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PubMed2018

Using mouse transgenic and human stem cell technologies to model genetic mutations associated with schizophrenia and autism.

Solid progress has occurred over the last decade in our understanding of the molecular genetic basis of neurodevelopmental disorders, and of schizophrenia and autism in particular. Although the genetic architecture of both disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Using the DISC1/NDE1 and CYFIP1/EIF4E loci as exemplars, we explore the opportunities and challenges of using animal models and human-induced pluripotent stem cell technologies to further understand/treat and potentially reverse the worst consequences of these debilitating disorders.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Animals↗

PubMed2025

Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.

Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1, and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2-NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.

Journal Article↗

PubMedDate not supplied

Close interrelation of motor development and cognitive development and of the cerebellum and prefrontal cortex.

Motor development and cognitive development may be fundamentally interrelated. Contrary to popular notions that motor development begins and ends early, whereas cognitive development begins and ends later, both motor and cognitive development display equally protracted developmental timetables. When cognitive development is perturbed, as in a neurodevelopmental disorder, motor development is often adversely affected. While it has long been known that the striatum functions as part of a circuit with dorsolateral prefrontal cortex, it is suggested here that the same is true for the cerebellum and that the cerebellum may be important for cognitive as well as motor functions. Like prefrontal cortex, the cerebellum reaches maturity late. Many cognitive tasks that require prefrontal cortex also require the cerebellum. To make these points, evidence is summarized of the close co-activation of the neocerebellum and dorsolateral prefrontal cortex in functional neuroimaging, of similarities in the cognitive sequelae of damage to dorsolateral prefrontal cortex and the neocerebellum, of motor deficits in "cognitive" developmental disorders, and of abnormalities in the cerebellum and in prefrontal cortex in the same developmental disorders.

Cerebellum↗

PubMed2004

Alteration of dopamine D1 receptor-mediated motor inhibition and stimulation during development in rats is associated with distinct patterns of c-fos mRNA expression in the frontal-striatal circuitry.

Dopamine D1 receptors have been implicated in various neurodevelopmental disorders, including attention-deficit/hyperactivity disorder. However, little is known about potential late maturational changes of the motor inhibitory and stimulatory role of these receptors. Here, we investigated the effects of a full and selective D1 receptor agonist, SKF-81297, on motor activity and expression of the plasticity-associated gene, c-fos, in the prefrontal cortex and striatum of juvenile and adolescent male rats. In general, SKF-81297 produced a biphasic effect on motor activity (locomotor and rearing activity), which consisted of an initial short inhibition followed by a long-lasting stimulation. These effects were dose- and age- dependent. The inhibitory phase was more pronounced in adolescent than in juvenile rats whereas the opposite was true for the stimulatory phase. During the initial inhibitory phase of the drug, c-fos mRNA expression was increased in the prefrontal cortex of juvenile rats but reduced in adolescent rats. There was also an increase in c-fos mRNA expression in the medial-dorsal striatum and olfactory tubercle, which was more evident in juvenile rats. In contrast, during the stimulatory phase, c-fos mRNA expression was increased in both the dorsal and ventral striatum, especially in the nucleus accumbens, as well as in the prefrontal cortex, in both age groups. The increase of c-fos mRNA in the dorsal striatum, however, was more pronounced in juvenile rats. These results indicate the presence of two distinct D1 receptor populations within the frontal-striatal circuitry, which have opposite effects on motor activity, and which have different maturational profiles.

