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PubMed2001

Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.

Autistic disorder is a neurodevelopmental disorder with a complex genetic etiology. Observations of maternal duplications affecting chromosome 15q11-q13 in patients with autism and evidence for linkage and linkage disequilibrium to markers in this region in chromosomally normal autism families indicate the existence of a susceptibility locus. We have screened the families of the Collaborative Linkage Study of Autism for several markers spanning a candidate region covering approximately 2 Mb and including the Angelman syndrome gene (UBE3A) and a cluster of gamma-aminobutyric acid (GABA(A)) receptor subunit genes (GABRB3, GABRA5, and GABRG3). We found significant evidence for linkage disequilibrium at marker D15S122, located at the 5' end of UBE3A. This is the first report, to our knowledge, of linkage disequilibrium at UBE3A in autism families. Characterization of null alleles detected at D15S822 in the course of genetic studies of this region showed a small (approximately 5-kb) genomic deletion, which was present at somewhat higher frequencies in autism families than in controls.

Alleles↗

PubMed2005

Comparative study of cerebral white matter in autism and attention-deficit/hyperactivity disorder by means of magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: Autism and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders whose pathophysiology is mostly unknown. As far as the symptoms are different and, in some aspects, opposed, we hypothesize that there must be biochemical differences in the brain of the afflicted children. The aim of the study is to analyze comparatively the metabolite concentration of the cerebral white matter in autism, in ADHD, and in a control group of healthy children to test the hypothesis that N-acetyl aspartate (NAA) is decreased in autism and increased in ADHD. PATIENTS AND METHODS: We included 21 autistic children according to DSM-IV criteria, 8 children with ADHD meeting the respective criteria of DSM-IV, and 12 healthy controls of similar age. Single-voxel proton magnetic resonance spectroscopy was performed on all of them with an echo time of 30 milliseconds and a repetition time of 2500 milliseconds. The voxel was placed in the left centrum semiovale. Metabolite ratios relative to creatine were reported for NAA, choline, and myoinositol. RESULTS: Although we did not observe differences between autistic children and controls, we found a mean higher concentration of NAA in the left centrum semiovale of ADHD children (2.2; SD, 0.21) than that found in autistic children (1.88; SD, 0.18) and controls (1.91; SD, 0.01), which was significant (P = .01 in parametric and in nonparametric test). CONCLUSION: We conclude that white matter of autistic children does not present alterations on MRS. We hypothesize that the higher concentration of NAA in the white matter of ADHD points to mitochondrial hypermetabolism. This may constitute a new substrate in the pathophysiology and merits further research.

Analysis of Variance↗

PubMed2004

Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data.

OBJECTIVE: The issue of thimerosal-containing vaccines as a possible cause of autistic spectrum disorders (ASD) and neurodevelopmental disorders (NDDs) has been a controversial topic since 1999. Although most practitioners are familiar with the controversy, many are not familiar with the type or quality of evidence in published articles that have addressed this issue. To assess the quality of evidence assessing a potential association between thimerosal-containing vaccines and autism and evaluate whether that evidence suggests accepting or rejecting the hypothesis, we systematically reviewed published articles that report original data pertinent to the potential association between thimerosal-containing vaccines and ASD/NDDs. METHODS: Articles for analysis were identified in the National Library of Medicine's Medline database using a PubMed search of the English-language literature for articles published between 1966 and 2004, using keywords thimerosal, thiomersal, mercury, methylmercury, or ethylmercury alone and combined with keywords autistic disorder, autistic spectrum disorder, and neurodevelopment. In addition, we used the "related links" option in PubMed and reviewed the reference sections in the identified articles. All original articles that evaluated an association between thimerosal-containing vaccines and ASD/NDDs or pharmacokinetics of ethylmercury in vaccines were included. RESULTS: Twelve publications that met the selection criteria were identified by the literature search: 10 epidemiologic studies and 2 pharmacokinetic studies of ethylmercury. The design and quality of the studies showed significant variation. The preponderance of epidemiologic evidence does not support an association between thimerosal-containing vaccines and ASD. Epidemiologic studies that support an association are of poor quality and cannot be interpreted. Pharmacokinetic studies suggest that the half-life of ethylmercury is significantly shorter when compared with methylmercury. CONCLUSIONS: Studies do not demonstrate a link between thimerosal-containing vaccines and ASD, and the pharmacokinetics of ethylmercury make such an association less likely. Epidemiologic studies that support a link demonstrated significant design flaws that invalidate their conclusions. Evidence does not support a change in the standard of practice with regard to administration of thimerosal-containing vaccines in areas of the world where they are used.

