Brain plasticity in paediatric neurology.

Plasticity includes the brain's capacity to be shaped or moulded by experience, the capacity to learn and remember, and the ability to reorganize and recover after injury. Mechanisms for plasticity include activity-dependent refinement of neuronal connections and synaptic plasticity as a substrate for learning and memory. The molecular mechanisms for these processes utilize signalling cascades that relay messages from synaptic receptors to the nucleus and the cytoskeleton to control the structure of axons and dendrites. Several paediatric neurological disorders such as neurofibromatosis-1, Fragile X syndrome, Rett syndrome, and other syndromic and non-specific forms of mental retardation involve lesions in these signalling pathways. Acquired disorders such as hypoxic-ischaemic encephalopathy, lead poisoning and epilepsy also involve signalling pathways including excitatory glutamate receptors. Information about these 'plasticity pathways' is useful for understanding their pathophysiology and potential therapy.     

Rett syndrome: from bed to bench

Rett syndrome (RTT), a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic, disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a synaptopathy (disease of the synapse) and thus potentially amenable to rational therapeutic intervention.     

Monogenic causes of nonspecific X-linked mental retardation molecular aspects

Mental retardation (MR) is a symptom in a large group of clinical conditions and affects around 3% of the population. MR is divided into syndromic, if it is characterized by distinctive clinical features and nonspecific when mental retardation is the only defining manifestation. Although genetic causes of X-linked mental retardation (XLMR) are heterogenous and complex, recent findings have led to the identification of an increasing number of genes involved in these conditions. Eight genes involved in nonspecific X-linked mental retardation have been identified so far, including FMR2, GDI1, OPHN1, PAK3, ARHGEF6, IL1RAPL, TM4SF2, and FACL4. Four other MECP2, RSK2, ARX, ATR-X are involved in syndromic and nonspecific forms of MR. Recent research has shown that these genes encode for proteins involved in signaling pathways which regulate cytoskeleton organization, synaptic vesicle transport and establishment of connections between neuronal cells. These findings provide insight into the molecular mechanisms of crucial processes for the development of intellectual and cognitive functions.     

先天性心脏病伴神经发育障碍的临床表现及遗传学研究进展

近年来研究发现先天性心脏病(CHD)患儿伴神经发育障碍(NDDs)的风险正逐年增加,包括认知、适应性、运动、语言、孤独症谱系障碍等。已通过结构及功能神经成像等影像学检查证实CHD患儿大脑发育存在异常,可能为宫内发育不良所致。拷贝数变异(CNVs)等基因异常对CHD伴NDDs具有重要影响。一些参与载脂蛋白E产生、Wnt信号传导通路和组蛋白修饰的基因变异以及1q21.1、16p13.1-11和8p23.1遗传位点变异均与CHD和NDDs相关。了解其中的相互联系对CHD患者的风险分层、疾病分类、筛查及药物治疗具有重要意义。     

X-chromosome inactivation: role in skin disease expression

The occurrence of X inactivation in mammals has the consequence that all women are functional mosaics. In X-linked skin disorders, Lyonization usually gives rise to a mosaic pattern, as manifest by the appearance of the lines of Blaschko. This arrangement of lesions is observed in male-lethal X-linked traits, such as incontinentia pigmenti, focal dermal hypoplasia, Conradi-Hünermann-Happle syndrome, oral-facial-digital syndrome type 1 and MIDAS (microphthalmia, dermal aplasia and sclerocornea) syndrome, as well as in various X-linked non-lethal phenotypes, such as hypohidrotic ectodermal dysplasia of Christ-Siemens-Touraine, IFAP (ichthyosis follicularis-alopecia-photophobia) syndrome and X-linked dyskeratosis congenita. Analogous X-inactivation patterns have been documented in human bones, teeth, eyes and, possibly, the brain. Patterns that are distinct from the lines of Blaschko are also seen, such as the lateralization observed in CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, and the chequerboard pattern seen in women heterozygous for X-linked congenital hypertrichosis. Exceptional cases of either severe or absent involvement in a woman heterozygous for an X-linked trait can be explained by skewing of X inactivation. Some X-linked skin disorders are caused by genes that escape inactivation, which is why heterozygous female 'carriers' of these disorders do not show mosaicism. A well-known example is X-linked recessive ichthyosis due to steroid sulphatase deficiency, the locus for which is situated at the tip of the short arm of the X chromosome and does not undergo Lyonization. On the other hand, in the case of Fabry disease, the gene encoding alpha-galactosidase A is subject to inactivation. Remarkably, however, the skin lesions of women do not show a mosaic pattern.Conclusion: In the various X-linked skin disorders, affected women show quite dissimilar degrees of involvement and forms of manifestation because X inactivation may give rise to different patterns of functional mosaicism. Paradoxically, no such pattern is observed in women with Fabry disease. Like many X-linked diseases, Fabry disease should neither be called recessive nor dominant, because these dichotomous terms are obscured by the mechanism of X inactivation.     