Animals↗

PubMed2004

Academic underachievement by people with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder that is associated with the under-expression of maternally imprinted genes at the 15q11-q13 chromosomal locus. In addition to a characteristic physical and behavioural phenotype, those with the syndrome have impaired social cognition, literal mindedness and inflexibility. The present authors investigated the relationship between the PWS cognitive and behavioural phenotype, educational experience, and levels of attainment in reading, writing and arithmetic. METHODS: All subjects from a population-based sample of people with PWS, augmented by those with PWS living in other regions together with a contrast group of people with learning disability (LD) of other aetiologies, are included in the present study. Those children over 3 years of age whose families consented or adults who themselves consented were assessed for ability and attainment (over 7 years of age), and information on functional ability was also obtained from an informant. Underachievement was defined as the difference between the score predicted from full-scale IQ and the actual achievement score. RESULTS: Commonly, levels of achievement were lower than would have been predicted on the basis of IQ among those in the groups with PWS and LD. In the group with PWS, underachievement across academic domains was positively correlated with the percentage of time in education in a special school and negatively correlated with Vineland Socialization domain standard score. There were no across-domain significant correlations in the group with LD. When using multiple regression analysis, the percentage of time in special school was the only predictor of underachievement and only in the group with PWS. However, some children with PWS in special schools did achieve as expected in at least one academic domain. CONCLUSIONS: Children with PWS may be placed in special schools largely because of their behavioural problems or physical disabilities, or expectations based on their PWS status. Their intellectual abilities may well be masked by their immature social behaviour. The present authors propose that a failure to recognize and address the specific educational needs which follow from this combination of poor socialization skills and complex maladaptive behaviours, in the context of relatively mild LD, may explain their findings.

Adolescent↗

PubMed1982

Long-term follow-up of children born after amniocentesis.

Paediatric and neurodevelopmental examinations were made of 122 children between the ages of 5 and 7 years. The mothers of 62 of these children had undergone amniocentesis for prenatal chromosome determination. The other 60 children were controls, matched for time of birth and maternal age. The fact that no difference between the groups was revealed in respect of paediatric and neurodevelopmental disorders, orthopaedic abnormalities, or respiratory problems during the neonatal period indicates that the risk for developmental complications is not increased in children born after amniocentesis in the second trimester.

Adult↗

PubMed1989

Mental illness and cognition in relation to age at puberty: a hypothesis.

Onset of puberty is usually considered to coincide with the last major step in brain development: the elimination of some 40% of neuronal synapses. Mean pubertal age has declined by some 4 years during the last 100 years. There is a relation between age at puberty and body build, and between body build and mental illness. The difference in body build between schizophrenia (S) and manic-depressive psychosis (MDP) is similar to that between late and early maturers. It is suggested that S affects late-maturing individuals and MDP very early maturers. The observed marked rise in MDP and decline in the most malignant forms of S (non-paranoid) are in agreement with MDP and S as neurodevelopmental disorders occurring at the extremes of maturation. Maturational irregularities are most likely to occur at the extremes, and it is suggested that abbreviation of the regressive process may have led to persistent redundancy of neuronal synapses in MDP and that prolongation of the process past the optimal has yielded an inadequate synaptic density in S. The lack of cerebral abnormality in the majority of MDP and the presence of only subtle structural deficits in S, are in agreement with this. The two disorders are probably as old as mankind, and early puberty is the necessary factor for the development of MDP and late puberty is the necessary factor for that of S. There is an inverse relation between spatial ability and rate of maturation, whereas verbal ability is unaffected by maturational rate. From a previous predominance in both sexes, spatial ability (Performance IQ scores) has been reduced to below verbal ability (Verbal IQ scores) in the female sex and in early maturing males.

Aging↗

PubMed2004

Autism in Angelman syndrome: implications for autism research.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, ataxia, and a happy/sociable disposition. Maternally, but not paternally, derived defects, such as duplications, within the AS critical region result in autistic symptomatology, suggesting that the UBE3A gene might be implicated in the causation of autism. This study examined the prevalence of autism in AS in 19 children representing three known molecular classes of AS. Children were studied over the course of 1 year. Forty-two percent of this population, eight of 19 children, met criteria for autism according to the Autism Diagnostic Observation Schedule (ADOS). Parents of children who were diagnosed with autism according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria as well as the ADOS - Generic, Module 1 (ADOS-G) were administered the Autism Diagnostic Interview - Revised (ADI-R). Data from the ADI-R were convergent with data from the ADOS-G in all cases. Children with comorbid autism and AS scored lower on measures of language, adaptive behavior, and cognition, and demonstrated a slower rate of improvement over the course of the study. Furthermore, they demonstrated deficits in communication and socialization that mirror those observed in children with idiopathic autism. The study highlights the phenotypic overlap between autism and AS and increases the probability that dysregulation of UBE3A may play a role in the causation of autism.

