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Results for “Neurodevelopmental Disorders”

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PubMed2006

Diffusion tensor magnetic resonance imaging tractography in cognitive disorders.

PURPOSE OF REVIEW: The advent of novel techniques for tracing connections in vivo, such as diffusion tensor magnetic resonance imaging tractography, allows us, for the first time in the human brain, to study the microstructural integrity of white matter fibres and perform virtual dissections of large scale neurocognitive networks. This review will outline the advantages and limitations of applying diffusion tensor magnetic resonance imaging to the study of cognitive and behavioural disorders in neurology and psychiatry. RECENT FINDINGS: Diffusion tensor magnetic resonance imaging has been used to re-explore the anatomy of white matter tracts in the living human brain and to create connectional models of brain function. Beyond its application to classical disconnection syndromes, diffusion tensor magnetic resonance imaging is becoming an important tool to extend the disconnectionist paradigm to neurodevelopmental and neurodegenerative disorders. SUMMARY: For the first time, we are able to correlate disconnecting lesions with clinical symptoms in vivo and test the disconnection mechanism directly in cognitive disorders. With diffusion tensor magnetic resonance imaging tractography alone and in combination with other magnetic resonance imaging techniques, researchers are able to detect abnormalities in white matter that are not visible with conventional magnetic resonance imaging.

Anisotropy↗

PubMed2026

[Tics and Tourette Syndrome].

Tics disorders and Tourette syndrome (TS) are neurodevelopmental conditions characterized by motor and/or vocal tics with onset in childhood. Their clinical presentation is heterogeneous and fluctuating over time, with exacerbations related to emotional, environmental, and medical factors. Diagnosis is clinical and based on medical history and neurological examination, following DSM-5-TR criteria, with ancillary testing rarely required. The prevalence of TS is estimated at 0.7%, while transient tic disorders affect up to 10% of children. The natural history is generally favorable, with symptom improvement during adolescence, although a subset of patients continues to experience tics into adulthood. Most individuals with TS present psychiatric comorbidities, particularly attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, which significantly impact quality of life and should be prioritized in management decisions. Treatment is recommended only when tics cause functional impairment and follows a stepwise approach including psychoeducation, behavioral interventions, and individualized pharmacological therapy. Comprehensive behavioral intervention for tics is considered first-line treatment when available. Alpha-2 adrenergic agonists and dopamine antagonists are the most commonly used pharmacological options. Neuromodulation therapies are reserved for severe, refractory cases. These recommendations from the Ibero-American Academy of Pediatric Neurology summarize current evidence and provide a practical, updated framework for the diagnosis and management of tic disorders and Tourette syndrome in pediatric patients.

Humans↗

PubMed2026

Biallelic ABCA13 Loss-of-Function Variants in a Child With Neurodevelopmental Delay: A Case Report.

ABCA13 encodes ATP-binding cassette subfamily A member 13, one of the largest members of the ABC transporter family. Rare ABCA13 variants have been reported in neuropsychiatric and neurodevelopmental phenotypes, including schizophrenia, bipolar disorder, autism spectrum disorder, intellectual disability, and developmental delay; however, the mode of inheritance remains uncertain, and most published cases have focused on heterozygous variants in the context of a possible dominant or susceptibility model. We report a 5-year-old boy with neurodevelopmental delay, skeletal foot deformities, nonspecific dysmorphic features, convergent strabismus, and behavioral abnormalities. Initial genome sequencing analysis was nondiagnostic. Reanalysis after 6 months identified two rare predicted loss-of-function variants in ABCA13 in trans: c.2510del, p.(Leu837TyrfsTer21), a frameshift variant, and c.12064C>T, p.(Arg4022Ter), a nonsense variant previously reported in a patient with unexplained intellectual disability. The identification of compound heterozygous predicted loss-of-function variants supports the possibility that biallelic disruption of ABCA13 may contribute to neurodevelopmental disease, whereas previously reported heterozygous variants may represent incompletely penetrant risk alleles, susceptibility factors, or candidate findings rather than fully penetrant dominant causes. This case expands the emerging clinical and genetic spectrum associated with ABCA13 and supports further evaluation of a recessive model in patients with intellectual disability and neurodevelopmental delay.

