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PubMed2026

Beyond the gene: isoform diversity as a key contributor to human brain disorders.

The human brain exhibits exceptional transcriptomic complexity, with alternative splicing, promoter usage, and polyadenylation generating extensive transcript-isoform diversity. Isoform dysregulation is increasingly implicated in neurodevelopmental and psychiatric disorders (NPDs), yet the landscape, function, and genetic regulation of brain isoforms remain poorly understood due to limitations of short-read RNA sequencing. Advances in long-read sequencing (LR-seq) enable scalable full-length transcriptome profiling with single-cell and spatial resolution across developmental stages. Here, we review recent progress in isoform discovery, quantification, functional annotation, and genetic regulation, highlighting emerging links to human neurodevelopment and disease. LR-seq studies have uncovered tens of thousands of previously unannotated brain isoforms, with neuronal maturation characterized by increased exon inclusion and progressive 3' untranslated region (3' UTR) lengthening. Isoform-resolved genetic mapping outperforms gene-level analyses for NPD gene discovery and mechanistic interpretation. We argue that a shift from gene-centric to isoform-centric frameworks is essential to fully capture regulatory complexity in human neurogenetics. Together, these advances establish isoform diversity as a fundamental yet underappreciated axis of brain gene regulation and a key entry point for dissecting NPD biology.

Humans↗
PubMed2026

Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.

MED25-related developmental disorder (Basel-Vanagaite-Smirin-Yosef syndrome) is a rare autosomal recessive disorder, defined by severe neurodevelopmental delay, corpus callosum abnormalities, ocular involvement, epilepsy, and marked facial appearance. MED25 pathogenic variants interfere with the functioning of the Mediator complex, which is responsible for RNA polymerase II transcription. We report a 9-year-old girl who presents with significant global developmental delay, agenesis of the corpus callosum, congenital cataracts, epilepsy, hypotonia, musculoskeletal abnormalities, and typical craniofacial features. Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe). The new classification of the missense variant as potentially pathogenic is supported by a systematic ACMG re-evaluation supported by segregation analysis, phenotypic specificity, computational prediction, and structural localization in the MED25 Activator Interaction Domain (ACID). Comparative phenotypic analyses show strong agreement with reported cases but add more data to fine-tune clinical spectrum. This article broadens the allelic and phenotypic spectrum of MED25-related developmental disorder and highlights the need for comprehensive evaluation across molecular, structural, and phenotypic pathways to elucidate variant signature in rare genetic disease models correctly.

Humans↗
PubMed2006

Porphyrinuria in childhood autistic disorder: implications for environmental toxicity.

To address a possible environmental contribution to autism, we carried out a retrospective study on urinary porphyrin levels, a biomarker of environmental toxicity, in 269 children with neurodevelopmental and related disorders referred to a Paris clinic (2002-2004), including 106 with autistic disorder. Urinary porphyrin levels determined by high-performance liquid chromatography were compared between diagnostic groups including internal and external control groups. Coproporphyrin levels were elevated in children with autistic disorder relative to control groups. Elevation was maintained on normalization for age or to a control heme pathway metabolite (uroporphyrin) in the same samples. The elevation was significant (P < 0.001). Porphyrin levels were unchanged in Asperger's disorder, distinguishing it from autistic disorder. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (P < 0.001) but not significantly in Asperger's. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (P = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder.

Administration, Oral↗
PubMed2001

The timing of neurodevelopmental abnormality in schizophrenia: an integrative review of the neuroimaging literature.

In this paper we will review recent neuroimaging research in schizophrenia, with an aim to critically evaluate several recent proposals concerning the nature and the timing of the neuroanatomic abnormalities underlying the disorder. Specifically, enlargement of cerebrospinal fluid spaces, deficits in cortical gray matter, and reduced volume of mesiotemporal structures have all been reported in patients in the first episode of schizophrenia, their first-degree relatives, and individuals with schizotypal personality disorder, supporting the possibility that these abnormalities reflect a genetically mediated neurodevelopmental disorder. These findings from the empirical literature will be synthesized from the perspective of dual cytoarchitectonic trends theory of neurodevelopment, as well as in relation to current conceptions of the schizophrenia prodrome. We believe that the evidence shows that sufficient groundwork has been laid to begin longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia, in order to more definitively determine the pathophysiology of the disorder. Such information could have significant implications in terms of understanding the prediction, treatment, and ultimately the prevention of schizophrenia.