Precholesterol sterols accumulate in lipid rafts of patients with Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata.

Systemic fetal dysmorphogenesis in disorders of postsqualene cholesterol biosynthesis is thought to be caused by disruption of Hedgehog signaling. Because precholesterol sterols such as 7-dehydrocholesterol and lathosterol can replace cholesterol in the activation of Hedgehog proteins, it is currently believed that cholesterol deficiency-related Hedgehog signaling block occurs further downstream, probably at the level of Smoothened. Experimentally, such a block in Hedgehog signaling occurs at sterol levels of <40 mug/mg protein. Recently, we studied autopsy material from 2 infants with fatal cholesterol biosynthetic disorders (Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata) in which the hepatic cholesterol levels were far greater. In this study, we demonstrate abnormal accumulation of sterol precursors of cholesterol in membrane lipid rafts (detergent resistance membranes) prepared from liver tissues of these 2 infants: 8-dehydrocholesterol and 7-dehydrocholesterol in lipid rafts of the infant with Smith-Lemli-Opitz syndrome and cholest-8(9)-ene-3beta-ol in lipid rafts of the infant with X-linked dominant chondrodysplasia punctata. We suggest that such alterations in the lipid raft sterol environment may affect the biology of cells and the development of fetuses with cholesterol biosynthetic disorders.     

Integrated care for autism assessment,diagnosis and intervention

Autism spectrum disorder is one of a group of conditions considered to be a neurodevelopmental disorder. These conditions, including ADHD, language disorders and intellectual disability frequently co-occur. Diagnostic pathways often focus on assessment of a named condition (e.g. autism spectrum disorder) in isolation, resulting in inefficiencies in service delivery; other services look holistically at the child's strengths and needs, and provide a neurodevelopmental diagnostic formulation. However, there is growing support for a change to this neurodevelopmental approach that informs recommendations for ongoing multiagency support and intervention for the child and their family. Whilst there may be different ways to deliver a successful neurodevelopmental pathway, the move to integrated commissioning offers an opportunity to redesign services to bring together teams; for example, CAMHS and child development services could deliver an integrated neurodevelopmental pathway, instead of separate single condition pathways. This paper presents the research and reasoning, as well as potential pitfalls, for services to deliver a neurodevelopmental approach, and what this means for clinical practice.     

Organelle disease: peroxisomal disorders

Peroxisomes are virtually ubiquitous organelles involved in numerous catabolic and anabolic pathways. Interest in peroxisomes stems from an expanding group of genetic diseases in which there is either deficiency of a specific peroxisomal function (single protein defects) or failure to assemble the organelle resulting in defects of multiple peroxisome functions (peroxisome biogenesis disorders). The paradigm for the former is X-linked adrenoleukodystrophy caused by mutations in the adrenoleukodystrophy gene and, for the latter, Zellweger syndrome caused by mutations in peroxin genes. Conclusion The identification and functional characterisation of the peroxisomal disease genes is proceeding at rapid pace helped immeasurably by work in various yeast model systems. The ultimate goal is to elucidate how the encoded proteins produce normal appearing and functioning peroxisomes. The achievement of this goal will lead to a better understanding of peroxisomal disorders, their pathogenesis and treatment.     

NELL2及其在促性腺激素释放激素分泌中的作用

机体的青春发育及生殖过程受下丘脑-垂体-性腺轴的调控.下丘脑促性腺激素释放激素(GnRH)神经元活化导致GnRH分泌增多是青春期启动的触发因素.GnRH神经元功能活动的调节机制非常复杂,有多种因子影响GnRH的分泌.谷氨酸作为最主要的兴奋性神经递质,可以通过多种机制促进GnRH的分泌.近年来有研究发现NELL2可能通过...     

