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PubMed2006

Infant motor development is associated with adult cognitive categorisation in a longitudinal birth cohort study.

BACKGROUND: The relationship between the age of reaching infant developmental milestones and later intellectual function within the normal population remains unresolved. We hypothesised that the age of learning to stand in infancy would be associated with adult executive function and that the association would be apparent throughout the range of abilities, rather than confined to extremes. METHODS: The Northern Finland 1966 Birth Cohort is based upon 12,058 live-born children in a geographic and temporally defined population. Information on age at learning to stand without support was obtained at one year. At age 33-35 a random sample of 104 subjects underwent a neuropsychological test battery including tests of executive function (cognitive categorisation), visuo-spatial memory, verbal learning and visual object learning. We investigated associations between developmental data and adult neuropsychological test scores. RESULTS: There was a significant linear relationship between age of learning to stand and adult categorisation: the earlier the attainment of the milestone, the better was the categorisation. No such relationships were observed between infant neurodevelopment and adult cognition in other neuropsychological domains. CONCLUSION: Even within the normal range of development, early development in the gross motor domain is associated with better adult executive function (in tests of categorisation). Investigation of the determinants and sequelae of normal neural development will facilitate research into a variety of neurodevelopmental disorders.

Adult↗

PubMedDate not supplied

Continuities and discontinuities in psychopathology between childhood and adult life.

The possible mechanisms involved in continuities and discontinuities in psychopathology between childhood and adult life are considered in relation to the findings from systematic, prospective, long-term longitudinal studies. Findings on schizophrenia, neurodevelopmental disorders, emotional disturbances, antisocial behaviour and substance abuse are used as conditions illustrating the key issues. The overarching themes are then discussed in relation to heterotypic continuity and psychopathologic progression, early age at onset and a range of possible mediating mechanisms - including genetic mediation, 'kindling' effects, environmental influences, coping mechanisms and cognitive processing of experiences. Some of the key research challenges that remain concern the testing of competing hypotheses on mediating processes, the changes involved in adolescence, the transition from prodromal phase to overt schizophrenia and the emergence of adolescent-limited antisocial behaviour. Greater use needs to be made of genetic research strategies and of the testing of possible cognitive processing mediation effects.

Adolescent↗

PubMed1988

Prediction in very preterm infants of satisfactory neurodevelopmental progress at 12 months.

This study was performed to find out how well ultrasound brain-scanning and neurological examination of very preterm infants, together and separately, predicted normal neurodevelopmental progress at 12 months corrected age. 111 infants born at less than 33 weeks gestation were scanned at discharge from the neonatal unit, and neurological examinations were performed at a gestation-equivalent age at or near term. During the first year of life repeated neurological and developmental testing was carried out. At 12 months a diagnosis of normal progress or of major or minor neurodevelopmental disorders was made. 56 (50 per cent) infants with both a favourable ultrasound scan and normal neurological findings had a 98 per cent (90 to 99 per cent) probability of normal progress at 12 months, and a 100 per cent (93 to 100 per cent) probability of having no major disorder. Separately, ultrasound scanning and neurological examination were not such good predictors of normal outcome, although they selected larger groups of infants with high probabilities of progressing normally. Ultrasound brain-scanning and neurological examination can be used in combination to identify potentially normal preterm infants when they are discharged to their homes.

Central Nervous System↗

PubMed1995

A case of paroxysmal tonic upward gaze associated with psychomotor retardation.

The authors report a female with paroxysmal tonic upward gaze similar to the cases reported by Ouvrier and Billson (1988). She developed abnormal eye-movements at the age of six months. Several anticonvulsants and levodopa were not effective in the control of the episodes; however, her upward eye-deviations spontaneously decreased during the one-year observation. Her clinical features were almost identical to those reported by Ouvrier and Billson, except that she had neurodevelopmental disorder and abnormal brain MRI. More data are required to clarify this unique phenomenon.

Anticonvulsants↗

PubMed1998

Diagnosis of Rett syndrome: can a radiograph help?

Rett syndrome (RS), a neurodevelopmental disorder almost exclusively affecting girls, is associated with severe intellectual and motor disability. In the absence of biological markers, diagnosis is determined by a set of clinical criteria. In a previous study in Scotland, shortening of the fourth metatarsal was reported clinically in 20% of classical RS cases aged 5 years or older. The Australian Rett Syndrome Study database has facilitated a population-based radiological study of the hands and feet of girls with RS. Straight radiographs of hands and feet were available from 94 cases, representing 70.1% of the known RS population in Australia. Control radiographs were matched for age, sex, and laterality. Relative shortening of the fourth metacarpal/metatarsal was assessed using the sign method. A short ulna (negative ulna variance) was defined as the distal articular surface of the ulna being at least 5mm proximal to the distal articular surface of the radius. A positive metacarpal sign was twice as common in verified cases of RS than in controls in the right but not the left hand. A short ulna was more common in subjects with RS than in controls. A short fourth metatarsal was also more common among subjects with RS. More than half (56.6%) the girls with RS over the age of 4 years had a negative ulnar variance in either wrist or a metatarsal sign in either foot. These findings will assist with the diagnosis of RS and may help direct research towards the location of the molecular defect.