Journal Article↗
PubMed2006

Movement-related potentials in high-functioning autism and Asperger's disorder.

Autism and Asperger's disorder (AD) are neurodevelopmental conditions that affect cognitive and social-communicative function. Using a movement-related potential (MRP) paradigm, we investigated the clinical and neurobiological issue of 'disorder separateness' versus 'disorder variance' in autism and AD. This paradigm has been used to assess basal ganglia/supplementary motor functioning in Parkinson's disease. Three groups (high functioning autism [HFA]: 16 males, 1 female; mean age 12y 5mo [SD 4y 4mo]; AD: 11 males, 2 females; mean age 13y 5mo [SD 3y 8mo]; comparison group: 13 males, 8 females; mean age 13y 10mo [SD 3y 11mo]) completed a cued motor task during electroencephalogram recording of MRPs. The HFA group showed reduced peak amplitude at Cz, indicating less activity over the supplementary motor area during movement preparation. Although an overall significant between-group effect was found for early slope and peak amplitude, sub-analysis revealed that the group with AD did not differ significantly from either group. However, it is suggested that autism and AD may be dissociated on the basis of brain-behaviour correlations of IQ with specific neurobiological measures. The overlap between MRP traces for autism and Parkinson's disease suggests that the neurobiological wiring of motor functioning in autism may bypass the supplementary motor area/primary motor cortex pathway.

Adolescent↗
PubMed2004

[Bridging the genomic approach and the neurodevelopmental and neurodenerative hypothesis of schizophrenia].

Schizophrenia is hypothesized as a neurodevelopmental and neurodegenerative disorder based on the following findings. 1. MRI studies have revealed brain structural abnormalities from the onset of schizophrenia and the progress of these structural abnormalities. 2. Histopathological studies have elucidated cytoarchitectural abnormalities in schizophrenic brains without gliosis. 3. Obstetric complications are one of the risk factors for schizophrenia. 4. Relapse of schizophrenia results in a deteriorating progress of the disorder. Furthermore, data from family, twin and adoption studies show evidence of a substantial genetic component in schizophrenia, Thus, a molecular genetic study combined with a neurodevelopmental and neurodegenerative hypothesis is required to elucidate the pathophysiology of schizophrenia. The positive association between neuregulin 1 and Icelandic schizophrenia that has been reproduced in Scottish and North European schizophrenia is one of the intriguing examples of this type of research. Neuregulin 1 regulates the cytoarchitecture of brain. Mice mutated for neuregulin 1 show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, the behavioral phenotypes of the neuregulin 1 hypomorphs are reversible with clozapine. We also demonstrated a positive association between schizophrenia and a 5-HT5A receptor polymorphism, Pro15Ser, that may have role in cell differentiation in the brain.

Animals↗
PubMed2007

Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1.

Recent advances in our understanding of the clinical and molecular features of the fragile-X mental-retardation 1 gene, FMR1, highlight the importance of single-gene disorders. 15 years after its discovery, FMR1 continues to reveal new and unexpected clinical presentations and molecular mechanisms. Loss of function of FMR1 is a model for neurodevelopmental and behavioural disorders, including mental retardation, autism, anxiety, and mood instability. In addition, overexpression and CNS toxicity of FMR1 mRNA causes a late-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). A similar mechanism is probably involved in premature ovarian failure, which affects up to 20% of female carriers of an altered FMR1 gene.

Adult↗
PubMed1993

Language, learning, and behavioral disturbances in childhood: a longitudinal perspective.

