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At least 19 recordsLinked to original sources
PubMed2025

Precision diagnostic and therapeutic interventions in rare genetic neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) include a broad spectrum of phenotypes spanning from intellectual disability (ID) to developmental delay (DD) and autism spectrum disorder (ASD). As neurodevelopmental phenotypes are a common presenting feature of an underlying genetic condition, professional medical organizations recommend genetic testing for all individuals with a NDD. When testing is pursued, identified genetic differences can lead to personalized clinical management with early diagnosis supporting the development of surveillance and intervention for co-occurring adverse health outcomes. Despite this, barriers to testing have prevented individuals from receiving a genetics referral and testing. Current therapeutic modalities including small molecule drugs, gene therapies, and antisense oligonucleotide therapies have emerged and shown promise in preclinical trials with therapeutic drugs gaining FDA approval. However, translational challenges are extensive, especially for identifying biomarkers of drug effects in the CNS. In this review, we discuss diagnostic approaches and clinical utility of genetic testing for rare genetic neurodevelopmental disorders, emerging development of individualized therapies, and progress for current therapeutics in addition to challenges with clinical translation and delivery. We will highlight opportunities for early diagnosis and treatment that are steadily gaining ground in favor of optimizing long-term health outcomes and improving quality of life for neurodiverse individuals. IMPACT: The path from genomics to therapeutics for neurodevelopmental disorders continues to present multiple opportunities and challenges. While emerging genome-wide sequencing and gene editing technologies deliver increased diagnostic yields and alternatives to life-long small molecule therapies, clinical translation has been challenging due to inherent cost and genetic heterogeneity. Limited access to genetic testing despite practice guidelines remains a barrier towards precision therapeutics for rare neurodevelopmental disorders, while pre-clinical investigations face obstacles when translating to human subjects. This review will summarize the impact of existing successes in diagnosis and therapeutics for neurodevelopmental disorders while highlighting ongoing challenges and areas of future opportunities.

Humans↗
PubMed2004

Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders.

Neurodevelopmental disorders typically have complex endophenotypes, which can include abnormalities in neuronal excitability, processing of complex information, as well as behaviors such as anxiety and social interactions. Converging experimental and clinical evidence suggests that altered interneuron development may underlie part of the pathophysiological process of such disorders. Consistent with this, mice with abnormal hepatocyte growth factor signaling exhibit disturbances in the development of specific interneuron subclasses that are paralleled by seizure activity and a complex behavioral phenotype. Mutations in molecules that regulate different aspects of interneuron development could provide the heterogeneity in genetic susceptibility that, when combined with environmental disturbances, results in a phenotypic spectrum that serves as the hallmark pathophysiology for autism, mental retardation, schizophrenia and other neurodevelopmental disorders.

Animals↗
PubMed2024

Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder.

PURPOSE: The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated. METHODS: We retrospectively studied the clinical and genetic data of individuals recruited from several centers with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing. RESULTS: We report 50 individuals with TAOK1 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 individuals with TAOK2 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%). CONCLUSION: We describe the largest cohort of TAOK1-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.

Humans↗
PubMed1989

Children with preschool minor neurodevelopmental disorders. V: Neurodevelopmental profiles at age 13.

A cohort of children diagnosed at age seven as suffering from deficits in attention, motor control and perception was compared at age 13 with a group of children without such problems. More than two-thirds of the index children no longer had any clearly detectable motor problems at 13, but they still had significantly prolonged complex reaction times. These results suggest that children with these deficits in the early school years have a fair biological prognosis by the early teen years.

Achievement↗
PubMed2005

Disorders of attention or learning in neurodevelopmental disorders.

Disorders of attention or learning commonly accompany neurodevelopmental disorders. The evaluation and diagnosis of these disorders is complex and does not always follow techniques used for typically developing children. These disorders are often underappreciated and inadequately addressed because they are overshadowed by the neurodevelopmental disorder. Nevertheless, failure to recognize, diagnose, and manage these disorders may result in unsuccessful community integration.

Attention Deficit and Disruptive Behavior Disorder↗
PubMedDate not supplied

An assessment of the impact of thimerosal on childhood neurodevelopmental disorders.