Congenital Infection and Disorders of Brain Development: With Special Reference to Congenital Cytomegalovirus Infection

ABSTRACT Intrauterine infections of various microorganisms have the potential to induce brain abnormalities in the fetus and newborn infant. Among the infectious pathogens, cytomegalovirus (CMV) is the most significant infectious cause of brain abnormalities, with variations from fatal cytomegalic inclusion disease to functional brain disorders, such as mental retardation or epilepsy. Here, we present three autopsy cases of congenital CMV infection, and we review the features of the brain abnormalities of congenital CMV infection. A ventriculofugal spread of infection seems to be characteristics of congenital CMV-infected brains and is suggested to be the cause of neuronal migration disorders, resulting in brain malformations, such as microcephaly, lissencephaly and polymicrogyria. We also present an experimental animal model for congenital CMV infection. With the model we showed that murine cytomegalovirus (MCMV) infection in the developing mouse brain caused a disturbance of neuronal migration and neuronal cell loss, detected with morphometric measurements by labeling the neuronal precursor cells with BrdU. As shown by immunohistochemical double staining of BrdU and viral-antigen, infected neuronal cells constituted only a part of the disordered neuronal cells, suggesting that an indirect effect of vital infection on neuronal cells also contributes the migration disorders presumably mediated by cytokines or the induction of apoptosis. Neuronal migration disorders caused by MCMV infection are also discussed with reference to those caused by X-irradiation.     

Practitioner Review: Attention-deficit hyperactivity disorder and autism spectrum disorder – the importance of depression

Young people with neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), show high rates of mental health problems, of which depression is one of the most common. Given that depression in ASD and ADHD is linked with a range of poor outcomes, knowledge of how clinicians should assess, identify and treat depression in the context of these neurodevelopmental disorders is much needed. Here, we give an overview of the latest research on depression in young people with ADHD and ASD, including possible mechanisms underlying the link between ADHD/ASD and depression, as well as the presentation, assessment and treatment of depression in these neurodevelopmental disorders. We discuss the implications for clinicians and make recommendations for critical future research in this area.     

Molecular mechanisms underlying the models of neurodevelopmental disorders in maternal immune activation relevant to the placenta

The rapid rise in the prevalence of autism spectrum disorders (ASD) and other psychiatric disorders displaying similar traits has increased the need to elucidate their molecular mechanisms. Epidemiological studies have shown that maternal infection during mid‐pregnancy is associated with increased risk of neurodevelopmental disorders such as ASD in offspring. Using maternal infection models, researchers have gathered evidence relevant to such disorders. A comprehensive summary of the changes in the brain structure, function, and behavior in offspring induced by maternal immune activation (MIA) has been reported. However, the molecular mechanisms underlying the association between MIA and improper brain development, which ultimately lead to neurodevelopmental disorders, have not been fully reviewed. This paper summarizes the currently known molecular mechanisms associated with the MIA model, with a special focus on the role of the placenta in fetal brain development.     

Maturing insights into the genetic architecture of neurodevelopmental disorders – from common and rare variant interplay to precision psychiatry

The categorisation of neurodevelopmental and psychiatric disorders by clinical syndromes, rather than by aetiology, continues to obstruct progress in biomarker identification as well as innovative drug development and effective treatment in general. There is a decisive move to think of neurodevelopmental disorders as a spectrum rather than discrete categorical entities. We might call them neurodevelopmental spectrum disorders (NSDs) ranging from intellectual disability (ID) to autism (ASD), and attention‐deficit/hyperactivity disorder (ADHD) (Kiser, Rivero, & Lesch, 2015 ).     

