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PubMed2005

Dermatoglyphic anomalies and neurocognitive deficits in sibling pairs discordant for schizophrenia spectrum disorders.

The neurodevelopmental hypothesis of schizophrenia suggests that adverse genetic loading in conjunction with environmental factors early in fetal life causes a disruption of neural development, decades before the symptomatic manifestation of the disease. Neurocognitive deficits have been observed early on the course of schizophrenia, and their association with an early developmental brain lesion has been postulated. Dermatoglyphics have been analyzed in schizophrenia as markers of prenatal brain injury because of their early fetal ontogenesis and susceptibility to the same environmental factors that can also affect cerebral development. The aim of our study was to conduct a comparative examination of neurocognitive functions and dermatoglyphic variables in 89 sibling pairs discordant for schizophrenia spectrum disorders. Therefore, we investigated the association between these two markers to explore the prenatal origin of cognitive deficits in schizophrenia. The affected siblings were significantly impaired on all the cognitive variables assessed (Wisconsin Card Sorting Test, Trail Making Test and Continuous Performance Test) and had a greater number of dermatoglyphic anomalies. These results suggest the influence of intrauterine environmental factors in the siblings affected with schizophrenia. However, we did not detect a significant association between these two vulnerability markers in the schizophrenic patients, suggesting the role of genetic or late environmental factors in the origin of the neurocognitive deficits found in these patients.

Adult↗
PubMed1988

Neurodevelopmental assessment of behaviorally disordered inner city boys.

The purpose of this study was to assess the usefulness of a recently developed neurodevelopmental instrument (Pediatric Early Education Exam "PEEX") for evaluating inner city boys thought to be "hyperactive" by their teachers. Thirty-nine boys (age x = 102.5 months, sd = 11.9; IQ x = 98, sd = 10; 97%, black) were evaluated. No relationship was found between overflow movements and neurodevelopmental subtest performance, intelligence, or educational functioning. The development of laterality was positively related to success in reading (t = 2.21, p less than 0.05). A sentence-copying task was related to success in reading (r = .38 p less than 0.01). The ability to answer questions about complex sentences was related to mathematical success (r = .32 p less than 0.05). A task involving the ability to follow verbal directions proved most sensitive to educational, intellectual, and social functioning.

Child↗
PubMed2006

Schizophrenia: a neurodevelopmental or a neurodegenerative disorder.

The functional decline and onset of psychosis that individuals with schizophrenia experience suggests that schizophrenia has a neurodegenerational origin. However, current research favors a neurodevelopmental model in which individuals with schizophrenia develop abnormalities during brain development. The abnormality that leads to psychosis and deterioration remains latent as the brain develops but emerges concurrently with the brain's normal development or after an outside event that leads to changes in brain function. Prenatal adversity may underlie the neurodevelopmental process and neurodegeneration of schizophrenia. Because psychosis may be a clinically identifiable marker of an underlying neuropathologic process associated with deterioration, the best way to treat the illness is to reduce the duration of untreated psychosis, aim for full remission of psychosis, and combine medication with other therapies.

Antipsychotic Agents↗
PubMed2006

Blockade of presynaptic voltage-gated calcium channels in the medial prefrontal cortex of neonatal rats leads to post-pubertal alterations in locomotor behavior.

Although the etiology of neurodevelopmental mental disorders remains obscure, converging lines of evidence using animal modeling suggest a critical role for activity-dependent neurodevelopmental processes during neonatal life. Here, we report the behavioral effects of a novel technique designed to induce targeted, transient disruption of activity-dependent processes in early development via reduction of calcium-mediated neurotransmitter release. We examined the post-pubertal behavioral effects of neonatal (postnatal day 7) medial prefrontal cortex infusion of either vehicle or N-type and P/Q-type presynaptic voltage-dependent calcium channel blockers (omega-conotoxins MVIIA and MVIIC respectively; 6.8 and 45 pmol infused respectively) in rat pups. In a test of amphetamine-induced behavioral sensitization, neonatal omega-conotoxin MVIIA treatment significantly increased locomotion following repeated amphetamine injections (1.5 mg/kg i.p.) and significantly decreased locomotion following repeated saline injections relative to animals treated neonatally with vehicle. However, there was no effect of conotoxin treatment on the long-term expression of amphetamine sensitization. Neonatal treatment with omega-conotoxins had no effect on the other behaviors assayed, namely, acoustic startle response, prepulse inhibition of startle, novelty- and amphetamine-induced (1.5 mg/kg i.p.) locomotion, and anxiety-like behavior in the elevated plus-maze. These data confirm that transient, region-specific disruption of synaptic transmission during early development can have long-term effects on behaviors relevant to neurodevelopmental mental disorders.