The prevalence of autism in the US has risen from 1 in approximately 2500 in the mid-1980s to 1 in approximately 300 children in the mid-1990s. The purpose of this study was to evaluate whether mercury from thimerosal in childhood vaccines contributed to neurodevelopmental disorders. Neurodevelopmental disorder dose-response curves for increasing mercury doses of thimerosal in childhood vaccines were determined based upon examination of the Vaccine Adverse Events Reporting System (VAERS) database and the 2001 US' Department of Education Report. The instantaneous dosage of mercury children received in comparison to the Food and Drug Administration (FDA)'s maximum permissible dose for the oral ingestion of methylmercury was also determined. The dose-response curves showed increases in odds ratios of neurodevelopmental disorders from both the VAERS and US Department of Education data closely linearly correlated with increasing doses of mercury from thimerosal-containing childhood vaccines and that for overall odds ratios statistical significance was achieved. Similar slopes and linear regression coefficients for autism odds ratios in VAERS and the US Department of Education data help to mutually validate each other. Controls employed in the VAERS and US Department of Education data showed minimal biases. The evidence presented here shows that the occurrence of neurodevelopmental disorders following thimerosal-containing childhood vaccines does not appear to be coincidental.

Autistic Disorder↗
PubMed2004

The relationship between perisylvian morphology and verbal short-term memory functioning in children with neurodevelopmental disorders.

Although children with neurodevelopmental disorders frequently present with reduced short-term memory functioning, the relationship between perisylvian morphology and verbal short-term memory functioning has received limited attention. Thus, examining this relationship in children with neurodevelopmental disorders was the focus of this exploratory study. Results suggested leftward asymmetry in the temporal bank of the planum temporale is related to better coding and storage of semantic material. In contrast, parietal bank morphology is related to coding and storage of phonological material, and presence of an extra gyrus in the parietal region is associated with reduced phonological working memory. Data also supported a relationship between pars triangularis morphology and verbal short-term memory functioning, but this is not material-specific.

Attention Deficit Disorder with Hyperactivity↗
PubMedDate not supplied

Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders?

The fatty acid compositions of red blood cell (RBC) phospholipids from a patient with autistic spectrum disorder (ASD) had reduced percentages of highly unsaturated fatty acids (HUFA) compared to control samples. The percentage of HUFA in the RBC from the autistic patient was dramatically reduced (up to 70%) when the sample was stored for 6 weeks at -20 degrees C. However, only minor HUFA reductions were recorded in control samples stored similarly, or when the autistic sample was stored at -80 degrees C. A similar instability in RBC HUFA compositions upon storage at -20 degrees C has been recorded in schizophrenic patients. In a number of other neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) and dyslexia, reduced concentrations of RBC HUFA have been recorded. The extent and nature of these aberrations require further assessment to determine a possible common biochemical origin of neurodevelopmental disorders in general. To facilitate this, a large scale assessment of RBC fatty acid compositions in patients with ASD, and related disorders, should be performed as a matter of urgency. Supplementing cells in culture with the tryptophan metabolite indole acrylic acid (IAA) affected the levels of cellular HUFA and prostaglandin production. Indole acroyl glycine (IAG), a metabolite of IAA excreted in urine, is found in high concentrations in patients with neurodevelopmental disorders including ASD, ADHD, dyslexia, Asperger's syndrome and obsessive compulsive disorder.

Asperger Syndrome↗
PubMed2004

Video-fluoroscopic study of swallowing in children with neurodevelopmental disorders.

BACKGROUND: Children with neurodevelopmental disorders can have feeding problems. Malnutrition and recurrent aspiration pneumonia can increase the risk of morbidity and mortality. Video-fluoroscopic study of swallowing (VFSS) is essential in understanding the pathological mechanisms involved during swallowing. METHODS: The aim of the present study was to assess the role of VFSS in assessment and management of four children with various neurodevelopmental disorders in a multidisciplinary feeding team. We describe the team approach, with the participation of child neurologist, radiologist with the rehabilitation team including the speech therapist, occupational therapist and dietician, in the assessment and plan of management. RESULTS: Video-fluoroscopic study of swallowing had been useful in assessing the type of swallowing problems with treatment goals targeted to the basic underlying pathophysiological mechanism. CONCLUSION: A child neurologist should be involved in the multidisciplinary oromotor rehabilitation program for neurologically impaired children with feeding problems.