Autistic Disorder↗

PubMed2006

[Autistic disorder: current psychopharmacological treatments and areas of interest for future developments].

Autistic disorder and the group of related conditions defined as pervasive developmental disorders are chronic neurodevelopmental disorders starting in early childhood and affecting a significant number of children and families. Although the causes and much of the pathophysiology of the disorder remain unknown, in recent years a number of available medication treatments have been identified as holding promise in alleviating some of the most disabling maladaptive behaviors, associated with pervasive developmental disorders. However these treatments do not address the core symptoms of the disease and oftentimes their side effects outweigh their benefits. Therefore there is substantial need for new medications that are safer and more effective in addressing the behavior symptoms of autism. The aim of this review is to highlight the available current pharmacotherapies and those emerging treatments with potential to enhance the treatment options of patients with pervasive developmental disorders.

Antidepressive Agents↗

PubMed2026

Comparative Proteomic Analysis of the Striatum in Heterozygous and Null DAT Knockout Rats.

Deregulation of striatal neurotransmission is a key pathogenetic mechanism in neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism. In the present study, we applied a proteomic approach to demonstrate shifts in striatal protein expression in rats with heterozygous (DAT-Het) and homozygous (DAT-KO) dopamine transporter (DAT) gene knockouts. These animals model dose-dependent ADHD- and autism-like behaviors, ranging from slightly increased activity and social disturbances in DAT-Het rats to a pronounced phenotype in DAT-KO rats. We revealed pronounced changes in the proteomic profiles of both groups, associated primarily with deregulation of proteins involved in energy and carbon metabolism. Furthermore, we identified changes in vesicular transport proteins specific to DAT-KO and DAT-Het rats. Since these changes involved SNARE complex components, we evaluated SNARE mRNA expression in our models and public transcriptomic data for mouse models of neurodevelopmental disorders, including Mbd5 gene haploinsufficiency and a polygenic model of ADHD. No significant changes in mRNA levels were revealed in any model. Thus, the identified protein expression changes likely depend on post-transcriptional mechanisms. These data suggest a deregulation of metabolism in DAT-Het rats, which becomes more pronounced in DAT-KO rats.

Animals↗

PubMed2026

Expanding the TBL1XR1 Disease Spectrum: Generalized Dystonia Associated with a New Genetic Variant.

BACKGROUND: A growing number of identified genes increasingly reveal genetic overlaps between neurodevelopmental disorders and combined dystonia syndromes. CASE REPORT: We report a 61-year-old man with a neurodevelopmental disorder, mild ataxic signs and generalized dystonia who had been misdiagnosed with cerebral palsy for 40 years. Whole-exome sequencing identified a novel heterozygous pathogenic frameshift variant in TBL1XR1. DISCUSSION: TBL1XR1 variants are classically associated with Pierpont syndrome and autism spectrum disorder. Although movement disorders have been reported, this case suggests generalized dystonia as a possible additional manifestation. It highlights the value of retrospective genetic phenotyping and next-generation sequencing in adults with long-standing neurodevelopmental diagnoses.

Humans↗

PubMed2026

Identification of biallelic loss-of-function PREP variants in three individuals with syndromic intellectual disability.

BACKGROUND: Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene PREP encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous PREP variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted. METHODS: Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected PREP variants. RESULTS: We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare PREP variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A>G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein. CONCLUSION: Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.

Female↗

PubMed2004

What ever happened to developmental Gerstmann's syndrome? Links to other pediatric, genetic, and neurodevelopmental syndromes.

Developmental Gerstmann's syndrome is a neurodevelopmental disorder infrequently described in the literature. The limited literature might result from controversy surrounding developmental Gerstmann's syndrome as a "true syndrome." Developmental Gerstmann's syndrome requires a tetrad of symptoms: left-right confusion, finger agnosia, dyscalculia, and dysgraphia, with constructional dyspraxia often included as a fifth symptom. The etiology of developmental Gerstmann's syndrome is unknown, but several hypotheses have been proposed, and none have been conclusively confirmed. Based on the paucity of recent research on developmental Gerstmann's syndrome, individuals who meet the criteria for the disorder could be given other diagnoses. A clustering of neuropsychologic features across other seemingly related disorders suggests that the conceptualization of the tetrad of symptoms traditionally associated with developmental Gerstmann's syndrome more appropriately reflects soft signs that are commonly associated with a number of other neurodevelopmental disorders. Thus, although developmental Gerstmann's syndrome is of historical interest to neurodevelopmental specialists, there appears to be no basis for considering this disorder as a unique syndrome.

