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PubMed2006

En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is a prevalent and inheritable neurodevelopmental disorder. Recent human genetic studies are consistent with the homeobox transcription factor, ENGRAILED 2 (EN2), being an ASD susceptibility gene. En2 knockout mice (En2(-/-)) display subtle cerebellar neuropathological changes similar to what has been observed in the ASD brain. To investigate whether En2(-/-) mice displayed abnormal behavior relevant to ASD, they were monitored in tasks designed to assess social maturation as well as learning and memory. Deficits in social behavior were detected in En2(-/-) mice across maturation that included decreased play, reduced social sniffing and allogrooming, and less aggressive behavior. Deficits in two spatial learning and memory tasks were also observed. Because locomotor activity was a component of many of the behavioral tasks, this was measured at various stages of development. Locomotor activity was not compromised in the knockout. However, a more thorough analysis of motor behavior in En2(-/-) mice revealed deficits in specific motor tasks. To determine whether neurochemical changes were associated with these behavioral phenotypes, monoamine levels in specific brain regions were assessed. A cerebellar-specific increase in serotonin and its metabolite was observed. Interestingly, several reports have suggested that the serotonin pathway is affected in ASD. We conclude that En2(-/-) mice display behavioral and neurochemical changes, in addition to genetic and neuropathological changes, relevant to ASD. Therefore, these mice may be useful as an animal model of autism.

Aggression↗

PubMed2005

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR=1.6, P=0.02) with a strong paternal effect (paternal transmissions: OR=3.2, P=0.0005; maternal transmissions: OR=1.00; P=1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved.

Amino Acid Substitution↗

PubMed1996

Autism spectrum disorders in children with physical or mental disability or both. I: Clinical and epidemiological aspects.

The prevalence of autism spectrum disorders was studied in all children with mental retardation and/or motor disability in a defined geographical region over a two-year follow-up period. In the general population, the prevalence of autistic disorder was 0.09% at the end of the follow-up period -a minimum estimate, as children with average intelligence were not screened. Autism spectrum disorders were found in 19.8% of children with mental retardation, including strictly defined autistic disorder (DSM-III-R criteria) in 8.9%; the two-year follow-up yielded a higher prevalence of 11.7% with autistic disorder. Among children with cerebral palsy, 10.5% had an autism spectrum disorder. Clear co-variation was found between mental retardation, epilepsy and autism spectrum disorders in this population of children with neurodevelopmental disorders.

Adolescent↗

PubMed2003

Attention deficit and hyperactivity disorder: review of genetic association studies.

Attention Deficit and Hyperactivity Disorder (ADHD) is a common idiopathic childhood neurodevelopmental disorder, exacting a significant clinical and public health toll. It impairs schooling and social adaptation, resulting in high rates of depression, conduct disorder, school dropouts, and substance abuse, and necessitating exposure of many children to prolonged courses of stimulant psychotropic medication. Although the biological basis of ADHD is unknown, it has been shown to possess considerable heritability. Candidate gene association studies proved to be a productive strategy leading to replicated association findings of genetic loci contributing to susceptibility to ADHD. Based on the mechanism of action of stimulant drugs effective in the alleviation of ADHD symptoms, current association studies have focused mainly on dopaminergic genes. Promising exploratory findings have also been reported for genes affecting other neurotransmitter systems. The current article reviews the rationale, methodology, and main findings in the field, and outlines future directions. Locating the actual genes mediating ADHD susceptibility will have far reaching implications for understanding the pathophysiology of ADHD as well as for understanding mechanisms of therapeutic drug action and genetic determinants of response.

Attention Deficit Disorder with Hyperactivity↗

PubMed1992

[Continuity and discontinuity of psychopathology: a study of patients examined as children and as adults. I. Antecedents of adult schizophrenic disorders].

The demographical stability of the Canton of Geneva made it possible for us to do a prospective study of all the children who had consulted the Child Psychiatry Service between 1963 and 1967 and who later consulted the public adult psychiatry services. On the basis of the adult diagnoses, wo looked for specific clinical "clusters" in childhood which would allow us to differentiate statistically the groups of children. We present here the results of the group of children who developed schizophrenia in adulthood. We found a specific childhood "cluster" which clearly distinguishes these children from the others. It includes: serious relational disorders, neurodevelopmental impairment, attention deficit and school learning disorders.