Angelman Syndrome↗

PubMed2006

Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene encoding methyl CpG binding protein 2 (MeCP2). Recently, a new isoform of MeCP2 including exon 1 was identified. This new isoform is more abundantly expressed in brain than the isoform including exons 2-4. Very little is known about the phenotypes associated with mutations in exon 1 of MECP2 since only a limited number of RTT patients carrying such mutations have been identified so far. In this study, we screened a cohort of 20 girls with RTT for exon 1 mutations by sequencing and multiplex ligation-dependent probe amplification (MLPA). We identified one girl with a novel exon 1 mutation (c.30delCinsGA) by sequencing and three with genomic rearrangements by MLPA. Comparison of the phenotypes showed that the girls carrying a mutation or rearrangement encompassing exon 1 were more severely affected than the girls with rearrangements not affecting exon 1.

Adolescent↗

PubMed2006

Germline mosaicism for a MECP2 mutation in a man with two Rett daughters.

Rett syndrome is a severe neurodevelopmental disorder that is caused by mutations in the X-linked gene, methyl-CpG binding protein 2 (MECP2). The majority of cases are sporadic, but rarely germline mosaicism can lead to familial cases. Here, we report the first case where germline mosaicism for a MECP2 mutation has been shown in a man. He has two affected daughters who are half sisters, and both have the c.808delC mutation. We show that this mutation is present at a low level in DNA extracted from the patient's semen. This case has implications for genetic counseling, and pre-natal testing should be offered for the partners of men who have a daughter with Rett syndrome.

Base Sequence↗

PubMed1996

An Angelman syndrome clinic: report on 24 patients.

OBJECTIVE: Angelman syndrome (AS) is a rare congenital neurodevelopmental disorder with complex genetic aetiology. Diagnosis may be difficult and there is severe life-long disability. An AS clinic was commenced in Sydney, Australia, in 1993 with the aim of gathering information about the natural history of AS, management issues and parental concerns. METHODOLOGY: Patients were referred from metropolitan Sydney, rural New South Wales and interstate. A questionnaire, history, physical examination and diagnostic tests were undertaken. RESULTS: In the first year, 24 patients with AS were assessed. There were 11 males and 13 females, whose ages ranged from 3 to 30 years. The mean age of diagnosis was 12.8 years. The diagnosis was made by neurologists in four cases, by clinical geneticists in three cases, by paediatricians in two cases and 15 cases were diagnosed at the AS clinic. A clear history of epilepsy was obtained in 19 (79%) and in 15 of these patients the age of onset was during the first 4 years of life. An EEG had been performed in 21 patients, and in two the EEG was reported as normal. Fifteen of the patients (62.5%) could walk independently and in this cohort there was a significant sex difference in walking: 10/11 males compared to 5/13 females (P > 0.01). Five patients (21%) were in full-time permanent care. Genetic testing with appropriate DNA probes from chromosome 15 (q11-13), complete in 20 families, showed deletion in 12 patients (60%),uniparental disomy in 1(5%) and no detectable abnormality in 7 (35%). CONCLUSIONS: The diagnosis of AS should be considered in any patient with severe developmental disability particularly if there is a movement disorder and lack of speech. The control of epilepsy is a major management problem. Further research is needed to establish the frequency and type of seizures, the response to anticonvulsants and to determine if improvement can be expected with age. The mobility of patients should be assessed regularly, to determine the most appropriate options for intervention.