OBJECTIVE: Investigate longitudinally the course of development of preschool learning impaired (LI) children to better understand the interaction between neurodevelopmental delay, behavioral/emotional disorders, and language development and disorders. METHOD: Relationships between developmental language disorders and emotional problems were investigated in 99 8-year-old specifically language impaired and control children originally assessed at age 4 years using the Achenbach Child Behavior Checklist and the Conners' Parents Questionnaire. RESULTS: LI children received higher behavior problem scores and were more likely to score in the clinical range than were control children. Neither degree of early language impairment nor amount of language improvement predicted 8-year behavioral/emotional status. LI children with the largest drop in IQ between ages 4 and 8 received the highest behavior problem scores. No significant comorbid relationship was seen between LI and attention-deficit hyperactivity disorder. CONCLUSIONS: The enhanced incidence of behavior problems reported heretofore may be related more to lower IQ than to linguistic deficit per se. Care must be taken to differentiate the symptoms of neurodevelopmental delay and emotional disturbance, however, preschool children with scores in the clinical range on such measures should be referred for additional evaluation.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Three Rett patients with both MECP2 mutation and 15q11-13 rearrangements.

Autism and Rett syndrome, a severe neurological disorder with autistic behavior, are classified as separate disorders on clinical and etiological ground. Rett syndrome is a monogenic X-linked dominant condition due to de novo mutations in the MECP2 gene, whereas autism is a neurodevelopmental and behavioral disorder with complex genetic basis. Maternally inherited duplications on 15q11-q13 are found in a fraction of autistic children suggesting that an abnormal dosage of gene(s) within this region might cause susceptibility to autism. Now we show that three Rett patients are carriers of both a MECP2 mutation and a 15q11-q13 rearrangement, suggesting that there might be a relationship between autism-related genes and the MECP2 gene.

Chromosomal Proteins, Non-Histone↗
PubMed2006

Considering the major mental disorders as clinical expressions of periodic pathological oscillations of the overall operating mode of brain function.

The consideration of the collective significance of the shared characteristics and overlaps in the clinical expression and pharmacological responses of the major mental disorders (namely, schizophrenia, bipolar disorders, obsessive compulsive disorder, anxieties/phobias, borderline syndrome and possibly others) supports the following: (1) These disorders have a common, initial neurodevelopmental origin. (2) They occur probabilistically on some of "at-risk" individuals whose pre-existing, extreme, temperamental/structural variance confers vulnerability for such occurrence. (3) Lastly, each of these syndromes can be considered as a clinical expression of oscillations (i.e., a switch to a pathologically ordered phase) of the overall, common operating mode of brain function. This mode based on a particular-for-our-brain, emergent quality of complexity, normally ensures the synchrony, coordination, subtlety and robust flexibility in the expression of the components of each of the various higher faculties of the brain, namely, the faculty of: (1) mood modulation; (2) coordination of feelings, thoughts and the responses to the external world; and (3) keeping constrain and limited but appropriate input of primitive drives. The conclusions in this paper have important ramifications in rethinking the current nosological procrustean flawed classification and the neurodevelopmental origin of the major mental disorders as well as the biases shown in selecting subjects for research. It also opens opportunities in the future development of novel, effective, economical and harmless therapies that will restore and maintain the normal phase of the operating mode of brain function. For example, the patient can wear an appropriate electronic device that sends a particular type of signal to the brain which will affect remission and prevent relapses without harm. We can thus avoid the use of pharmacological agents which have limited effectiveness, severe, long-term side-effects and financial burden to the patient.

Brain↗
PubMed2026

Decreased H3K79 acetylation and dysregulation of neurodevelopmental genes in fetal down syndrome.