ABCA13↗

PubMed2026

Complement component C4 and neuroimaging in psychiatry: A systematic review.

INTRODUCTION: Genomic, transcriptomic, and proteomic studies suggest that the complement system contributes to the pathophysiology of various psychiatric disorders partly through neurodevelopmental effects linked to C4A protein levels variations. We conducted a systematic review to characterize how brain micro- and macrostructure and connectivity vary with proxies of in vivo brain C4A protein levels in both psychiatric and general-population cohorts. METHODS: We used Medline, Web of Science, and Embase, and included all studies published before April 14, 2025. Inclusion criteria were: (1) inclusion of healthy controls and/or individuals with psychiatric disorders assessed according to recognized diagnostic manuals (DSM or ICD); (2) use of MRI-based neuroimaging; and (3) use of genomic, transcriptomic and/or proteomic approaches as proxies of in vivo brain C4A proteins levels. RESULTS: From 317 identified articles, 11 were included. Associations between C4A levels and brain structure were heterogeneous across regions. Only the mOFC, dlPFC, and entorhinal cortex were implicated in more than one study. Findings for the mOFC and dlPFC varied by the type of metrics and clinical status, whereas higher C4A levels were more consistently associated with smaller entorhinal cortex surface area and cortical thickness in pediatric, middle-aged, and older general-population cohorts. In addition, one study found higher genetically predicted C4A expression to be associated with higher TSPO levels. CONCLUSION: The limited number of available studies and their methodological heterogeneity make synthesis challenging. However, biological hypotheses such as excessive synaptic pruning or broader inflammatory effects on the brain may provide plausible explanatory frameworks for the reported associations.

Humans↗

PubMed2002

Minor physical anomalies and schizophrenia spectrum disorders: a prospective investigation.

OBJECTIVE: The authors prospectively assessed the relationship between minor physical anomalies identified in childhood and adult psychiatric outcome. METHOD: In 1972, minor physical anomalies were measured in a group of 265 Danish children ages 11-13. The examination was part of a larger study investigating early signs of schizophrenia spectrum disorders. Many of the subjects had a parent with schizophrenia, leaving them at high risk for developing a schizophrenia spectrum disorder. In 1991, adult psychiatric outcome data were obtained for 91.3% (N=242) of the original subjects, including 81 who were at high risk. RESULTS: Individuals with a high number of minor physical anomalies developed schizophrenia spectrum disorders significantly more often than they developed a no mental illness outcome. Further, individuals with a high number of minor physical anomalies tended to develop schizophrenia spectrum disorders more often than other psychopathology. Among individuals at genetic high risk, higher numbers of minor physical anomalies may interact with pre-existing vulnerabilities for schizophrenia to increase the likelihood of a schizophrenia spectrum disorder outcome. CONCLUSIONS: Minor physical anomalies may provide important clues to understanding schizophrenia spectrum disorders from a neurodevelopmental perspective. Minor physical anomalies appear to signal stressors relevant to schizophrenia spectrum development, especially in those at genetic risk for schizophrenia.

Adolescent↗

PubMedDate not supplied

[Rett syndrome as a hodogenesis disorder].

In the last few years, Rett syndrome is conceived as a peculiar form of neurodevelopmental post-migrational disorder affecting dendritogenesis. In this article the clinical pathochronic pattern of classical forms is reviewed and the recent neurobiological and genetic evidences suggesting possible future explanations of its nature and origin are discussed.

Child, Preschool↗

PubMed2001

[Schizophrenia and delusions in middle aged and elderly patients. Epidemiology and etiological hypothesis].

Knowledge of the similarities and differences between early- and late-onset schizophrenia and between late-onset schizophrenia and paranoid disorder of old age and very old age is fragmentary. We compared diagnosis, subtypes, syndromes and symptoms between first-episode schizophrenia (ICD-9: 295) and paranoid disorder (ICD-9: 297, 298.3/4.) over the life cycle in a population-based (N = 232) and a clinical first-admission sample (N = 1109). Apart from different age patterns of the sexes only two symptom groups were significantly different between early- and late-onset illness: paranoid and systematic delusions showed a linear increase, symptoms of disorganisation a linear decrease over the life cycle. Clearly different between early- and late-onset illness were the neurobiological and psychological risk factors, suggesting that both neurodevelopmental and neurodegenerative disorder causes psychopathology typical of schizophrenia. Late- (40 to 60) and very-late-onset (over 60) cases of both groups of illness showed the same symptom profiles, merely the number of symptoms being higher in the group diagnosed with schizophrenia. Age was the only factor significantly contributing to a clinico-diagnostic differentiation of schizophrenia from paranoid disorder beyond age 40.