Adolescent↗
PubMed2005

[Neurodevelopmental disorders and epilepsy].

INTRODUCTION AND DEVELOPMENT: Neurodevelopmental disorders and the epilepsies share common etiologies and pathologies. The severity of impairment and the variety of symptoms associated with neurodevelopmental disorders or with particular epilepsy syndromes reflect focal or global, structural or functional dysfunction of neuronal networks. The complex relationship between neurodevelopmental disorders and epilepsy is secondary to common factors that include genetics, cognition, motor and language function. The epileptic encephalopathies are associated with regression or slowing of cognitive, language or behavior and the accepted working hypothesis is that this is a direct consequence of the seizures or of the interictal epileptiform activity, as opposed to the associated medical condition. The evidence that recurrent seizures or abnormal electrical activity can cause specific cognitive, language or behavioral abnormalities even in accepted epileptic encephalopathies is still controversial. Data from animal studies and the clinical experience from epileptic encephalopathies of early life imply that there are developmental time windows crucial to the type of epilepsy syndrome and to cognitive and behavioral outcome. CONCLUSION: The management of children in whom a neurodevelopmental disorder coexists with epilepsy is a difficult problem that requires a multidisciplinary approach that addresses both the epilepsy and the specific cognitive or behavioral problem and is tailored to the needs of the individual child.

Epilepsy↗
PubMed2007

Variation in incidence of neurodevelopmental disorders with season of birth.

BACKGROUND: The etiologies of autism spectrum disorder and many neurodevelopmental disorders are largely unknown. The detection of a seasonal variation of birth of children diagnosed with a certain disorder could suggest etiological factors that follow a seasonal pattern. We examined the seasonal variation of births of children diagnosed with any of 4 common childhood neuropsychiatric disorders: autism spectrum disorder, hyperkinetic disorder, Tourette syndrome, and obsessive-compulsive disorder. METHODS: The study cohort consisted of all children born in Denmark from 1990 through 1999 identified in the Danish Medical Birth Register (n = 669,995). Outcome data consisted of both inpatient and outpatient diagnoses reported to the Danish National Psychiatric Registry from 1995 through 2004 using the International Classification of Diseases, 10th edition, diagnostic coding system. Logistic regression combined with spline (a smoothing method) was used to estimate the variation with season of birth for each disorder. Estimates of risk of each disorder with season of birth were adjusted for differences in follow-up time and change in incidence over time. RESULTS: No convincing variations in season of birth were observed for any of the 4 disorders, or for the autism-spectrum-disorder subtypes. CONCLUSION: Although we cannot rule out the possibility of seasonal variation of birth for a range of childhood neurodevelopmental disorders, we find little evidence that seasonal environmental factors are related to these disorders.

Attention Deficit Disorder with Hyperactivity↗
PubMed1985

Children with minor neurodevelopmental disorders. III: Neurological and neurodevelopmental problems at age 10.

Two previous papers have presented the results of behavioural and educational follow-up at age 10 of children diagnosed at age seven having minimal brain dysfunction (MBD), motor perception dysfunction (MPD) or attention deficit disorder (ADD), and normal control children. The present paper is concerned with the neurological and neurodevelopmental problems of these groups of children at age 10. 25 per cent of the children with severe MBD and almost 55 per cent with mild to moderate MBD had had neurological problems at age seven, but no longer had any demonstrable neurological deficit at age 10. The findings were similar in the MPD group, and the neurological status of the ADD group was similar to that of the controls. These findings are in contrast to the high rates of severe behavioural and/or school-achievement problems among the children in the MBD group, and indicate that the three-year prognosis with regard to neurological dysfunction is fairly good, but is gloomy as far as behavioural and school-achievement problems are concerned.

Achievement↗
PubMed2002

Melatonin treatment for sleep disorders in children with neurodevelopmental disorders: an observational study.

