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PubMed2003

beta-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation.

We have mapped and sequenced both chromosome breakpoints of a balanced t(6;11)(q14.2;q25) chromosome translocation that segregates with a schizophrenia-like psychosis. Bioinformatics analysis of the regions revealed a number of confirmed and predicted transcripts. No confirmed transcripts are disrupted by either breakpoint. The chromosome 6 breakpoint region is gene poor, the closest transcript being the serotonin receptor 1E (HTR1E) at 625 kb telomeric to the breakpoint. The chromosome 11 breakpoint is situated close to the telomere. The closest gene, beta-1,3-glucuronyltransferase (B3GAT1 or GlcAT-P), is 299 kb centromeric to the breakpoint. B3GAT1 is the key enzyme during the biosynthesis of the carbohydrate epitope HNK-1, which is present on a number of cell adhesion molecules important in neurodevelopment. Mice deleted for the B3GAT1 gene show defects in hippocampal long-term potentiation and in spatial memory formation. We propose that the translocation causes a positional effect on B3GAT1, affecting expression levels and making it a plausible candidate for the psychosis found in this family. More generally, regions close to telomeres are highly polymorphic in both sequence and length in the general population and several studies have implicated subtelomeric deletions as a common cause of idiopathic mental retardation. This leads us to the hypothesis that polymorphic or other variation of the 11q telomere may affect the activity of B3GAT1 and be a risk factor for schizophrenia and related psychoses in the general population.

Base Sequence↗

PubMed2005

Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder.

Major depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P < 0.05, fold change > 1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder.

Adult↗

PubMed2005

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia.

Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val(108/158)Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies. We also find Val(108/158)Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence.

Adult↗

PubMed2005

The neurodevelopmental model of schizophrenia: update 2005.

Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental 'hits', but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier 'lesions'. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia.

Adult↗

PubMed2005

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder.

In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3' end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders.

Cloning, Molecular↗

PubMed2005

Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions.

Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.

Aryldialkylphosphatase↗

PubMed2006

The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia.

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

Animals↗

PubMed2006

The role of phospholipases A2 in schizophrenia.

A range of neurotransmitter systems have been implicated in the pathogenesis of schizophrenia based on the antidopaminergic activities of antipsychotic medications, and chemicals that can induce psychotic-like symptoms, such as ketamine or PCP. Such neurotransmitter systems often mediate their cellular response via G-protein-coupled release of arachidonic acid (AA) via the activation of phospholipases A2 (PLA2s). The interaction of three PLA2s are important for the regulation of the release of AA--phospholipase A2 Group 2 A, phospholipase A2 Group 4A and phospholipase A2 Group 6A. Gene variations of these three key enzymes have been associated with schizophrenia with conflicting results. Preclinical data suggest that the activity of these three enzymes are associated with monoaminergic neurotransmission, and may contribute to the differential efficacy of antipsychotic medications, as well as other biological changes thought to underlie schizophrenia, such as altered neurodevelopment and synaptic remodelling. We review the evidence and discuss the potential roles of these three key enzymes for schizophrenia with particular emphasis on published association studies.

Antipsychotic Agents↗

PubMed2006

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder.

Linkage studies suggest that chromosome 22q12-13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case-control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker 'risk' haplotype showed a frequency of approximately 10% in the combined case group versus approximately 1% in controls (P-value 2.8 x 10(-7)). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment.

Animals↗

PubMed2003

Null mutation of the arginine-vasopressin gene in rats slows attentional engagement and facilitates response accuracy in a lateralized reaction time task.