Aging↗
PubMed2024

The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND.

PURPOSE: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.

Humans↗
PubMed2003

Genetic and neurodevelopmental influences in autistic disorder.

OBJECTIVE: In the past, autism was considered to be largely psychogenic. However, research in the last 2 decades indicates that autism is largely caused by genetic factors that lead to abnormal brain development. This article reviews research into the genetic and neurodevelopmental factors underlying autism. METHODS: We review the findings from genetic and brain-imaging studies of autism over the past 15 years and synthesize these findings as a guide for future research. RESULTS: Genome scans and association studies have suggested potential genomic regions and genes, respectively, that may be involved in the etiology of autism, and there have been some replications of these results. Similarly, the findings that brain volume is exaggerated in autism and corpus callosum size is reduced have also been independently replicated. Unfortunately, studies of other subcortical structures remain inconclusive or contradictory. CONCLUSIONS: Overwhelming evidence now supports a neurobiological basis for autism. However, further refinements will be needed to guide future studies, particularly to identify the most informative phenotypes to investigate. Additionally, studies examining the role of genetic factors in the brain abnormalities underlying autism will likely lead to further findings that will enhance our understanding of autism's causes.

Agenesis of Corpus Callosum↗
PubMed2003

Williams syndrome: 15 years of psychological research.

Williams syndrome is a rare genetic disorder caused by a microdeletion of about 20 genes on chromosome 7q11.23. The importance of this syndrome for theories and models of cognition became apparent about 15 years ago, when Bellugi, Sabo, and Vaid (1988) argued that Williams syndrome was a paradigm case of the independence of language from cognition. In particular, it was argued that individuals with Williams syndrome have "intact" language despite severe mental retardation. More recent findings indicate a more complex relation between language and characteristics associated with this syndrome. The articles in this special issue form 3 overlapping clusters: articles concerned with language development relative to cognitive development, articles concerned with other aspects of cognition, and articles concerned with interpersonal relations and personality. Together, these articles provide strong evidence of the importance of the study of neurodevelopmental genetic disorders for enhancing understanding of the complex manner in which initial genetic differences impact both behavior and processing strategies from infancy through adulthood. Our hope is that this issue will motivate further studies, informed by the genetic-developmental approach, on both Williams syndrome and other neurodevelopmental genetic disorders.

Cognition Disorders↗
PubMed2004

Characterizing the musical phenotype in individuals with Williams Syndrome.

Williams Syndrome (WS), a neurodevelopmental genetic disorder, is characterized by peaks and valleys in mental function: substantial impairments in cognitive domains such as reasoning, arithmetic ability, and spatial cognition, alongside relatively preserved skills in social domains, face processing, language, and music. We report the results of a comprehensive survey on musical behaviors and background administered to the largest sample of individuals with WS to date (n = 118, mean age = 20.4), and compare the results to those obtained from a control group of typically developing normal individuals (n = 118, mean age = 20.9) and two groups of individuals with other neurodevelopmental genetic disorders, Autism (n = 30, mean age = 18.2) and Down Syndrome (n = 40, mean age = 17.2). Individuals with WS were found to be rated higher in musical accomplishment, engagement, and interest than either of the comparison groups, and equivalent on most measures to the control group. Compared to all other groups including the controls, the WS individuals displayed greater emotional responses to music, manifested interest in music at an earlier age, and spent more hours per week listening to music. In addition, the effects of music listening (whether positive or negative) tended to last longer in the WS group. A factor analysis extracted seven principal components that characterize the musical phenotype in our sample, and discriminant function analysis of those factors was able to successfully predict group membership for the majority of cases. We discuss the neurobiological implications of these findings.