The study aim was to quantify melatonin-associated improvement in sleep by means of a parent-completed sleep diary during routine outpatient activity. An investigation into sleep disturbance was made at neurology outpatient appointments. Those parents who identified a problem were asked to complete a sleep diary, after which treatment was initiated. The first week of the diary was completed before treatment, the second when established on the maximum dose of melatonin required. Forty-nine patients (26 males, 23 females) aged from one to 13 years, were treated between 1997 and 1998: 28 of these returned interpretable diaries. In a further 18 patients, an assessment could be made of the usefulness of the treatment. Patients were fairly typical of those attending a tertiary centre, the most common primary diagnosis being epilepsy (n=26). Only seven patients were visually impaired. Of the 46 patients who were assessed, 34 showed an improvement. No adverse effects were attributed to the treatment.

Adolescent↗
PubMed2002

Anticonvulsant drug use and low bone mass in adults with neurodevelopmental disorders.

BACKGROUND: Use of anticonvulsant drugs among adults with neurodevelopmental disorders may be an important risk factor for both osteoporosis and skeletal fractures. AIM: To determine the relationship between anticonvulsant drug use and both low bone mass and bone fractures in such adults. DESIGN: Cross-sectional study of 273 adults with neurodevelopmental disorders, 40% of whom were receiving one or more anticonvulsant drugs. SETTING: Single Canadian long-term care facility. METHODS: Demographic data were abstracted from each resident's chart in a standardized manner, including body mass, degree of mobility, major falls within the previous 12 months, and all medications. Quantitative calcaneal ultrasonography was performed on each resident without knowledge of their current drug use. The Quantitative Ultrasound Index was employed to express 'bone stiffness'. Low bone mass was defined as a T-score 2.5 SDs below the norm for young healthy adults. RESULTS: Compared to non-users (15.5%), low bone mass was more prevalent among those taking either one (20.3%; OR 1.7, 95%CI 0.6-4.4) or two or more anticonvulsant agents (42.2%, OR 5.9, 95%CI 2.2-16.2). The risk of recent skeletal fractures was not significantly greater in those taking a single anticonvulsant than in non-users (28.6% vs. 21.6%; OR 1.0, 95%CI 0.4-2.8), but tended to be higher in those taking two or more (48.7%; OR 2.2, 95%CI 0.8-5.9). CONCLUSIONS: Adults with neurodevelopmental disorders residing in a long-term care facility have a high rate of both low bone mass and skeletal fractures, especially with concomitant use of anticonvulsant drugs. These individuals should be assessed for the presence of low bone mass, and may warrant prophylactic treatment against bone loss, including calcium and vitamin D supplementation.

Adult↗
PubMed2025

ELFN1 deficiency: The mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy.

PURPOSE: Synaptic communication deficits are central to many neurodevelopmental disorders. However, for rare monogenic conditions, these disorders remain poorly defined, with limited understanding of their molecular etiology. A homozygous frameshift variant in the synaptic cell adhesion molecule ELFN1 was reported in a family with 3 affected siblings with epileptic encephalopathy, alongside a missense variant of uncertain significance in a cohort study involving a family with intellectual disability. Therefore, we sought to evaluate the role and mechanism of biallelic ELFN1 variants in disease pathogenesis. METHODS: We describe 8 newly identified individuals from 5 unrelated families, all carrying homozygous ELFN1 variants, including frameshift and in-frame deletions. By integrating data from these cases with clinical details from 6 previously reported individuals, we delineate the phenotypic spectrum associated with ELFN1 variants. RESULTS: Clinical features include varying degrees of developmental delay/intellectual disability, epilepsy, and movement disorders. Molecular investigations reveal that these variants disrupt ELFN1 protein trafficking to the cell surface, resulting in loss of function. Functional modeling in mice and zebrafish demonstrates the role of Elfn1 loss in motor activity abnormalities and seizures. CONCLUSION: Our findings establish ELFN1 deficiency as the cause of a distinct, rare neurodevelopmental disorder, providing a foundation for future investigations into its pathophysiology and therapeutic strategies.

Humans↗
PubMed2026

Biallelic EZH1 Nonsense Novel Variant in Two Siblings with Neurodevelopmental Disorder and Central Precocious Puberty: A Case Report from a Consanguineous Saudi Family.