BACKGROUND: Down syndrome (DS), the most prevalent chromosomal disorder caused by trisomy 21, manifests intellectual disability and cognitive dysfunction. Cumulative studies confirm epigenetic pathways including DNA methylation and non-coding RNAs drive DS pathological progression. Histone post-translational modifications (PTMs) are core epigenetic regulators of fetal brain development. However, genome-wide PTM alterations and their downstream functions in fetal DS brains remain poorly characterized, leaving a key gap in revealing epigenetic mechanisms underlying DS neurodevelopmental defects. To address this, we aimed to establish the first comprehensive landscape of histone PTMs in fetal DS cortex and investigate whether specific PTM changes contribute to aberrant neurodevelopmental gene expression. METHODS: Fetal cortexs from control and DS groups were subjected to global histone modification profiling via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). We detected mono-, di-, and tri-methylation, acetylation, homocysteinylation and malonylation on all four core histones (H2A, H2B, H3, H4). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to map genomic binding profiles of H3 lysine 79 acetylation (H3K79ac). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to quantify mRNA levels of candidate neurodevelopmental genes. RESULTS: HPLC-MS/MS analysis identified 172 distinct histone PTMs in control fetal cortices and 168 PTMs in DS fetal cortical samples. Quantitative comparison of 22 quantifiable histone PTMs revealed that H3K79ac showed the most prominent reduction in DS samples, with a 34% decrease (P<0.05). Chromatin immunoprecipitation (ChIP)-seq verified specific H3K79ac occupancy at the genomic loci of three vital neurodevelopmental genes: TNFSF13B, NXPH1 and CAMK4. Correspondingly, qRT-PCR revealed aberrant transcription levels of these three genes in DS fetal cortices. CONCLUSIONS: This study establishes the first quantitative landscape of histone PTMs in in DS fetal cortical tissues. We demonstrate that depleted H3K79ac acts as a candidate epigenetic driver of DS neuropathology by disrupting the transcription of critical neurodevelopmental genes. This work reveals a novel epigenetic mechanism and a promising therapeutic target for DS-related neurodevelopmental disorders.

Down syndrome (DS)↗
PubMed2006

CACNA1H mutations in autism spectrum disorders.

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by impaired social interaction, communication skills, and restricted and repetitive behavior. The genetic causes for autism are largely unknown. Previous studies implicate CACNA1C (L-type Ca(V)1.2) calcium channel mutations in a disorder associated with autism (Timothy syndrome). Here, we identify missense mutations in the calcium channel gene CACNA1H (T-type Ca(V)3.2) in 6 of 461 individuals with ASD. These mutations are located in conserved and functionally relevant domains and are absent in 480 ethnically matched controls (p = 0.014, Fisher's exact test). Non-segregation within the pedigrees between the mutations and the ASD phenotype clearly suggest that the mutations alone are not responsible for the condition. However, functional analysis shows that all these mutations significantly reduce Ca(V)3.2 channel activity and thus could affect neuronal function and potentially brain development. We conclude that the identified mutations could contribute to the development of the ASD phenotype.

Autistic Disorder↗
PubMed2005

Supportive neurodevelopmental evidence for ADHD as a developmental disorder.

A baby is dependent on its primary caregiver (hereafter referred to as 'mother') for its emotional regulation. The development of emotional self-regulation is dependent on the growth and myelinisation of connections between cortical (control) and limbic (emotion) structures in the infant brain. The subcortical sympathetic limbic system is dominant from birth, and it is only at 14-18 months of age that the parasympathetic cortical inhibitory part develops. The maturation of specifically the right orbitofrontal cortex, which dominates both the sympathetic and parasympathetic limbic systems, is essential for the regulation of emotion for the rest of an individual's life. Behavioral hyperactivity, impulsivity and inattention are considered normal for children in the early practising phase (10-14 months). This stage is characterised by sympathetic dominance stimulated by the ventral tegmental limbic circuit. We hypothesise that children with Attention Deficit Hyperactivity Disorder remain stuck in this phase, and accordingly do not enter the next stage of emotional development, i.e., the late practising period, in which the lateral tegmental limbic circuit, which stimulates the parasympathetic system develops. Parental reactions, which may contribute to this block in emotional development, include: largely ignoring their child, until the child does something the parent disapproves of, then scolding the child, without consoling the child again afterwards. This leads susceptible children to develop defensive hyperactivity and inattention in order to avoid a shame state they are unable to cope with. Implications for therapy are that caregivers should be taught firstly to give lots of positive attention to their child, and if necessary to scold, to console the child immediately afterwards. If this can be achieved consistently, the child will have the chance to develop their parasympathetic lateral limbic circuit, and eventually right orbitofrontal dominance over both limbic circuits, which translates into the ability to self-regulate their emotional states.