Adolescent↗
PubMed2006

Neurodevelopmental origins of depressive disorders.

Depression is a common and devastating neuropsychiatric disorder, and a better understanding of its pathophysiology is needed to improve diagnosis, treatment and prevention. By considering the developmental dimensions of genetic and environmental factors, new insights have been found into the etiology and pathophysiology of depression. Specifically, we begin to understand how certain vulnerability factors affect the maturation of brain circuits involved in emotional function to increase the risk for depressive disorders later in life. These new findings might help us to better categorize and manage this complex disease.

Animals↗
PubMed2026

Expanding the clinical spectrum of ARV1-related disease beyond classical developmental and epileptic encephalopathy.

PURPOSE: Biallelic pathogenic variants in ARV1 are classically associated with developmental and epileptic encephalopathy-38 (DEE38), a severe infantile-onset disorder characterized by drug-resistant epilepsy, profound neurodevelopmental impairment, and early mortality. However, emerging evidence suggests broader phenotypic variability. We aimed to expand the clinical and molecular spectrum of ARV1-related disease through a retrospective case series and structured literature review. METHODS: We retrospectively identified five unrelated Saudi Arabian families with biallelic pathogenic or likely pathogenic ARV1 variants confirmed by whole-exome sequencing. Clinical, neurodevelopmental, neurophysiological, neuroimaging, and multisystem findings were reviewed. A structured literature review was performed to integrate previously reported cases. RESULTS: We identified marked clinical heterogeneity, including a novel ARV1 missense variant (c.214G>T; p.Asp72Tyr), which remains classified as a variant of uncertain significance according to ACMG/AMP criteria despite multiple computational predictions supporting a deleterious effect. Clinical severity ranged from severe developmental and epileptic encephalopathy with drug-resistant epilepsy and early mortality to milder static neurodevelopmental phenotypes with sustained seizure remission and long-term survival into adulthood. Families harboring the same homozygous frameshift variant exhibited markedly different clinical severity, supporting the absence of a strict genotype-phenotype correlation. Multisystem involvement included neurological, cardiac, skeletal, sensory, gastrointestinal, and genitourinary manifestations, and metabolic phenocopies contributed to diagnostic delays. CONCLUSION: Our findings demonstrate that ARV1-related disease represents a broad multisystem clinical spectrum, with classical DEE38 representing its most severe presentation rather than its sole manifestation. Recognition of milder phenotypes, prolonged seizure remission, and marked phenotypic variability has important implications for diagnosis, prognostic counseling, and multidisciplinary long-term surveillance. Early genomic testing should be considered in patients with early-onset epilepsy and multisystem involvement, particularly in consanguineous populations.

ARV1↗
PubMed1999

Atrophic and static (neurodevelopmental) schizophrenic psychoses: premorbid functioning, symptoms and neuroleptic response.

The question of whether schizophrenic-like disorders are neurodevelopmental or degenerative in origin has been argued since the time of Kraepelin. The authors provide evidence for the existence of two etiologically distinct endophenotypes of the psychoses contained within the rubric of familial non-affective psychosis (schizophrenia), one atrophic and the other neurodevelopmental. The atrophic psychosis, identified by progressive ventricular enlargement throughout adult illness, evidences progressive impairment of interests, relationships, and withdrawal from latency through adolescence, with emergence of trait-like negative symptoms which are only marginally responsive to conventional neuroleptics. This psychosis also exhibits delayed response of positive symptoms during neuroleptic treatment, and may also proceed to a praecox dementia in later life. In contrast, a putative neurodevelopmental psychosis, associated with static ventricles during the course of adult illness, also demonstrates preadolescent impairments, but impairments which do not progress to marked negative symptoms. Conventional neuroleptics appear to have little effect (except sedation) on positive symptoms, but appear to induce negative symptomatology and partial disengagement from the burden of persistent psychotic thought processes in such static ventricle psychoses. Thus, separate patterns of illnesses with different prodromal features, different treatment response patterns, and different patterns of residual (negative) symptoms appear to characterize patients with psychosis who have expanding as opposed to stable cerebral-ventricles at doses of neuroleptic at 10 mg haloperidol equivalents/day.