Adolescent↗

PubMed2004

Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1-stimulated neurite outgrowth of cerebellar granule neurons.

Stimulation of the neuronal cell adhesion molecule L1 in cerebellar granule neurons (CGNs) enhances neurite outgrowth and this response is inhibited by the primary alcohol ethanol. Because primary alcohols suppress the formation of the signaling lipid phosphatidic acid (PA) by phospholipase D (PLD), this observation prompted us to investigate whether PLD plays a role in the L1-mediated neurite outgrowth in CGNs. In the cerebellum of postnatal day 8 mice, PLD2 protein was abundantly expressed, while PLD1 expression was not detected. The L1-stimulated neurite outgrowth was inhibited by primary alcohols and by overexpression of lipase-deficient PLD2. Increases in cellular PA levels by direct PA application or overexpression of wild-type PLD2 mimicked the L1-dependent stimulation of neurite outgrowth. Furthermore, it was found that L1 stimulation in CGNs increased PLD activity concomitantly with phosphorylation of extracellular signal-regulated kinase (ERK), both of which were inhibited by the MAP kinase-ERK kinase (MEK) inhibitor. These results provide evidence that PLD2 functions as a downstream signaling molecule of ERK to mediate the L1-dependent neurite outgrowth of CGNs, a mechanism that may be related to alcohol-related neurodevelopmental disorders.

Alcohols↗

PubMed2006

Gene expression is differentially regulated by neurotransmitters in embryonic neuronal cortical culture.

Neurotransmitters and their receptors have been involved in both proper brain development and neurodevelopmental disorders. The role that nicotinic receptors play in immature cortical neurons was initially investigated by gene profiling using Affymetrix DNA arrays. Both short (15 min) and prolonged (18 h) treatments with nicotine did not induce modification in gene expression, whereas a significant down-regulation of c-fos protein levels was observed after 18 h treatment. Conversely, a brief treatment with the glutamatergic agonist NMDA triggered up-regulation of immediate early genes and transcription factors, which remained unaffected by pre-treatment for 18 h with nicotine. Calcium imaging studies revealed that NMDA activated a sustained increase in intracellular calcium concentration in the majority of neurons, whereas nicotine evoked only a transient calcium increase in a smaller percentage of neurons, suggesting that the calcium signalling response was correlated with activation of gene expression. Nicotine effects on immature cortical neurons perhaps do not require gene regulation but may be still acting on signalling pathways.

Animals↗

PubMed2004

Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice.

Deficits in social interaction are important early markers for autism and related neurodevelopmental disorders with strong genetic components. Standardized behavioral assays that measure the preference of mice for initiating social interactions with novel conspecifics would be of great value for mutant mouse models of autism. We developed a new procedure to assess sociability and the preference for social novelty in mice. To quantitate sociability, each mouse was scored on measures of exploration in a central habituated area, a side chamber containing an unfamiliar conspecific (stranger 1) in a wire cage, or an empty side chamber. In a secondary test, preference for social novelty was quantitated by presenting the test mouse with a choice between the first, now-familiar, conspecific (stranger 1) in one side chamber, and a second unfamiliar mouse (stranger 2) in the other side chamber. Parameters scored included time spent in each chamber and number of entries into the chambers. Five inbred strains of mice were tested, C57BL/6J, DBA/2J, FVB/NJ, A/J and B6129PF2/J hybrids. Four strains showed significant levels of sociability (spend- ing more time in the chamber containing stranger 1 than in the empty chamber) and a preference for social novelty (spending more time in the chamber containing stranger 2 than in the chamber containing the now-familiar stranger 1). These social preferences were observed in both male and female mice, and in juveniles and adults. The exception was A/J, a strain that demonstrated a preference for the central chamber. Results are discussed in terms of potential applications of the new methods, and the proper controls for the interpretation of social behavior data, including assays for health, relevant sensory abilities and motor functions. This new standardized procedure to quantitate sociability and preference for social novelty in mice provides a method to assess tendencies for social avoidance in mouse models of autism.

Age Factors↗

PubMed2007

Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2-/y knockout mice.

