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Results for “neurodevelopmental”

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At least 19 recordsLinked to original sources

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↗

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↗

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↗

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↗

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)↗

PubMed2026

Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND).

PURPOSE: TCF7L2 (OMIM 602228; HGNC:11641) is a transcription factor and a critical effector of the Wnt/ β-Catenin pathway. In 2021, 11 pediatric patients with monoallelic predicted loss-of-function (pLOF) TCF7L2 variants and syndromic features were observed. Characterization of patients with pLOF TCF7L2 variants and neurodevelopmental features-herein referred to as TCF7L2-related neurodevelopmental disorder-is urgently needed. METHODS: We leveraged multiple methods (eg, GeneMatcher, DECIPHER, literature review, and public/private repositories) to identify an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features and phenotypically characterized them. We also retrospectively searched for an independent cohort of adults with pLOF TCF7L2 variants (n = 11) from more than 60,000 PennMedicine BioBank patients. RESULTS: Among 76 patients with pLOF TCF7L2 variants, speech delay (95.3%), craniofacial dysmorphisms (73.3%), ophthalmologic conditions (65.5%), autism (62.1%), and orthopedic abnormalities (52.6%) were the most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PennMedicine BioBank patients, an association of nominal significance with type 2 diabetes with renal manifestations (odds ratio = 5.8; P = .03) was detected, warranting further investigation. CONCLUSION: This study represents the most comprehensive characterization of TCF7L2-related neurodevelopmental disorder to date, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectra. We opened a Simons Searchlight natural history study that is now available for patient enrollment to enhance the understanding of this condition.

Neurodevelopmental syndrome↗

PubMed1990

Early predictors of neurodevelopmental outcome at 12-36 months in very low-birthweight infants.

We followed-up 71 preterm survivors, 36 (50.7%) females and 35 (49.3%) males, correlating the results of neurological examinations (NE) at 40 weeks of corrected gestational age (GA) and the cerebral ultrasound (US) diagnosis with the neurodevelopmental outcome at 12-36 months of life. All 34 children with normal NE at term presented adequate neurodevelopmental outcome; these subjects have a normal US scan or a scan that is pathologic for uncomplicated hemorrhage. Of the 6 children with pathologic NE, but a normal US, 3 (50%) had a normal outcome, while 2 (34%) had mild impairments and 1 (16%) grave neurodevelopmental deficits. Of the 31 subjects with pathologic NE and US, 12 (39%) showed a normal outcome, and 6 (19%) had mild and 13 (42%) grave neurodevelopmental deficits; signs of parenchymal lesions with or without periventricular hemorrhage were particularly correlated to US. We conclude that the combination of the results of NE at 40 weeks GA and brain US are useful in early neurodevelopmental prognosis in very low-birthweight infants.

Child, Preschool↗

PubMed1988

Prediction of early school-age problems by a preschool neurodevelopmental examination of children at risk neonatally.

A group of 350 children who had had neonatal developmental risk-factors were assessed at the age of five years with a neurodevelopmental examination. At nine years they were assessed again for neuropaediatric, motor, psycholinguistic, cognitive and school-achievement problems. (Children with major handicaps were excluded). Poor performance at age five was significantly associated with failure in the nine-year examinations and with school problems. Sensitivity of the five-year neurodevelopmental examination in predicting problems at nine years was 0.30 to 0.50, and its predictive value for an abnormal performance was 0.30 to 0.60. Predictively, the neurodevelopmental examination was accurate in defining children without later problems, but less satisfactory in defining those who did develop problems. Multiple linear regression analyses between the neurodevelopmental examination and the scores at nine years revealed low explanatory power. A shortened neurodevelopmental examination, based on the best predictors, seemed to be as efficient as the full examination.

Brain Damage, Chronic↗

PubMed2023

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Male↗

PubMed2025

RNA sequencing offers new diagnostic opportunities in neurodevelopmental disorders: A systematic review.

PURPOSE: Transcriptomics by way of RNA sequencing (RNAseq) has emerged as a means to increase the diagnostic yield in genetic conditions. In this systematic review, we focus on the contribution of transcriptomics to improve the diagnostic yield in neurodevelopmental disorders. METHODS: We performed a systematic literature search in PubMed until January 2024, including articles describing diagnostic RNAseq on at least 1 individual with a primary neurodevelopmental phenotype. We extracted data on cohort size, phenotype, sample tissue, previously used diagnostic methods, added diagnostic yield of RNAseq, the use of control samples, and technical aspects of the RNA sequencing methodology. RESULTS: A total of 17 articles were eligible for inclusion in the systematic review. We found an average added diagnostic yield of 15.5% through RNA sequencing for individuals with neurodevelopmental disorders. There is heterogeneity in the tissue type, reported quality measures, and the computational pipeline. CONCLUSION: The significantly increased diagnostic yield demonstrates the value of this novel tool in the diagnostic setting of neurodevelopmental disorders. Our results offer an overview of common methodologies for RNAseq and allow us to formulate recommendations for genetic labs and clinicians when implementing RNAseq as a diagnostic tool. Lastly, we provide recommendations for future publications to increase transparency and reproducibility.

Humans↗

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

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↗

PubMed1985

Effect of early neurodevelopmental therapy in normal and at-risk survivors of neonatal intensive care.