Adolescent↗

PubMed2026

Clinical and biochemical footprints of inherited disorders of autophagy.

Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.

Autophagosome↗

PubMedDate not supplied

[Neurodevelopmental hypothesis in functional psychosis].

Evidence from several studies supports the neurodevelopmental hypothesis of schizophrenia. Others suggest a substantial body of evidence attesting to a possible neurodevelopmental origin of affective disorders. However, there is little evidence that any risk factor or neurodevelopmental marker is specific to any diagnostic category within functional psychoses. Some authors have proposed a new model which implies a continuity within the category of psychosis based on a psychopathological continuum. This research strategy has important and useful advantages which are discussed in this review.

Brain↗

PubMed2004

A longitudinal study of premorbid IQ Score and risk of developing schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses.

CONTEXT: Longitudinal studies indicate that a lower IQ score increases risk of schizophrenia. Preliminary evidence suggests there is no such effect for nonpsychotic bipolar disorder. To our knowledge, there are no prior population-based, longitudinal studies of premorbid IQ score and risk of developing severe depression requiring hospital admission. OBJECTIVES: To investigate the association between premorbid IQ score and risk of developing schizophrenia, other nonaffective psychoses, bipolar disorder, and severe depression and to investigate effects of confounding and examine possible causal pathways by which IQ may alter these risks. DESIGN: Historical cohort study, using record linkage for hospital admissions during a 27-year follow-up period. SETTING: Survey of Swedish conscripts (1969-1970). PARTICIPANTS: Population-based sample of 50,087 male subjects. Data were available on IQ score at conscription and on other social and psychological characteristics. MAIN OUTCOME MEASURES: International Classification of Diseases, Eighth Revision or Ninth Revision diagnoses of schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses. RESULTS: There was no association between premorbid IQ score and risk of bipolar disorder. Lower IQ was associated with increased risk of schizophrenia, severe depression, and other nonaffective psychoses. Risk of schizophrenia was increased in subjects with average IQ compared with those with high scores, indicating that risk is spread across the whole IQ range. CONCLUSIONS: Lower IQ score was associated with increased risk for schizophrenia, severe depression, and other nonaffective psychoses, but not bipolar disorder. This finding indicates that at least some aspects of the neurodevelopmental etiology of bipolar disorder may differ from these other disorders.

Adolescent↗

PubMed2025

Distinct patterns of de novo coding variants contribute to Tourette Syndrome etiology.

Tourette syndrome (TS) is a highly heritable childhood-onset neuropsychiatric disorder characterized by persistent motor and vocal tics. While both common and rare variants contribute to TS susceptibility, the role of rare de novo mutations (DNMs) remains incompletely characterized. Here, we report findings from the largest TS whole-exome sequencing study to date, analyzing 1,466 TS trios alongside 6,714 autism spectrum disorder (ASD) trios and 5,880 unaffected sibling controls from the Simons Simplex Collection (SSC) and SPARK cohorts. Leveraging a trio-based design across these cohorts enabled calibrated assessment of DNM burden while controlling for background mutation rates. We observed a significant exome-wide enrichment of protein-truncating DNMs in TS probands, particularly within genes intolerant to loss-of-function variation (pLI ≥ 0.9), with little contribution from damaging missense variants. Notably, TS probands did not exhibit enrichment in previously implicated ASD or developmental delay (DD) genes, but elsewhere in the genome, suggesting a distinct rare variant architecture. Using a Bayesian statistical framework that integrates both de novo and rare inherited coding variants, we identified three candidate TS risk genes with FDR ≤ 0.05: PPP5C , EXOC1 , and GXYLT1 . Literature shows that they have prior links to neurodevelopmental and psychiatric disorders. These findings reveal a rare variant burden in TS that is genetically distinguishable from ASD, underscore the importance of loss-of-function mutations in TS risk, and nominate novel candidate genes for future functional investigation.