Long-term sleep disturbances in children: A cause of neuronal loss

Short-term sleep loss is known to cause temporary difficulties in cognition, behaviour and health but the effects of persistent sleep deprivation on brain development have received little or no attention. Yet, severe sleep disorders that last for years are common in children especially when they have neurodevelopmental disabilities. There is increasing evidence that chronic sleep loss can lead to neuronal and cognitive loss in children although this is generally unrecognized by the medical profession and the public. Without the restorative functions of sleep due to total sleep deprivation, death is inevitable within a few weeks. Chronic sleep disturbances at any age deprive children of healthy environmental exposure which is a prerequisite for cognitive growth more so during critical developmental periods. Sleep loss adversely effects pineal melatonin production which causes disturbance of circadian physiology of cells, organs, neurochemicals, neuroprotective and other metabolic functions. Through various mechanisms sleep loss causes widespread deterioration of neuronal functions, memory and learning, gene expression, neurogenesis and numerous other changes which cause decline in cognition, behaviour and health. When these changes are long-standing, excessive cellular stress develops which may result in widespread neuronal loss. In this review, for the first time, recent research advances obtained from various fields of sleep medicine are integrated in order to show that untreated chronic sleep disorders may lead to impaired brain development, neuronal damage and permanent loss of developmental potentials. Further research is urgently needed because these findings have major implications for the treatment of sleep disorders.     

重视神经发育障碍儿童睡眠障碍

神经发育障碍儿童的临床表现各异,但同时合并睡眠障碍的比例非常高,且发生率、严重度、病程、治疗难度及复发率各方面均明显高于正常发育儿童。此外,睡眠紊乱对这些神经发育障碍儿童在认知、情绪、社会发展和行为表现等多领域的损害也更为显著,甚至会严重影响家人的睡眠质量和生活质量。但是,一直以来,儿科临床人员对睡眠障碍的认识相对较少,也缺乏睡眠评估和诊治的能力。因此,从神经发育障碍儿童合并睡眠障碍的病因和危险因素分析开始,介绍其相应的临床症状、评估手段以及干预办法,以期帮助儿科临床人员在诊治神经发育障碍儿童过程中,提高其对睡眠症状的评估及干预水平,通过改善睡眠提升此类患儿的白天功能水平、康复治疗效果以及家人的睡眠质量和生活质量。     

基于亚低温床垫与高压氧舱结合的新生儿智能调控系统——一种发明专利的介绍

儿童神经发育障碍（neurodevelopmental disorders, NDDs）是由多种遗传性或获得性病因导致的一组慢性发育性脑功能障碍疾病,主要包括智力发育障碍、发育性言语或语言障碍、孤独症谱系障碍、发育性学习障碍、注意缺陷多动障碍、抽动障碍和其他神经发育障碍等。随着NDDs研究水平和诊治技术的提高,儿童NDDs研究取得了很大进步。为进一步提高儿科医生对儿童NDDs认识的广度和深度,该文就儿童NDDs研究进展作一综述。     

提高对单基因遗传自身炎症性疾病的认识

1999年始提出了自身炎症性疾病（AIDs）的概念,其主要为基因异常导致的单基因疾病,符合孟德尔遗传规律;到目前为止,已有20多种单基因AIDs被认识。其临床主要表现包括发热、皮疹、浆膜炎、关节炎、脑膜炎和葡萄膜炎,也常伴有淋巴结肿大和脾肿大;几乎所有患儿均存在炎症标记物增加,如白细胞、血小板、C反应蛋白（CRP）、红细胞沉降率（ESR）。当患儿出现上述临床表现,无法用另一种原因解释时（如感染或恶性肿瘤）,应怀疑AIDs的可能,应尽可能进行基因检测以明确诊断。值得注意的是,同一种基因突变可以引起不同临床表型;另一方面,同一种临床表型可以由多个不同的基因突变所致。对基因检测结果的解读要基于一定遗传学知识基础,密切结合临床表型,特别是对于一些在人群中发生率很高的变异更要细心分析。     

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??The clinical manifestations of neurodevelopmental disorders in children are varied?? though co-occurring sleep disorders in the population is very common. The incidence?? severity?? course?? treatment difficulty and recurrence rate are also significantly higher than those of typically developing children. In addition?? sleep disorders result in more significant impairment in children with neurodevelopmental disorders in terms of cognition?? emotion?? behavior and social development?? and even negatively affect the family sleep quality and quality of life. However?? pediatric clinicians have been lacking knowledge of sleep disorders?? as well as the capability of assessment and treatment. Therefore?? begin with the etiology and risk factors of sleep disorders in children with neurodevelopmental disorders?? the clinical symptoms and the methods of assessment and intervention are introduced to help pediatric clinicians to enhance the diagnosis and treatment of sleep disorders in the children with neurodevelopmental disorders?? and improve the children’s daytime function?? rehabilitation efficacy and family sleep quality and quality of life through promoting sleep.