Diagnosis, Differential↗

PubMed2003

Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases.

OBJECTIVE: To assess the possible toxicity of thimerosal-containing vaccines (TCVs) among infants. METHODS: A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 micro g of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life. RESULTS: In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05-3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01-1.27) and 7 months (RR: 1.07; 95% CI: 1.01-1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder. CONCLUSIONS: No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed.

Cohort Studies↗

PubMed2003

The behavioral neurogenetics of fragile X syndrome: analyzing gene-brain-behavior relationships in child developmental psychopathologies.

Analyzing gene-brain-behavior linkages in childhood neurodevelopmental disorders, a research approach called "behavioral neurogenetics," has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene-brain-behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.

Adolescent↗

PubMed2005

Neurodevelopmental disabilities: beyond the diagnosis.

Increasingly clinicians are taking more active roles in the management of children with neurodevelopmental disorders. Management of these children extends beyond traditional boundaries of health. The purpose of this review is to provide clinicians with an approach to the management of children with neurodevelopmental disorders. Patient advocacy is crucial for effective practice when working with children with neurodevelopmental disabilities. An effective advocate understands how a child's impairments relate to his/her limitations and works to prevent barriers to participation. The advocate recognizes the multiple domains in a child's health and life that must be addressed. An overall management program should be developed in cooperation with the child's primary advocates, his/her family. There are multiple different therapies, each with its own goals, that should be coordinated and prioritized as part of this plan. Federal programs can provide some of these therapies for children.

Adolescent↗

PubMed2004

Trends in environmentally related childhood illnesses.

Tracking incidence or prevalence of diseases and using that information to target interventions is a well-established strategy for improving public health. The need to track environmentally mediated chronic diseases is increasingly recognized. Trends in childhood illnesses are 1 element of a framework for children's environmental health indicators, which also includes trends in contaminants in the environment and in concentrations of contaminants in bodies of children and their mothers. This article presents data on 3 groups of important childhood diseases or disorders that seem to be caused or exacerbated, at least in part, by exposure to environmental agents and for which nationally representative data are available. They are asthma, childhood cancers, and neurodevelopmental disorders. Data were used from the National Health Interview Survey for asthma and neurodevelopmental disorders; the Surveillance, Epidemiology, and End Results Program for childhood cancer incidence; and the National Vital Statistics System for childhood cancer mortality. The prevalence of children with asthma doubled between 1980 and 1995, from 3.6% in 1980 to 7.5% in 1995. The annual incidence of childhood cancer increased from 1975 until approximately 1990 and seems to have become fairly stable since. Childhood cancer mortality has declined substantially during the past 25 years. Incidence of certain types of cancers has increased since 1974, including acute lymphoblastic leukemia, central nervous system tumors, and non-Hodgkin's lymphoma. Approximately 6.7% of children aged 5 to 17 were reported to have attention-deficit/hyperactivity disorder in 1997-2000, and approximately 6 of every 1000 children were reported to have received a diagnosis of mental retardation during the same period.

Adolescent↗

PubMed2026

Maternal immune activation disrupts epigenomic and functional maturation of cortical excitatory neurons.

Elevated levels of maternal pro-inflammatory cytokines following severe infection during gestation can disrupt offspring neural development and increase the risk of neurodevelopmental disorders. The viral mimetic Poly(I:C) reproduces the effects of gestational influenza exposure, leading to behavioral outcomes that recapitulate neurodevelopmental disorder phenotypes. Although Poly(I:C)-induced maternal immune activation (PIC-MIA) alters the epigenome, behavior and cognition of offspring in adulthood, it remains unclear when these changes occur and how MIA influences the epigenomic regulatory programming across the transition from embryonic development to the mature brain. Here, we examined the effects of PIC-MIA on the epigenomic maturation of the frontal cortex, focusing on excitatory neuron-specific DNA methylation and transcriptomic dynamics throughout perinatal development. Mid-gestation PIC-MIA disrupted development of the excitatory neuron transcriptome, with the largest alterations observed at birth. PIC-MIA altered the development of the mature DNA methylation program of excitatory neurons at thousands of genomic regulatory regions that normally gain or lose methylation during development. Transcription factor binding site analyses of these differentially methylated regions revealed a significant enrichment of Tbr1 motifs within hyper-methylated deep-layer neuron-specific regions at birth. Notably, transcriptional targets of Tbr1 were down-regulated at birth despite up-regulation of Tbr1 transcription, suggesting PIC-MIA uncouples Tbr1 expression from its regulatory function in deep-layer neurons. Electrophysiological recordings of intrinsic and firing properties further confirmed a lasting disruption in deep-layer neuronal activity. Our results suggest that mid-gestation MIA may alter the development of deep-layer neurons through an epigenomic blockade of Tbr1 function, thereby perturbing normal cortical circuit formation.