Journal Article↗

PubMed2024

Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients' neurons.

Autism spectrum disorders (ASDs) are highly heritable and result in abnormal repetitive behaviors and impairment in communication and cognitive skills. Previous studies have focused on the genetic correlation between ASDs and other neuropsychiatric disorders, but an in-depth understanding of the correlation to other disorders is required. We conducted an extensive meta-analysis of common variants identified in ASDs by genome-wide association studies (GWAS) and compared it to the consensus genes and single nucleotide polymorphisms (SNPs) of Schizophrenia (SCZ). We found approximately 75% of the GWAS genes that are associated with ASD are also associated with SCZ. We further investigated the cellular phenotypes of neurons derived from induced pluripotent stem cell (iPSC) models in ASD and SCZ. Our findings revealed that ASD and SCZ neurons initially follow divergent developmental trajectories compared to control neurons. However, despite these early diametrical differences, both ASD and SCZ neurons ultimately display similar deficits in synaptic activity as they mature. This significant genetic overlap between ASD and SCZ, coupled with the convergence towards similar synaptic deficits, highlights the intricate interplay of genetic and developmental factors in shaping the shared underlying mechanisms of these complex neurodevelopmental and neuropsychiatric disorders.

Humans↗

PubMed2006

Validation of a Portuguese version of a generic health quality-of-life questionnaire for children with neurological and neuropsychiatric disorders, including epilepsy.

PURPOSE: To validate a Portuguese version of a generic HRQL instrument already used for children with epilepsy. To analyze differences of scores among children with epilepsy and co-morbidities in contrast to other neurological and neuropsychiatric diagnosis, especially Attention Deficit and Hyperactivity Disorder (ADHD). METHODS: A total of 194 children (64 with epilepsy, 94 with ADHD and 38 with other neurological or neuropsychiatric diagnosis) were consecutively seen in a neuropaediatric ambulatory unit. Parents or caregivers responded to a Portuguese version of ICIS (Impact of Childhood Illness Scale). The questionnaire was analyzed for internal consistency and face validity. Clinical and socio-demographic variables were also analyzed. RESULTS: Internal consistency, analyzed by Cronbach's alpha showed good results for total and combined scores and all sections of ICIS, except for the section "impact of illness and its treatment". The diagnostic categories differed in several ICIS sections, with the worst scores for children with epilepsy and co-morbidities. Children who only had epilepsy had a worse score on the section about treatment impact compared with children with ADHD, but better scores in relation to disease impact in development and parents/family. In the epilepsy group, HRQL scores were worst for symptomatic epilepsy, whilst seizure control and socioeconomic factors affected each section of the instrument in different ways. CONCLUSIONS: ICIS Portuguese version has good psychometric properties. It is a useful tool for analyzing HRQL in children with epilepsy and other neurodevelopmental and psychiatric disorders. Epilepsy and psychiatric co-morbidity seems to have an additive impact on a child's HRQL. This result is clinically important since epilepsy management must include not only seizure control but also mental health support.

Adolescent↗

PubMed2006

Minor physical anomalies across ethnic groups in a first episode psychosis sample.

Minor physical anomalies (MPAs) are more prevalent amongst individuals with psychosis, supporting a neurodevelopmental model for psychotic disorders. The aim of this study was to investigate the possibility that neurodevelopmental adversity contributes to the excess of psychosis found in some ethnic groups in the UK. Subjects with first onset psychosis and healthy neighbourhood controls were enrolled in the AESOP study in South East London and Nottingham between 1997 and 1999. MPA rates were estimated in four broad ethnic groupings (White, African Caribbean, Black African and Other). Patients (n=245) had a higher mean total MPA score than healthy controls (n=158). This held true across each of the four ethnic groupings. The results of this study suggest that neurodevelopmental factors play a role in the aetiology of psychosis across all ethnic groups.

Adult↗

PubMed1996

Human fetal hippocampal development: I. Cytoarchitecture, myeloarchitecture, and neuronal morphologic features.