Rett syndrome (RTT) is an inborn neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 gene (MECP2). Besides mental retardation, most patients suffer from potentially life-threatening breathing arrhythmia. To study its pathophysiology, we performed comparative analyses of the breathing phenotype of Mecp2-/y knockout (KO) and C57BL/6J wild-type mice using the perfused working heart-brainstem preparation (WHBP). We simultaneously recorded phrenic and efferent vagal nerve activities to analyse the motor pattern of respiration, discriminating between inspiration, postinspiration and late expiration. Our results revealed respiratory disturbances in KO preparations that were similar to those reported from in vivo measurements in KO mice and also to those seen in RTT patients. The main finding was a highly variable postinspiratory activity in KO mice that correlated closely with breathing arrhythmias leading to repetitive apnoeas even under undisturbed control conditions. Analysis of the pontine and peripheral sensory regulation of postinspiratory activity in KO preparations revealed: (i) prolonged apnoeas associated with enhanced postinspiratory activity after glutamate-induced activation of the pontine Kölliker-Fuse nucleus; and (ii) prolonged apnoeas and lack of reflex desensitization in response to repetitive vagal stimulations. We conclude that impaired network and sensory mediated synaptic control of postinspiration induces severe breathing dysfunctions in Mecp2-/y KO preparations. As postinspiration is particularly important for the control of laryngeal adductors, the finding might explain the upper airway-related clinical problems of patients with RTT such as apnoeas, loss of speech and weak coordination of breathing and swallowing.

Animals↗

PubMed2001

Dyslexia: cultural diversity and biological unity.

The recognition of dyslexia as a neurodevelopmental disorder has been hampered by the belief that it is not a specific diagnostic entity because it has variable and culture-specific manifestations. In line with this belief, we found that Italian dyslexics, using a shallow orthography which facilitates reading, performed better on reading tasks than did English and French dyslexics. However, all dyslexics were equally impaired relative to their controls on reading and phonological tasks. Positron emission tomography scans during explicit and implicit reading showed the same reduced activity in a region of the left hemisphere in dyslexics from all three countries, with the maximum peak in the middle temporal gyrus and additional peaks in the inferior and superior temporal gyri and middle occipital gyrus. We conclude that there is a universal neurocognitive basis for dyslexia and that differences in reading performance among dyslexics of different countries are due to different orthographies.

Adult↗

PubMed1999

Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.

Programmed cell death (apoptosis) occurs during normal development of the central nervous system. However, the mechanisms that determine which neurons will succumb to apoptosis are poorly understood. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors for only a few hours during late fetal or early neonatal life triggered widespread apoptotic neurodegeneration in the developing rat brain, suggesting that the excitatory neurotransmitter glutamate, acting at NMDA receptors, controls neuronal survival. These findings may have relevance to human neurodevelopmental disorders involving prenatal (drug-abusing mothers) or postnatal (pediatric anesthesia) exposure to drugs that block NMDA receptors.

Animals↗

PubMed2001

Establishment and maintenance of DNA methylation patterns in mouse Ndn: implications for maintenance of imprinting in target genes of the imprinting center.

Ndn is located on chromosome 7C, an imprinted region of the mouse genome. Imprinting of Ndn and adjacent paternally expressed genes is regulated by a regional imprinting control element known as the imprinting center (IC). An IC also controls imprint resetting of target genes in the region of conserved synteny on human chromosome 15q11-q13, which is deleted or rearranged in the neurodevelopmental disorder Prader-Willi syndrome. Epigenetic modifications such as DNA methylation, which occur in gametes and can be stably propagated, are presumed to establish and maintain the imprint in target genes of the IC. While most DNA becomes substantially demethylated by the blastocyst stage, some imprinted genes have regions that escape global demethylation and may maintain the imprint. We have now analyzed the methylation of 39 CpG dinucleotide sequences in the 5' end of Ndn by sodium bisulfite sequencing in gametes and in preimplantation and adult tissues. While sperm DNA is completely unmethylated across this region, oocyte DNA is partially methylated. A distinctive but unstable maternal methylation pattern persists until the morula stage and is lost in the blastocyst stage, where low levels of methylation are present on most DNA strands of either parental origin. The methylation pattern is then substantially remodeled, and fewer than half of maternally derived DNA strands in adult brain resemble the oocyte pattern. We postulate that for Ndn, DNA methylation may initially preserve a gametic imprint during preimplantation development, but other epigenetic events may maintain the imprint later in embryonic development.

Animals↗

PubMed1986

Prognosis of the very low birthweight baby in relation to gender.

The effects of gender on mortality and morbidity of all neonates weighing less than 1500 g admitted to King's College Hospital Neonatal Intensive Care Unit during 1980-82 (n = 271) were examined. Very low birthweight boys had a significantly higher mortality and more postnatal complications than girls. The higher incidence of respiratory distress syndrome and pulmonary interstitial emphysema in boys was associated with increased mortality in the first year. Surviving boys had significantly more problems, including lower Apgar scores at five minutes, more frequent apnoeic attacks and bradycardic episodes, transient tachypnoea, neonatal anaemia, and lower blood calcium and phosphate concentrations. Surviving children were followed up at 1 and 2 years of age. Development of boys at 1 year was significantly delayed compared with girls in all fields save locomotor. Although at 2 years some of the differences had diminished, those in language and personal social skills were more pronounced. More than twice as many boys as girls had major neurodevelopmental disorders.