Adolescent↗

PubMed2005

[Movement disorders in Rett syndrome].

INTRODUCTION: Rett syndrome is a progressive neurodevelopmental disorder with onset in early childhood occurring almost exclusively in females and caused by mutations in methyl-CpG- binding protein 2 (MECp2) and is one of the most frequent causes of mental retardation in females. Regression is a defining feature of Rett syndrome and during the regression period the patients develop autistic behaviour. This is the reason why Rett syndrome has been classified as a pervasive developmental autistic spectrum disorder. However movement disorders are so exuberant, characteristic and unique in Rett syndrome that is very difficult to an experienced clinician mistake both situations. DEVELOPMENT: We can define Rett syndrome as a condition which manifests in the majority of the cases as a hyperkinetic movement disorder and progresses (at varying rates) to a bradykinetic disorder. The aim of this publication is to characterize and describe movement disorders in Rett syndrome based on a revision of the literature and the personal experience of the author.

Movement Disorders↗

PubMed2005

A two-phased population epidemiological study of the safety of thimerosal-containing vaccines: a follow-up analysis.

BACKGROUND: Thimerosal is an ethylmercury-containing preservative in vaccines. Toxicokinetic studies have shown children received doses of mercury from thimerosal-containing vaccines (TCVs) that were in excess of safety guidelines. Previously, an ecological study showing a significant association between TCVs and neurodevelopmental disorders (NDs) in the US was published in this journal. MATERIAL/METHODS: A two phased population-based epidemiological study was undertaken. Phase one evaluated reported NDs to the Vaccine Adverse Event Reporting System (VAERS) following thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccines in comparison to thimerosal-free DTaP vaccines administered from 1997 through 2001. Phase two evaluated the automated Vaccine Safety Datalink (VSD) for cumulative exposures to mercury from TCVs at 1-, 2-, 3-, and 6-months-of-age for infants born from 1992 through 1997 and the eventual risk of developing NDs. RESULTS: Phase one showed significantly increased risks for autism, speech disorders, mental retardation, personality disorders, and thinking abnormalities reported to VAERS following thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines. Phase two showed significant associations between cumulative exposures to thimerosal and the following types of NDs: unspecified developmental delay, tics, attention deficit disorder (ADD), language delay, speech delay, and neurodevelopmental delays in general. CONCLUSIONS: This study showed that exposure to mercury from TCVs administered in the US was a consistent significant risk factor for the development of NDs. It is clear from these data and other recent publications linking TCVs with NDs that additional ND research should be undertaken in the context of evaluating mercury-associated exposures and thimerosal-free vaccines should be made available.

Child↗

PubMed2025

DNA methylation and machine learning: challenges and perspective toward enhanced clinical diagnostics.

DNA methylation is an epigenetic modification that regulates gene expression by adding methyl groups to DNA, affecting cellular function and disease development. Machine learning, a subset of artificial intelligence, analyzes large datasets to identify patterns and make predictions. Over the past two decades, advances in bioinformatics technologies for arrays and sequencing have generated vast amounts of data, leading to the widespread adoption of machine learning methods for analyzing complex biological information for medical problems. This review explores recent advancements in DNA methylation studies that leverage emerging machine learning techniques for more precise, comprehensive, and rapid patient diagnostics based on DNA methylation markers. We present a general workflow for researchers, from clinical research questions to result interpretation and monitoring. Additionally, we showcase successful examples in diagnosing cancer, neurodevelopmental disorders, and multifactorial diseases. Some of these studies have led to the development of diagnostic platforms that have entered the global healthcare market, highlighting the promising future of this field.

Humans↗

PubMed2002

Neonatal development of projections from the basolateral amygdala to prefrontal, striatal, and thalamic structures in the rat.