To characterize better the process of anatomic development of the human hippocampus, we studied the cytoarchitecture, myeloarchitecture, and neuronal morphology in human fetal and postnatal hippocampi. Twenty cases were studied in which the ages ranged from 9 weeks gestation through 62 years. Fixed, paraffin-embedded, hippocampal sections were stained with cresyl violet for Nissl substance and immunolabeled for myelin basic protein. The hippocampal region at 9 weeks contains 4 layers: a ventricular zone, an intermediate zone, a homogeneous-appearing hippocampal plate comprised of bipolar-shaped neurons, and a wide marginal zone. At 15-19 weeks, individual subfields can be distinguished. A distal-to-proximal gradient of cytoarchitectural and neuronal morphologic maturity is seen, with the subiculum appearing more developed than the ammonic subfields and the dentate gyrus appearing least mature. Within each subfield, an "inside-out" gradient of maturity is also evident. By 32-34 weeks gestational age, neurons in CA2 and CA3 have undergone rapid enlargement and morphologic maturation, surpassing CA1, which still contains some immature neurons. The dentate gyrus is the latest area to develop, only assuming a mature cytoarchitecture after 34 weeks. The essential cytoarchitectural appearance of the hippocampal subfields is stable after birth, although there is progressive neuronal enlargement and a decrease in neuronal density throughout childhood into adulthood. Myelination is first evident near term, with strong myelin basic protein immunoreactivity present in the angular bundle, alveus, and fimbria and relatively scant immunoreactivity in the nascent perforant pathway. Myelination in the hippocampus increases in childhood until adolescence, after which the pattern remains unchanged. These studies delineate normal neuroanatomic development and can be used to understand better the mechanisms underlying human neurodevelopmental and neurodegenerative disorders of the hippocampal formation.

Cytoskeleton↗

PubMed2003

Polymicrogyria and absence of pineal gland due to PAX6 mutation.

Identification of genes involved in human cerebral development is important for our understanding of disorders with potential neurodevelopmental causes such as epilepsy and learning disability. Murine models suggest that PAX6 plays a key role in human brain development. With magnetic resonance imaging in 24 humans heterozygous for defined PAX6 mutations, we demonstrated widespread structural abnormalities including absence of the pineal gland and unilateral polymicrogyria.

Abnormalities, Multiple↗

PubMed2003

Imprinting evolution and the price of silence.

In contrast to the biallelic expression of most genes, expression of genes subject to genomic imprinting is monoallelic and based on the sex of the transmitting parent. Possession of only a single active allele can lead to deleterious health consequences in humans. Aberrant expression of imprinted genes, through either genetic or epigenetic alterations, can result in developmental failures, neurodevelopmental and neurobehavioral disorders and cancer. The evolutionary emergence of imprinting occurred in a common ancestor to viviparous mammals after divergence from the egg-laying monotremes. Current evidence indicates that imprinting regulation in metatherian mammals differs from that in eutherian mammals. This suggests that imprinting mechanisms are evolving from those that were established 150 million years ago. Therefore, comparing genomic sequence of imprinted domains from marsupials and eutherians with those of orthologous regions in monotremes offers a potentially powerful bioinformatics approach for identifying novel imprinted genes and their regulatory elements. Such comparative studies will also further our understanding of the molecular evolution and phylogenetic distribution of imprinted genes.

Alleles↗

PubMed2005

Small RNAs in human brain development and disorders.

Small RNA is a variable and abundant type of non-coding RNAs in brain. The function of these RNAs is mainly unknown. A specific class of small RNA, microRNA, is dynamically regulated in neurogenesis and in embryo brain development. The genes for synaptic formation and some mental retardation disorders are putative targets for microRNA predicted by computational algorithms. The molecular pathways for mental development, common forms of autisms, schizophrenia, and affective disorders have yet to be elucidated. The hypothesis proposed here is that small regulatory RNAs, specifically microRNAs, play a role in human brain development and pathogenesis of brain disorders, especially of neurodevelopmental conditions. Pilot tests using comprehensive arrays of microRNAs demonstrate that microRNAs derived from postmortem human brains are applicable for microRNA expression profiling. The abundant expression of many regulatory small RNAs in human brain implies their biological role that must be tested by functional assays in neurons and by genetic and comparative expression profiling.

Brain↗