Child Development↗

PubMed1988

Ataxic cerebral palsy and genetic predisposition.

It was calculated that in the 962 family members of 36 patients with ataxic cerebral palsy there were 75 (8%) with a history of neurodevelopmental disorder and 31 (3%) with a major congenital malformation. This was not significantly greater than expected, and does not support the hypothesis of a genetic non-Mendelian role in the aetiology of ataxic cerebral palsy.

Ataxia↗

PubMed1999

Prolonged QT interval in Rett syndrome.

Rett syndrome is a severe neurodevelopmental disorder of unknown aetiology. A prolonged QT interval has been described previously in patients with Rett syndrome. To investigate QT prolongation and the presence of cardiac tachyarrhythmias in Rett syndrome electrocardiography and 24 hour Holter monitoring were performed prospectively in a cohort of 34 girls with Rett syndrome. The corrected QT value was prolonged in nine patients. Compared with a group of healthy controls of a similar age range, the patients with Rett syndrome had significantly longer corrected QT values. Clinical severity was not a predictor for prolonged QT intervals in the Rett syndrome cohort. The prolonged QT syndrome is a serious and potentially lethal cardiac disorder and should be considered in all girls with Rett syndrome.

Adolescent↗

PubMed2026

Psychiatric and neurological predictors of early ADHD medication discontinuation across the lifespan: a multinational study.

BACKGROUND: Early discontinuation of attention-deficit/hyperactivity disorder (ADHD) medication is common and linked to worse outcomes. Identifying clinical predictors could aid personalised treatment yet evidence is inconsistent across ages and countries/regions. OBJECTIVE: Investigate psychiatric and neurological comorbidity as predictors of early ADHD medication discontinuation in new ADHD medication users across age groups, sex and countries/regions. METHODS: Using health records from eight countries/regions, we identified 1 000 411 (44% female) new ADHD medication users (2011-2020). Discontinuation was defined as a ≥180 day gap between dispensations. We examined 23 indicators of psychiatric or neurological comorbidity, severity and psychotropic medication use. Associations were estimated using Cox regression, pooled with random-effects meta-analyses and stratified by age-at-initiation and sex. FINDINGS: Discontinuation rates varied widely (children 19%-61%, adolescents 37%-68%, young adults 52-67%, adults 38%-68%). In pooled analyses, earlier discontinuation in children was predicted by intellectual disability, autism and use of psychotropic medications (HR range 1.32-1.51), while conduct/oppositional defiant disorder (CD/ODD) was protective (HR 0.83, 95% CI 0.73 to 0.94). In adolescents, no indicators remained statistically significant after multiple-testing control. In young adults, CD/ODD (HR 1.42, 95% CI 1.30 to 1.55), and in adults, schizophrenia (HR 1.25, 95% CI 1.09 to 1.44) and tic disorders (HR 1.27, 95% CI 1.11 to 1.46) predicted earlier discontinuation. Statistical heterogeneity was substantial, largely driven by US estimates. In meta-analyses excluding the USA, additional associations emerged. For example, in children, OCD and anxiety disorders predicted earlier discontinuation, while eating disorders and antidepressants/anxiolytics were protective in adults. Associations with schizophrenia, tic disorders and CD/ODD were no longer significant. Country-specific analyses showed similar association patterns, except in the USA, Hong Kong and the UK. Sex differences were limited. CONCLUSIONS: Children with neuropsychiatric comorbidity and related comedication are more likely to discontinue ADHD medication early, whereas few consistent predictors were seen from adolescence onwards. Marked cross-country variation, particularly in the USA, points to system-level influences on treatment patterns. CLINICAL IMPLICATIONS: Improving ADHD medication persistence will require consideration of healthcare context and age-specific strategies, including close monitoring for children with complex neuropsychiatric profiles, and consideration of broader factors in adolescents and adults, where clinical predictors were limited.

Humans↗

PubMed2026

Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.

BACKGROUND: Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. METHODS: We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations. RESULTS: In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying PTPN11 variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in HRAS, PTPN11 and SOS1 genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers. CONCLUSION: Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.

Human Genetics↗

PubMed2005

Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects.

BACKGROUND AND METHODS: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. RESULTS: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male-male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male-male and 74 male-female/female-female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male-female/female-female ASP (MLS = 2.62 v 0.00, for non-male and male-male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at approximately 112 cM, and maternal MLS = 1.83 at approximately 135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at approximately 30 cM; paternal MLS = 0.02). CONCLUSION: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.

Autistic Disorder↗