Attention Deficit Disorder with Hyperactivity↗
PubMed2023

De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features.

PURPOSE: Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder. METHODS: Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB. RESULTS: Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFBR104G and MRTFBA91P variants also display a decreased level of actin binding within critical RPEL domains, resulting in increased transcriptional activity and changes in the organization of the actin cytoskeleton. CONCLUSION: The MRTFBR104G and MRTFBA91P variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggest that these variants act as a gain of function.

Animals↗
PubMed2005

The Oxford-Durham study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder.

BACKGROUND: Developmental coordination disorder (DCD) affects approximately 5% of school-aged children. In addition to the core deficits in motor function, this condition is associated commonly with difficulties in learning, behavior, and psychosocial adjustment that persist into adulthood. Mounting evidence suggests that a relative lack of certain polyunsaturated fatty acids may contribute to related neurodevelopmental and psychiatric disorders such as dyslexia and attention-deficit/hyperactivity disorder. Given the current lack of effective, evidence-based treatment options for DCD, the use of fatty acid supplements merits investigation. METHODS: A randomized, controlled trial of dietary supplementation with omega-3 and omega-6 fatty acids, compared with placebo, was conducted with 117 children with DCD (5-12 years of age). Treatment for 3 months in parallel groups was followed by a 1-way crossover from placebo to active treatment for an additional 3 months. RESULTS: No effect of treatment on motor skills was apparent, but significant improvements for active treatment versus placebo were found in reading, spelling, and behavior over 3 months of treatment in parallel groups. After the crossover, similar changes were seen in the placebo-active group, whereas children continuing with active treatment maintained or improved their progress. CONCLUSIONS: Fatty acid supplementation may offer a safe efficacious treatment option for educational and behavioral problems among children with DCD. Additional work is needed to investigate whether our inability to detect any improvement in motor skills reflects the measures used and to assess the durability of treatment effects on behavior and academic progress.

Attention Deficit Disorder with Hyperactivity↗
PubMed2005

Predictors of schizophrenia--a review.

Schizophrenia is an aetiologically heterogeneous syndrome that usually becomes overtly manifest in adolescence and early adulthood, but in many cases subtle impairments in neurointegrative function are present from birth; hence it is considered to be a disorder with a neurodevelopmental component. The strongest risk factor that has been identified is familial risk with genetic loading. Other risk factors include pregnancy and delivery complications, infections during pregnancy, disturbances of early neuromotor and cognitive development and heavy cannabis use in adolescence. Unfortunately, to date it has not been possible to utilize the predictors of the disorder that have been identified in primary preventative interventions in a general population. However, some authors have claimed that in future it might be possible to reduce the risk for developing schizophrenia through general health policy. In clinical settings, it is helpful to map out possible early risk factors, at least familial risk for psychosis, especially in child, adolescent and young adult mental patients. Furthermore, in the future we may have predictive models combining data from genetic factors for schizophrenia, antenatal risk factors, childhood and adolescent development and clinical symptomatology, as well as brain structural and functional abnormalities.

Adolescent↗
PubMed2005

Language disorder in schizophrenia as a developmental learning disorder.

Receptive language disorder in schizophrenia is hypothesized to represent a learning disorder that involves a neurodevelopmental etiology. It is argued that a preexisting developmental language disorder may characterize a subset of schizophrenia patients. A primary deficit in the temporal dynamics of brain function is assumed to cause receptive language disorder in schizophrenia. This hypothesized core deficit includes both disturbance in the processing of rapid, sequential information and disruptions to patterns of brain activation and synchronization. These timing deficits may alter the way associative connections are formed and/or accessed in semantic memory. It is suggested that abnormalities in second-messenger pathways of subcortical-cortical circuitry offer an etiological nexus for language dysfunction in schizophrenia and developmental dyslexia.

Brain↗