Adult↗
PubMed2006

Speed of naming in children with Williams and Down syndromes.

BACKGROUND: Williams syndrome (WS) and Down syndrome (DS) are two neurodevelopmental genetically based disorders which exhibit mental retardation with a unique cognitive profile. Naming in individuals with WS and DS has been investigated in several studies, with results indicating that the performance of children with WS and DS is at a similar level and below mental age expectations on naming tasks. METHOD: Speed of naming pictures, colours, numbers, letters and words was assessed in 8 individuals with WS, 10 individuals with DS, and 18 mental age controls. All stimuli were presented on a computer monitor and reaction times for naming were recorded. RESULTS: Our results indicated that speed of naming in children with DS and WS is not statistically different to that of mental age controls. However, error analysis in naming words and pictures revealed qualitative differences between the three groups. CONCLUSION: These results challenge the tenet of increased naming speed in children with WS compared to mental age controls. The findings are discussed in the light of current evidence concerning the linguistic abilities of children with neurodevelopmental disorders and those with typical development.

Child↗
PubMed2026

ARX mutation-associated interneuron defects provide insights into mechanisms underlying developmental epilepsies.

Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures, whereas its loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and its relationship to seizure phenotype, Arx conditional mutant mouse lines were investigated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that ARX abrogation results in defects in cIN density and distribution, as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence to medial ganglionic eminence identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation and sequencing revealed that ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation and cIN migration. Investigation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates the number and distribution of cINs in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate that ARX positively regulates cIN migration by derepressing LMO1's repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX, who was diagnosed with developmental epileptic encephalopathy. Together, our data provide novel insights into how ARX and its target genes regulate cIN development and migration and into the pathogenic mechanisms underlying a spectrum of neurodevelopmental disorders linked to loss of ARX.

Animals↗
PubMed1994

Methylphenidate and ADHD: influence of age, IQ and neurodevelopmental status.

Sixty-nine children with attention deficit hyperactivity disorder (ADHD) underwent blind methylphenidate trials. 36 had ADHD alone (with or without a learning disability) and 33 had additional neurodevelopmental disorders. Of the children with ADHD alone, 88 per cent improved significantly on methylphenidate. This did not differ significantly from the 69 per cent response rate for children with ADHD and other neurodevelopmental disorders. The results confirm and add to the research literature indicating that ADHD children who are of preschool age and/or who have co-existing neurological disorders may benefit from methylphenidate.

Adolescent↗
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↗
PubMed2005

Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system structural defects in children with optic nerve hypoplasia.

OBJECTIVE: Optic nerve hypoplasia (ONH) is a heterogeneous disease with variable findings of pituitary insufficiency, CNS and neurodevelopmental abnormalities. We characterized the spectrum of endocrinopathy in a cohort of children with ONH and attempted to correlate the presence of different midline CNS findings with the degree of hypopituitarism. The correlation of variable CNS abnormalities with the presence of a seizure disorder and neurodevelopmental delay was also examined. METHODS: Charts of 56 patients with ONH referred to our endocrine clinics between 1990 and 2000 were reviewed. Neurodevelopmental assessment was based on questionnaires sent to families during the study period. RESULTS: Forty-six patients (82%) had hypopituitarism, with growth hormone deficiency being the most common endocrinopathy. All patients with diabetes insipidus, hypocortisolism, and hypogonadotropin hypogonadism also had combined pituitary hormone deficiency. Evolving pituitary hormone deficiency was observed in two of 37 patients diagnosed with hypopituitarism in the first 3 years of life. No single midline CNS finding correlated with the presence of hypopituitarism or a seizure disorder. However, hydrocephalus or a seizure disorder was more commonly seen in patients with developmental delay. CONCLUSION: ONH is a heterogeneous disorder with possible multifactorial etiologies. All patients with this diagnosis deserve a comprehensive endocrine and neurodevelopmental evaluation.

Adolescent↗