At a corrected age of 3 months, 80 low birth-weight infants were assigned to normal or at-risk groups on the basis of a neurodevelopmental assessment scale. Both groups were further divided into intervention and non-intervention sub-groups (20 infants in each). Intervention consisted of monthly hospital-based neurodevelopmental therapy in addition to a home exercise programme. Infants were re-assessed by a physiotherapist at 6, 9, and 12 months, and were tested at 12 months by an independent psychologist blinded for infant group. Mean birthweight and gestational age were similar for normal and at-risk groups. At-risk infants had higher mean neurodevelopmental scores throughout the study period and lower 1-year development quotients (DQ) than normals. In neither normal nor at-risk groups did neurodevelopmental therapy alter the pattern of development or the outcome.

Child Development↗

PubMed1986

Early predictors of neurodevelopmental outcome of very low-birthweight infants at three years.

Seventy-nine premature infants weighting less than 1501 g at birth but appropriate for gestational age underwent a neurodevelopmental examination at one, three, six, nine and 12 months post-term, and a standard neurological examination and the Stanford-Binet Intelligence Scale at three to four years of age. Children were classified as normal, suspect or abnormal on the three-year neurological examination, on the IQ test, and on composite neurodevelopmental outcome at age three years. Results showed that items from both the nine- and 12-month neurodevelopmental examinations correctly classified about 80 per cent of the children as to composite outcome at three years. In addition, the 12-month examination enabled correct prediction for 89 per cent of the children as to neurological outcome and for 82 per cent as to IQ. Neurodevelopmental examination of high-risk infants in the last quarter of the first year of life (post-term) should assist pediatricians in predicting which children will be normal and which will require early intervention.

Cerebral Palsy↗

PubMed1988

Prediction of neurodevelopmental impairment at four years from brain ultrasound appearance of very preterm infants.

The neurodevelopmental status of 171 very preterm infants whose brains had been scanned prospectively with ultrasound was assessed blind at four years using a wide range of tests, including tests of cognitive function. Highly significant correlations were found between the ultrasound appearance of the brain and outcome. The probability of a major neurodevelopmental impairment among the 137 children who had a normal ultrasound scan or uncomplicated periventricular haemorrhage at discharge from the unit was 7 per cent; and for any neurodevelopmental impairment (major plus minor) it was 22 per cent. The probabilities for major, or any, neurodevelopmental impairment among the 18 children who had ventricular dilatation were 33 and 50 per cent, respectively; and for the 16 with hydrocephalus and/or cerebral atrophy (loss of brain-tissue from any cause) the probabilities were 56 and 69 per cent. Impairments predicted from lesions detected by ultrasound were largely neurological. There was no evidence that cognitive impairments could be predicted among infants free of neurological impairments.

Atrophy↗

PubMed1990

Prediction of neurodevelopmental outcome in the preterm infant: MR-staged myelination compared with cranial US.

In this prospective study, 26 very preterm infants underwent magnetic resonance (MR) imaging of the brain at 44 weeks postmenstrual age (PMA) for staging of myelination. Neurodevelopmental outcome was assessed at 1 year of age. A significant correlation was demonstrated between delayed myelination and neurodevelopmental outcome (Chi 2 = 16.6, P = .01). A significant correlation was also found between ultrasound (US) findings in the neonatal period and outcome at 1 year (Chi 2 = 22.9, P = .03). To establish the criterion with the best predictive value, a multiple regression analysis was performed with periventricular-intraventricular hemorrhage, periventricular leukomalacia (PVL), and the stage of myelination at 44 weeks PMA as independent variables and neurodevelopmental outcome at 1 year of age as a dependent variable. Staging of myelination with MR imaging in the early postnatal period of very preterm infants had predictive value with regard to neurodevelopmental outcome. Detection of PVL with US, however, showed a better correlation with outcome, a result that seems to limit the potential role of MR imaging in this population for this purpose only.

Cerebral Hemorrhage↗

PubMed1992

Value of cranial ultrasound and magnetic resonance imaging in predicting neurodevelopmental outcome in preterm infants.

In this prospective study, cranial ultrasound was performed to detect periventricular-intraventricular hemorrhage and periventricular leukomalacia in 33 preterm infants of less than 32 weeks' gestation. At 44 weeks postmenstrual age magnetic resonance imaging was performed to detect the stage of myelination. Neurodevelopmental outcome was assessed at 3 years of age in 31 children (2 children died in the first year of life). Significant correlations were found between neurodevelopmental outcome and ultrasound findings (chi 2 = 32.8; P less than .0001) and stage of myelination (chi 2 = 20.5; P less than .0005). To establish the criterion with the best predictive factor, multiple regression analysis was performed with outcome as dependent variable and periventricular-intraventricular hemorrhage, periventricular leukomalacia, and stage of myelination as independent variables. It appeared that the detection of periventricular leukomalacia with ultrasound showed the best predictive factor for neurodevelopmental outcome. Routine magnetic resonance imaging at 44 weeks postmenstrual age should not be performed just for the purpose of predicting neurodevelopmental outcome more reliably.

Brain↗

PubMed1990

Delayed visual maturation: ophthalmic and neurodevelopmental aspects.

Delayed visual maturation (DVM) can present as an isolated anomaly (type 1A), but can be compounded by perinatal problems (type 1B), severe neurodevelopmental delay (type 2), or ocular anomalies/nystagmus (type 3), in which group the common feature appears to be nystagmus. The neurodevelopmental and ophthalmic aspects of 26 infants with DVM were studied. Onset of visual improvement, rate of acquisition of normal vision and eventual outcome were studied quantitatively, using an adaptation of the acuity card procedure. Neurodevelopmental assessment was performed after visual improvement. The results support the long-held clinical impression that if blindness is the presenting feature, neurodevelopmental outlook is excellent. DVM could represent a defect in the extrageniculostriate visual system, and the onset of vision in all types--and the development of nystagmus in type 3--could herald the emergence of geniculostriate function.

Blindness↗