Journal Article↗

PubMed2006

Shape deformation of the insula in schizophrenia.

Schizophrenia has been conceptualized to be a neurodevelopmental disorder. Neuroimaging evidence was generally findings of volumetric reductions in various brain structures. The shape analysis of the insula can uncover unique structural deformity in the neurodevelopmental disorder, which cannot be revealed from a simple volume measurement. The objective of this study was to demonstrate a subtle change of the insula in schizophrenia using our special shape analysis technique. Subjects were 23 patients with schizophrenia and 23 normal healthy subjects. A landmark-based structural and surface shape analysis of the insula was performed using high-spatial resolution magnetic resonance imaging. A characteristic finding was that the frontotemporal sides of the right insula were deformed in the patients with schizophrenia compared with normal controls. This deformation can be associated with abnormal development of the frontal and temporal lobes in schizophrenia.

Adult↗

PubMed1994

Assessing the legacy of the GBG model.

A critique of the article by Bryden, McManus, and Bulman-Fleming ("Evaluating the empirical support for the Geschwind-Behan-Galaburda model of cerebral lateralization") is presented. Bryden et al. expose some of the principal weaknesses of the cerebral lateralization model put forth by Geschwind and colleagues and contribute an important meta-analysis of findings concerning the model's predicted relationship between immune disorders and handedness. Nonetheless, the theory put forth by Geschwind and colleagues retains an important legacy despite a multitude of faulty assumptions and predictive failures. Also offered is a brief synopsis of a new model that explains the many positive relationships found among various neurodevelopmental disorders and medical conditions, as well as why abnormal handedness distributions occur in some but not other neurodevelopmental disorders.

Child↗

PubMed2001

Autism and Parkinson's disease.

The pathogenesis of Parkinson's disease, a neurodegenerative disorder, is multifaceted, having a variety of genetic and environmental factors. There is considerable evidence to support the role of toxins, particularly pesticides and herbicides, in at least some of those affected (presumably, mostly the genetically vulnerable). The pathogenesis of autism is no less complex, but little is known about the potential role of toxins for autism, a neurodevelopmental disorder. The incidence of autism appears to be rising, and early exposure to synthetic chemicals is one suspect for this rise. Impaired detoxification of certain chemicals may be common to autism and Parkinson's disease. Further study of environmental influences for either disorder may lead to important insights regarding causation for both, and perhaps for other neurodegenerative and neurodevelopmental disorders as well.

Autistic Disorder↗

PubMed2006

Developmental neurotoxicity of industrial chemicals.

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

Adolescent↗

PubMed2004

Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association.

OBJECTIVE: After concerns about the possible toxicity of thimerosal-containing vaccines in the United States, this study was designed to investigate whether there is a relationship between the amount of thimerosal that an infant receives via diphtheria-tetanus-whole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccination at a young age and subsequent neurodevelopmental disorders. METHODS: A retrospective cohort study was performed using 109 863 children who were born from 1988 to 1997 and were registered in general practices in the United Kingdom that contributed to a research database. The disorders investigated were general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, encopresis, and enuresis. Exposure was defined according to the number of DTP/DT doses received by 3 and 4 months of age and also the cumulative age-specific DTP/DT exposure by 6 months. Each DTP/DT dose of vaccine contains 50 microg of thimerosal (25 microg of ethyl mercury). Hazard ratios (HRs) for the disorders were calculated per dose of DTP/DT vaccine or per unit of cumulative DTP/DT exposure. RESULTS: Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses (Cox's HR: 1.50 per dose at 4 months; 95% confidence interval [CI]: 1.02-2.20). Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders (HR: 0.87; 95% CI: 0.81-0.93), unspecified developmental delay (HR: 0.80; 95% CI: 0.69-0.92), and attention-deficit disorder (HR: 0.79; 95% CI: 0.64-0.98). For the other disorders, there was no evidence of an association with thimerosal exposure. CONCLUSIONS: With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders.

Attention Deficit Disorder with Hyperactivity↗