The neurophysin vasopressin is thought to play an important role in emotional behavior and aspects of cognition in the rat, and the pathophysiology of this system has been implicated in two neurodevelopmental disorders, namely autism and schizophrenia. Genetic deficiency of vasopressin in rats, resulting from a null mutation of the vasopressin gene, causes alterations of brain development with resulting behavioral and neurochemical phenotypes in adulthood. We previously demonstrated that partial vasopressin deficiency (rats heterozygous for the null mutation) produces enhanced visuospatial attention and motor speeding. Here, the results of studies of homozygous Brattleboro rats that are fully vasopressin deficient are reported. We trained subjects to perform a lateralized reaction time task that measures visuospatial divided attention; in task conditions in which the duration of target stimuli was varied from trial to trial, homozygous Brattleboro rats showed a performance phenotype that consisted of more accurate responding for longer duration, and less accurate responding for briefer duration, target stimuli. No differences in response times were measured. Further experiments revealed that two separate processes produced this complex phenotype: a relatively slowed period of attentional engagement (resulting in compromised detection of fast onset-fast offset stimuli) that only partially masks a generally more accurate pattern of responding. These results, taken with earlier data, indicate that vasopressin plays a critical role in regulating visual attention and cognition, either directly, or via early alterations in neurodevelopment.

Animals↗

PubMed2004

Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens.

Gestational disruption of neurodevelopment has been proposed to lead to pathophysiological changes similar to those underlying schizophrenia. We induced such disruption by treating pregnant rat dams with methylazoxymethanol acetate (MAM) on gestational day 17 (GD17). Total brain size and that of the prefrontal cortex and hippocampus were reduced in adult rats exposed prenatally to MAM. When locomotor activity was assessed in an open field, MAM-exposed rats were hyper-responsive to a mild stress and to amphetamine (2 mg/kg, s.c.). They also engaged in less social interaction than controls. We studied, by microdialysis, the effect of amphetamine on extracellular dopamine in the nucleus accumbens and the medial prefrontal cortex of freely moving control and MAM-exposed rats. Amphetamine (2 mg/kg, s.c.) induced an increase in dopamine release that was larger in the nucleus accumbens of MAM-exposed rats than in controls, whereas no difference was seen in the medial prefrontal cortex. In controls, amphetamine infused into the medial prefrontal cortex (50 microM) led to a slight decrease in extracellular dopamine in the nucleus accumbens. This effect was absent in MAM-exposed rats, where a transient increase in nucleus accumbens dopamine levels was seen after amphetamine infusion. These results show that the late gestational disruption of neurogenesis in the rat leads to behavioral changes that mimic positive and negative schizophrenia symptoms, and also to a dysregulation of subcortical dopamine neurotransmission. This study contributes to the evaluation of the validity of the prenatal MAM GD17 treatment in rats as an animal model for schizophrenia.

Amphetamine↗

PubMed2006

Neonatal ventral hippocampal lesions produce an elevation of DeltaFosB-like protein(s) in the rodent neocortex.

Rats that have sustained bilateral excitotoxic lesions of the ventral hippocampus (VH) as neonates develop behavioral abnormalities as adults (hyper-responsiveness to stress, diminished prepulse inhibition, and increased sensitivity to dopamine agonists), which resemble certain aspects of schizophrenia. Although this behavioral profile is thought to reflect dysregulation of the mesolimbic dopamine system, the precise neuroanatomical and neurochemical substrates that mediate the emergence of these abnormalities during brain maturation are unclear. In order to identify putative sites responsible for the development of behavioral abnormalities following neonatal lesions of the VH, we utilized the chronic neuronal activity marker DeltaFosB. By comparison to sham lesioned animals, bilateral destruction of the VH elevated DeltaFosB expression throughout the caudate putamen and neocortex of animals lesioned as neonates. These increases were not observed in rats lesioned as young-adults, suggesting that DeltaFosB induction in the cortex of neonatally lesioned rats may be related to altered cortical neurodevelopment. Accumulating evidence implicates DeltaFosB in mediation of the long-lasting effects of altered dopaminergic neurotransmission on behavior. The present findings are consistent with this proposal and suggest that elevated expression of DeltaFosB identifies overactive neurons that may contribute to the enhanced sensitivity to stress and dopaminergic agonists of rats that have sustained bilateral ventral hippocampal lesions as neonates.