Adolescent↗

PubMed2004

Trisomy 21 and Rett syndrome: a double burden.

Rett syndrome is a severe neurodevelopmental disorder generally affecting girls. Affected individuals are apparently normal at birth but later pass through a period of regression with loss of hand and communication skills and the development of hand stereotypies and dyspraxia. Mutations in the methyl-CpG binding protein 2 (MECP2) gene, have now been found to cause Rett syndrome in up to 80% of classical cases. We report a girl with Down syndrome, one of three children with birth defects in a family of five. From the age of 18 months she developed symptomatology considered by her primary physician to be very characteristic of Rett syndrome. However, this remained a clinical diagnosis till the age of 12 years. Laboratory confirmation of the dual diagnosis, which includes a R168X mutation in the MECP2 gene in addition to trisomy 21, has now been possible. The presence of one neurological or developmental disorder does not necessarily preclude a diagnosis of Rett syndrome.

Child↗

PubMed2006

Clinical neurological abnormalities in young adults with Asperger syndrome.

Children with Asperger syndrome (AS), a neurodevelopmental disorder falling in the autism spectrum disorders, have an increased rate of neurological abnormalities, especially in motor coordination. While AS is a lifelong condition, little is known about the persistence of neurological abnormalities in adulthood. Twenty young adults with AS were compared with 10 healthy controls using a structured clinical neurological rating scale. The score for neurological abnormalities was higher in the AS group. In addition, a subscore for neurological soft signs indicating defective functioning of the central nervous system with a non-localizing value was significantly higher in the AS subjects. This preliminary study indicates that neurological abnormalities, soft signs in particular, represent a non-specific vulnerability factor for AS. Consistent with other features of AS, neurological abnormalities seem to persist into adulthood.

Adult↗

PubMed2005

Recognition and optimal management of schizophrenia and related psychoses.

Schizophrenia continues to remain one of the major unsolved conditions of our time, contributing significantly to causes of disability worldwide. Advances in neuroimaging have demonstrated that schizophrenia appears to be primarily a neurodevelopmental disorder. The dopamine theory of schizophrenia continues to hold sway but interest is growing in the role of other neurotransmitters. Genetic linkage studies continue to suggest that specific chromosomes have a role in the aetiology of the condition but the findings are, as yet, inconsistent. A new generation of drug therapies and reforms of the mental health system have meant that it is now possible to treat the majority of those with this condition in the community albeit, in some instances, against their will. The medical complications of both the disorder, the lifestyle changes resulting from the disorder and the new and older medications have come to prominence in recent years. The development of guidelines for treatment has the potential to reduce the variability in clinical practice that currently exists in the management of the condition.

Antipsychotic Agents↗

PubMed2006

EEG evidence for the presence of an action observation-execution matching system in children.

In the adult human brain, passive observation of actions performed by others activates some of the same cortical areas that are involved in the execution of actions, thereby contributing to action recognition. This mechanism appears to occur through activation of a population of action-coding cells known as mirror neurons (MN). In the adult motor cortex, performing actions and observing human movement reduces the magnitude of the mu (8-13 Hz) rhythm, possibly reflecting MN system activity. Despite the wealth of information available regarding the adult MN system, little is known about its existence in children. Here, we used EEG to probe mu rhythm modulation in 15 children during observation and execution of hand actions. Our data show that mu rhythm attenuation occurs in children under 11 years old during observation of hand movements. Similarly to what has been reported in adults, observation of goal/object-orientated movement produces greater modulation of the mu rhythm than intransitive movement. These data confirm the existence of an observation-execution matching system in the immature human brain and may be of clinical value in the understanding of neurodevelopmental disorders associated with a faulty MN system, such as autism spectrum disorder.

Brain Mapping↗

PubMed1994

Executive function abilities in autism and Tourette syndrome: an information processing approach.