Recently, an animal model for neurodevelopmental disorders has been developed. In this model, the effects of an early neonatal (postnatal day 7 [Pd 7]) basolateral amygdala lesion are compared with the effects of a lesion later in life (Pd 21). The reported data indicate that amygdala damage at a specific point early in life results in enduring behavioral disturbances that become more manifest after puberty, for example, only an early lesion resulted in a disruption of the prepulse inhibition, which is also observed in people suffering from schizophrenia. Accordingly, it was postulated that the early damage may affect the neuroanatomic and neurochemical organization and functioning of other brain structures. This was studied by use of the anterograde tracers biotinylated dextran amine and Phaseolus vulgaris-leucoagglutinin. At neonatal days 7, 9, 11, 13, and 26, amygdaloid fibers were in particular present in the mediodorsal thalamus (MDT), nucleus accumbens (Acb), and prefrontal cortex (PFC). The development of the topography of the amygdaloid innervation, however, differed markedly for the MDT and Acb compared with the PFC. For the MDT and Acb, no major changes in innervation were observed between Pd 7 and Pd 26, whereas the innervation of the PFC reorganized from a neonatal diffuse (Pd 7 and 9) to a restricted pattern (Pd 11, 13, and 26). In addition, the innervation changed to an adult-like bilaminar pattern. These data provide information on the circuitry that may be involved in the aberrant neurodevelopment of neonatally amygdala-lesioned rats, which have been proposed as an animal model for neurodevelopmental psychopathological disorders.

Aging↗

PubMed2025

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson Syndrome.

Sex-specific penetrance in autosomal dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1 R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety and hypotonia. Orchiectomy unmasks a growth deficiency phenotype in male Chd1 R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open novel avenues to understand the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

CHD1↗

PubMed2002

Neonatal development of projections to the basolateral amygdala from prefrontal and thalamic structures in rat.

Recently an animal model for neurodevelopmental disorders has been developed. In this model the effects of an early neonatal [postnatal day 7 (Pd7)] basolateral amygdala lesion are compared with the effects of a lesion later in life (Pd21). Early amygdala damage results in enduring behavioral disturbances that become more manifest after puberty. These disturbances were not present in animals lesioned at Pd21. Accordingly it was postulated that the early damage may affect the neuroanatomical and neurochemical organization and functioning of other brain structures. To obtain information on the innervation of the amygdala during normal development, we used the retrograde tracer fluoro-gold. From neonatal day 7 onward (studied until Pd19), retrogradely labeled cells were present in the caudal and rostral thalamus, the substantia innominata, and the prefrontal but not the caudal cortex. Development of the topography of the projecting cells differed substantially for the thalamic regions and substantia innominata vs. the cortical regions. In thalamic regions and substantia innominata, no changes were observed during the studied period (Pd7-Pd9). In the prefrontal cortex, the number of labeled cells increased (from Pd7 to Pd13), the topography of the location of the cells changed from unilateral to bilaminar (from Pd9 to Pd13), and the number of subareas in which the cells were present increased (from Pd7 to Pd13). In the caudal cortex, relatively few cells were present up to Pd15. From Pd17 onward, a bilaminar topography of the location of the cells was observed. These data provide information on the circuitry that may be involved in the aberrant neurodevelopment of neonatally amygdala-lesioned rats, which has been proposed as an animal model for neurodevelopmental psychopathological disorders.

Aging↗

PubMed2026

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome.

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male-protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open avenues toward understanding the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

Male↗

PubMed2026

Sex and tissue resolved co-expression networks reveal a female placental-brain axis protective against prenatal PCB exposure.

BACKGROUND: Neurodevelopmental disorders have a strong male bias that is poorly understood. The placenta provides molecular information about environmental interactions with genetics (including biological sex) that shape developmental processes in the brain. We investigate placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). RESULTS: To understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta RNAseq data, we use weighted gene correlation network analysis (WGCNA) to create gene networks that could be compared across sex or tissue. WGCNA reveals that expression within most correlated gene networks is significantly and strongly associated with PCB exposure, but frequently in opposite directions between male-female and placenta-brain comparisons. In WGCNA and differentially expressed gene analyses, more transcriptional changes are observed in male brain than placenta, but the reverse is seen in females. Furthermore, female X-inactive specific transcript (Xist) levels correlate with sex-specific and non-monotonic PCB dose response, suggesting an X-linked protective epigenetic mechanism. The transcriptomic effects of low-dose PCB exposure are significantly opposed by dietary folic acid supplementation across both sexes but are strongest in female placentas. PCB and folic acid interacting gene networks are enriched in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipid, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. CONCLUSIONS: A female protective effect in response to prenatal PCB exposure appears to be mediated by dose-dependent sex differences in transcriptional modulation of placental metabolic pathways.