Age Factors↗

PubMed2006

Permanent, sex-selective effects of prenatal or adolescent nicotine exposure, separately or sequentially, in rat brain regions: indices of cholinergic and serotonergic synaptic function, cell signaling, and neural cell number and size at 6 months of age.

Nicotine is a neuroteratogen that disrupts neurodevelopment and synaptic function, with vulnerability extending into adolescence. We assessed the permanence of effects in rats on indices of neural cell number and size, and on acetylcholine and serotonin (5HT) systems, conducting assessments at 6 months of age, after prenatal nicotine exposure, adolescent exposure, or sequential exposure in both periods. For prenatal nicotine, indices of cell number and size showed few abnormalities by 6 months, but there were persistent deficits in cerebrocortical choline acetyltransferase activity and hemicholinium-3 binding to the presynaptic choline transporter, a pattern consistent with cholinergic hypoactivity; these effects were more prominent in males than females. The expression of 5HT receptors also showed permanent effects in males, with suppression of the 5HT(1A) subtype and upregulation of 5HT(2) receptors. In addition, cell signaling through adenylyl cyclase showed heterologous uncoupling of neurotransmitter responses. Nicotine exposure in adolescence produced lasting effects that were similar to those of prenatal nicotine. However, when animals were exposed to prenatal nicotine and received nicotine subsequently in adolescence, the adverse effects then extended to females, whereas the net effect in males was similar to that of prenatal nicotine by itself. Our results indicate that prenatal or adolescent nicotine exposure evoke permanent changes in synaptic function that transcend the recovery of less-sensitive indices of structural damage; further, prenatal exposure sensitizes females to the subsequent adverse effects of adolescent nicotine, thus creating a population that may be especially vulnerable to the lasting behavioral consequences of nicotine intake in adolescence.

Acetylcholine↗

PubMed2006

The ups and downs of Wnt signaling in prevalent neurological disorders.

In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/beta-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/beta-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

Alzheimer Disease↗

PubMed1991

Slow-to-recover brain-injured patients: rationale for treatment.

Approximately 10-20% of head injury survivors sustain extensive neurological damage and remain minimally or inconsistently responsive to stimuli for 3-6 months postinjury. These patients, designated as slow to recover (STR), may be candidates for sensory stimulation programs rather than traditional rehabilitation. Medical and insurance personnel have resisted referral and payment for treatment because of the lack of objective measures of progress, a theoretical basis for treatment, and evidence of treatment efficacy. A valid, reliable assessment tool has recently been developed (Western Neuro Sensory Stimulation Profile) that assesses low-level cognitive/communicative function and documents improvement in STR patients. This article addresses the theoretical rationale for treatment. Evidence from four areas--sensory deprivation, enriched environments, nervous system plasticity, and sensitive periods of neurodevelopment--suggests that sensory stimulation programs are potentially beneficial for STR patients. Speech-language pathologists are encouraged to study the recovery patterns of STR patients and to determine the efficacy of treatment strategies.

Brain↗

PubMed2002

Assessment of infant physiology and neuronal development using magnetic resonance imaging.

Previous work has demonstrated both that there are substantial individual differences in the rate of physiological development,and that infants with risk factors for Sudden Infant Death Syndrome (SIDS) develop more slowly, suggesting that their increased vulnerability may be due to delayed neuronal development associated with compromised development in fetal or early neonatal life. This project aims to test the hypothesis that individual differences in the rate of physiological development of infants correlate with measurable differences in the rate of brain development as assessed by magnetic resonance imaging (MRI). Sixty infants were recruited to this study in three different groups that are known to have differing rates of physiological development. MRI was performed successfully in 49 cases at 6 weeks of age without sedation. Forty-one of these cases had full follow-up (15 normal; 19 IUGR; 11 'high risk'). Postnatal physiological development was assessed by measuring age-related deep body temperature patterns during sleep. Neuronal development was assessed by subjective analysis of MRI images and objective measurements relating to myelination using T1 and diffusion weighted (23 cases) MRI images. As expected the normal group acquired the adult temperature pattern earlier, but this was not statistically significant. All MRI scan appearances were within normal limits. Ranking cases subjectively in order of maturity revealed no significant pattern. The normal group had a significantly higher myelination score than the IUGR and 'high risk' groups (P = 0.001). This trend was also shown by the diffusion weighted myelination score but did not reach statistical significance. No significant differences were seen in both the subjective and objective MRI measurements and development of nocturnal temperature patterns. The results suggest there may be differences in neurodevelopment between the different groups at 6 weeks of age but these are not linked to late development of temperature patterns. It is therefore unlikely that this related to a global delay in maturation.