This study used information processing paradigms to provide a detailed examination of executive function abilities in autism. The performance of non-retarded autistic children was compared with that of two matched control groups, one with Tourette Syndrome and the other developmentally normal. Autistic subjects performed as well as controls on tasks requiring global-local processing and inhibition of neutral responses. In contrast to both control groups, however, the autistic sample was significantly impaired on a measure of cognitive flexibility. The performance of children with Tourette Syndrome did not differ from that of normal controls on any task. These results refine our knowledge about executive dysfunction in autism and suggest a new conceptual framework and general method for investigating the cognitive underpinnings of neurodevelopmental disorders.

Adolescent↗

PubMed2005

Aversion, awareness, and attraction: investigating claims of hyperacusis in the Williams syndrome phenotype.

BACKGROUND: Williams syndrome (WS), a neurodevelopmental disorder, is characterized by pervasive cognitive deficits alongside a relative sparing of auditory perception and cognition. A frequent characteristic of the phenotype is adverse reactions to, and/or fascination with, certain sounds. Previously published reports indicate that people with WS experience hyperacusis, yet careful examination reveals that the term 'hyperacusis' has been used indiscriminately in the literature to describe quite different auditory abnormalities. METHOD: In an effort to clarify and document the incidence of auditory abnormalities in and among people with WS we collected data from parents of people with WS (n = 118) and comparison groups of people with Down syndrome, autism, and normal controls. RESULTS: Our findings revealed four phenomenologically separate auditory abnormalities, all of which were significantly more prevalent in WS than the three comparison groups. Among people with WS, we found relatively few reports of true hyperacusis (lowered threshold for soft sounds) or auditory fascinations/fixations, whereas 80% reported fearfulness to idiosyncratically particular sounds, and 91% reported lowered uncomfortable loudness levels, or 'odynacusis.' CONCLUSIONS: Our results confirm anecdotal reports of an unusual auditory phenotype in WS, and provide an important foundation for understanding the nature of auditory experience and pathology in WS. We conclude by reviewing the ways in which the present findings extend and complement recent neuroanatomical and neurophysiological findings on auditory function in people with WS.

Awareness↗

PubMed2005

Tourette's syndrome: performance on tests of behavioural inhibition, working memory and gambling.

BACKGROUND: Tourette's syndrome (TS) is a neurodevelopmental disorder associated with fronto-striatal dysfunction. There is debate as to the extent to which TS is associated with cognitive impairment. Some authors argue that any impairments seen are attributable to comorbid psychiatric symptomatology, whilst others have suggested that uncomplicated TS is associated with mild deficits limited primarily to inhibitory processes. The present study was designed to examine this issue using carefully screened participants with TS and experimental measures thought to involve different areas of the frontal lobes. METHODS: Adolescents with TS who were screened for comorbid psychiatric disorder were compared with a healthy control group on a set of executive measures. Two tasks involving behavioural inhibition were used: a Sentence Completion task in which sentences had to be completed first with straightforward and then with nonsensical endings, and a Flanker task in which a central stimulus was surrounded by either compatible or incompatible flankers. Working memory was assessed using an N-back task, and reward learning was assessed using a Gambling task. Both accuracy and reaction times were measured for each task. RESULTS: The TS group differed significantly from the control group on both the Sentence Completion task and on the Flanker task. On the Sentence Completion task, they were slower to make both sensible and nonsensical completions, and they had higher error scores on the nonsensical completions. On the Flanker task, the TS participants were less accurate than the control group, since they were poorer on the incompatible but not the compatible trials. A similar interaction with trial type was found for speed, where the TS participants were slowed more by the incompatible versus compatible trials, although overall their performance tended to be faster than the controls. The TS group did not differ significantly from the control group on measures of working memory or reward learning. CONCLUSIONS: The findings provide further evidence that uncomplicated TS is not associated with widespread executive impairments. However, it was not clear that any differences between the groups could be attributed solely to selective inhibitory impairment.

Adolescent↗