Female↗

PubMed2002

FOXP2: novel exons, splice variants, and CAG repeat length stability.

FOXP2 is a transcription factor containing a polyglutamine tract, a zinc-finger motif, and a forkhead DNA-binding domain. The FOXP2 gene is located on 7q31. A missense mutation in the forkhead domain (exon 14) and a balanced reciprocal translocation t(5;7)(q22;q31.2) with a breakpoint between exons 3b and 4 have recently been associated with a speech and language disorder (SPCH1). The role of FOXP2 in this neurodevelopmental disorder suggests that mutations in FOXP2 could cause other neuropsychiatric disorders. To begin investigation of this possibility, we examined the genomic structure and CAG/CAA repeat region of FOXP2. We detected little polymorphism and no expansions in the FOXP2 CAG/CAA repeat in 142 individuals with progressive movement disorders. We found evidence of alternate splice variants and six previously undetected exons: three 5' untranslated exons (s1, s2, s3), two additional untranslated exons (2a and 2b) between exons 2 and 3, a translated exon (4a) between exons 4 and 5, and a longer version of exon 10 (10+) that contains an alternate stop codon and produces a truncated protein (FOXP2-S). Our results suggest that FOXP2 spans at least 603 kb of genomic DNA, more than twice the previously defined region, and provide evidence of a promoter region flanking exon s1. This demonstration of additional FOXP2 exons and splice variants should facilitate understanding of FOXP2 function and the search for additional FOXP2 mutations.

Alternative Splicing↗

PubMed2024

Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.

PURPOSE: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. METHODS: A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. RESULTS: The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. CONCLUSION: Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Humans↗

PubMed2000

Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder. Evidence from twin, adoption, and family studies provide support for a genetic contribution to the etiology of ADHD. Several candidate gene studies have identified an association between a 7-repeat variant in exon 3 of the dopamine 4 receptor gene (DRD4) and ADHD. However, in spite of the positive reports finding association of the exon 3 VNTR with ADHD, several other polymorphisms within DRD4 have been identified that conceivably could contribute to risk for ADHD. Recently, another common polymorphism of the DRD4 gene has been described involving a 120-bp repeat element upstream of the 5' transcription initiation site. In this report, we describe results of analysis of the DRD4 120-bp repeat promoter polymorphism in a sample of 371 children with ADHD and their parents, using the transmission disequilibrium test (TDT). Results showed a significant preferential transmission of the 240-bp (long) allele with ADHD. Exploratory analyses of the Inattentive phenotypic subtype of ADHD strengthened the evidence for linkage. These data add further support for the role of DRD4 variants conferring increased risk for ADHD, and imply that additional studies of DRD4 and other related genes are needed.

Adolescent↗

PubMed2005

Source memory in children with autism spectrum disorders.

The evidence to date regarding memory processes in children with autism spectrum disorders (ASD) remains equivocal. Although children with these neurodevelopmental disorders have been shown to display exceptional memories for fact-based information, they seem to be less able to attach meaning or context to their memories. Thus, this study investigated the specific role of source memory in autism. Children with ASD were compared to a chronological and mental age-matched comparison group of typically developing children. Although children with autism performed similarly to controls on a fact recognition measure, their performance on a source memory task was significantly lower. The findings indicated, however, that the nature of source memory confusion in children with autism does not appear to reflect a generalized deficit in attaching context to memories but rather is dependent on the specific to-be-remembered information that, in this study, involves social aspects of context.

Adolescent↗

PubMedDate not supplied

[Magnetoencephalography in cognitive disorders involving frontal lobes].

INTRODUCTION AND DEVELOPMENT: Frontal lobe, more specifically prefrontal cortex, is one of the brain regions that undergoes more protracted ongoing development. The wider the developmental window of one brain structure, the more vulnerable the functions related to it. Hence, executive functions, which are mediated by prefrontal networks, seems to be specially vulnerable during childhood. Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders. Functional neuroimaging techniques have shown a dysfunction in a fronto-striatal network in this disorder, that is likely subserving deficits in executive processes, such as in response inhibition. DISCUSSION: This review focuses on contributions of neuroimaging techniques, with high spatial (SPECT, PET and fMRI), temporal (ERP) and spatio-temporal (MEG) resolution, to the neurofunctionality of ADHD.

Attention Deficit Disorder with Hyperactivity↗