mediated neurite outgrowth of rat postnatal day 6 cerebellar granule cells grown on a substratum of NgCAM, the chick homologue of L1, was inhibited by 48.6% in the presence of ethanol with a half-maximal concentration of 4.7 mM. The same effect was found with soluble L1-Fc, thus showing that the inhibitory effect is not dependent on cell adhesion. In contrast, neither laminin nor N-cadherin-mediated neurite outgrowth was inhibited by physiologic concentrations of ethanol. We conclude that one mechanism of ethanol's toxicity to the developing central nervous system may be the inhibition of L1-mediated neurite outgrowth.

Animals↗

PubMed2000

Fetal alcohol exposure alters neurosteroid modulation of hippocampal N-methyl-D-aspartate receptors.

The actions of ethanol on brain ligand-gated ion channels have important roles in the pathophysiology of alcohol-related neurodevelopmental disorders and fetal alcohol syndrome. Studies have shown that N-methyl-d-aspartate (NMDA) receptors are among the ligand-gated ion channels affected by prenatal ethanol exposure. We exposed pregnant dams to an ethanol-containing liquid diet that results in blood ethanol levels near the legal intoxication limit in most states (0.08%). Primary cultures of hippocampal neurons were prepared from the neonatal offspring of these dams, and NMDA receptor function was assessed by patch clamp electrophysiological techniques after 6-7 days in culture in ethanol-free media. Unexpectedly, we did not detect any changes in hippocampal NMDA receptor function at either the whole-cell or single-channel levels. However, we determined that fetal alcohol exposure alters the actions of the neurosteroids pregnenolone sulfate and pregnenolone hemisuccinate, which potentiate NMDA receptor function. Western immunoblot analyses demonstrated that this alteration is not due to a change in the expression levels of NMDA receptor subunits. Importantly, in utero ethanol exposure did not affect the actions of neurosteroids that inhibit NMDA receptor function. Moreover, the actions of pregnenolone sulfate on type A gamma-aminobutyric acid and non-NMDA receptor function were unaltered by ethanol exposure in utero, which suggests that the alteration is specific to NMDA receptors. These findings are significant because they provide, at least in part, a plausible mechanistic explanation for the alterations in the behavioral responses to neurosteroids found in neonatal rats prenatally exposed to ethanol and to other forms of maternal stress (Zimmerberg, B., and McDonald, B. C. (1996) Pharmacol. Biochem. Behav. 55, 541-547).

Animals↗