Brain↗

PubMed2003

Indicators of children's development: considerations when constructing a set of national Child Health Indicators for the European Union.

BACKGROUND: In a recent project, commissioned by the European Union, a set of Child Health Indicators were identified and recommended for use in all Member States. In that work, by a group of European experts, children's development was one of the key areas that were reviewed to clarify its role in this set of indicators. This paper deals with neurological (in a broad sense), social and moral aspects of development; other aspects, such as nutrition and physical growth, mental health, quality of life were dealt with in other areas. METHODS: A number of methods are used to monitor children's neurodevelopment, to identify early deviations that could be treated or alleviated. Few tests fulfil basic criteria of screening and quality of evidence. For Child Health Programmes, developmental surveillance is instead recommended. As a proxy to social development, as part of children's process of adaptation into society, education indicators are recommended, such as suggested by OECD and UNICEF. Moral development is discarded as an indicator, because norms and values vary too much between countries. CONCLUSION: For now the Child Health Indicators of Life and Development Project found no ground to recommend any particular method or combination of methods for a general monitoring of children's neurological, intellectual, language and moral development, and for including the results as national indicators of children's health and well-being in EU. For social development, indicators in the educational area seem most promising, as they have been proposed and used by OECD and UNESCO. In an ambitious monitoring programme, these indicators could be included as determinants of children's health and development.

Adaptation, Psychological↗

PubMed2003

Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study.

OBJECTIVE: To evaluate the impact of maternal hypothyroxinaemia during early gestation (fT4 below the lowest tenth percentile and TSH within the reference range: 0.15-2.0 mIU/l) on infant development, together with any subsequent changes in fT4 during gestation. DESIGN: A prospective 3-year follow-up study of pregnant women and their children up to the age of 2 years. MEASUREMENTS: Child development was assessed by means of the Bayley Scales of Infant Development in children of women with hypothyroxinaemia (fT4 below the tenth percentile at 12 weeks' gestation) at 12 weeks' gestation (cases), and in children of women with fT4 between the 50th and 90th percentiles at 12 weeks' gestation, matched for parity and gravidity (controls). Maternal thyroid function (fT4 and TSH) was assessed at 12, 24 and 32 weeks' gestation. The mental and motor function of 63 cases and 62 controls was compared at the age of 1 year, and of 57 cases and 58 controls at the age of 2 years. RESULTS: Children of women with hypothyroxinaemia at 12 weeks' gestation had delayed mental and motor function compared to controls: 10 index points on the mental scale (95% CI: 4.5-15 points, P = 0.003) and eight on the motor scale at the age of 1 year (95% CI: 2.3-12.8 points, P = 0.02), as well as eight index points on the mental (95% CI: 4-12 points, P = 0.02), and 10 on the motor scale (95%CI: 6-16 points, P = 0.005) at the age of 2 years. Children of hypothyroxinaemic women in whom the fT4 concentration was increased at 24 and 32 weeks' gestation had similar scores to controls, while in the controls, the developmental scores were not influenced by further declines in maternal fT4 at 24 and 32 weeks' gestation. CONCLUSIONS: Maternal hypothyroxinaemia during early gestation is an independent determinant of a delay in infant neurodevelopment. However, when fT4 concentrations increase during pregnancy in women who are hypothyroxinaemic during early gestation, infant development appears not to be adversely affected.

Adult↗