Neurodevelopmental disorders (NDDs) are a group of conditions that impair the development and function of the central nervous system. Recently, variants in the EZH1 gene have been associated with neurodevelopmental disorders. Here, using whole-exome sequencing coupled with confirmatory Sanger sequencing, we identified a homozygous nonsense variant in EZH1 in two affected siblings. Both parents were heterozygous carriers of the variant. The variant is predicted to result in a 44-amino acid C-terminal truncation within the catalytic SET domain, leading to loss of protein function. RT-qPCR analysis revealed significantly reduced EZH1 mRNA expression in patient-derived peripheral blood cells. The index patient (female) also exhibited elevated gamma-glutamyl transferase (GGT) levels and hypoalbuminemia, whereas the affected male presented with central precocious puberty. This study further expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.

Child↗
PubMed2026

Hemizygous loss-of-function variants of EIF1AX are associated with a syndromic neurodevelopmental disorder.

Pathogenic variants of genes encoding initiation factors can cause neurological diseases, including neurodevelopmental disorders and brain abnormalities. The eukaryotic translation initiation factor 1 A, X-linked (EIF1AX) is a gene located at Xp22.12 that plays an important role in the regulation of translation initiation. Here, we identified de novo hemizygous EIF1AX variants in male individuals with neurodevelopmental disorders and explored their possible involvement in these neurological disorders. We performed trio-based exome or whole genome sequencing in four families. The pathogenicity of EIF1AX variants was evaluated using a molecular dynamic simulation and transgenic Drosophila models. We identified four de novo hemizygous EIF1AX variants in four male individuals with variable neurodevelopmental delay, dysmorphic features, behavioral problems, ophthalmological abnormalities, and structural abnormalities in the brain. One variant was predicted to cause a splicing alteration, and minigene analysis confirmed exon skipping leading to the generation of a premature termination codon. In transgenic Drosophila harboring wild-type (WT) EIF1AX or the three other EIF1AX missense variants, overexpression of WT and the p.(Asn17Asp) variant caused structural abnormalities in the compound eye, whereas the p.(Lys64Glu) and p.(Asp90Gly) variants significantly reduced these eye abnormalities. In addition, WT overexpression resulted in significant axonal toxicity in the Drosophila optic nerve, causing a significant reduction in the number of axons, whereas all mutants showed only a mild reduction in axonal number. Our findings indicated that all variants resulted in different degrees of EIF1AX loss-of-function. Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males.

Humans↗
PubMed2026

Polygenic risk score for neurodevelopmental disorders and cognitive impairment at long-term follow-up of first-episode psychosis.

BACKGROUND: One of the most outstanding contributions to the understanding of the etiopathogenesis of schizophrenia spectrum disorders (SSD) was the neurodevelopmental hypothesis. SSD and neurodevelopmental disorders (NDD) share pathogenetic mechanisms and overlapping clinical and cognitive impairment features. METHODS: We investigated whether polygenic risk scores (PRSs) for NDD are associated with cognitive performance in patients with first-episode psychosis (FEP). The sample comprised 127 patients with FEP who were followed up for a mean of 20.9 years. Cognitive examination was performed using the MoCA test at follow-up. Pearson coefficient correlations and multiple regression analyses were performed to examine the contribution of the three PRSs for rare neurodevelopmental conditions (PRSNDD), attention-deficit hyperactivity disorder (PRSADHD) and autism spectrum disorder (PRSASD) to cognitive impairment after allowing for the effect of covariates. Furthermore, we examined the interconnections between the PRS for NDD and cognitive impairment using network analysis (NA), including core premorbid variables. RESULTS: PRSNDD showed significant associations with impairment on visuospatial/executive, attention, and language MoCA subtests, after allowing for the influence of covariates. PRSNDD and PRSADHD, but not PRSASD, were significantly associated with worse performance on the total MoCA score. Moreover, in the network analysis, the relationships between PRSs for NDD and cognitive impairment were highly interconnected with premorbid variables and PRSs for schizophrenia and educational attainment. CONCLUSIONS: These results provide evidence for a possible direct genetic effect on cognitive performance for the PRS of common genetic variations related to neurodevelopment and attention deficit hyperactivity disorder in patients with FEP.

Cognitive impairment↗