MeCP2与神经发育性疾病

作为一种转录抑制因子,甲基化CpG结合蛋白2（MeCP2）含有结合甲基化DNA和转录抑制两个特征性的结构域,具有调节转录激活、调节染色体构象、参与RNA剪切等多种功能,在神经发育过程中起着重要的作用。近来的研究表明,MeCP2基因突变与Rett综合征、孤独症等多种神经发育性疾病相关,已成为研究基因型与人类神经发育性疾病关系的一个热点。就MeCP2在Rett综合征、孤独症及药物成瘾方面的进展作一综述。     

Drosophila modeling of heritable neurodevelopmental disorders

Heritable neurodevelopmental disorders are multifaceted disease conditions encompassing a wide range of symptoms including intellectual disability, cognitive dysfunction, autism and myriad other behavioral impairments. In cases where single, causative genetic defects have been identified, such as Angelman syndrome, Rett syndrome, Neurofibromatosis Type 1 and Fragile X syndrome, the classical Drosophila genetic system has provided fruitful disease models. Recent Drosophila studies have advanced our understanding of UBE3A, MECP2, NF1 and FMR1 function, respectively, in genetic, biochemical, anatomical, physiological and behavioral contexts. Investigations in Drosophila continue to provide the essential mechanistic understanding required to facilitate the conception of rational therapeutic treatments.     

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review

Neurodevelopmental disorders – including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders – manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence – from two or more studies from independent research groups, with results going into the same direction – of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.     

The contribution of GABAergic dysfunction to neurodevelopmental disorders

GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the brain. The GABAergic system is indispensable for maintaining the balance between excitation and inhibition (E/I balance) required for normal neural circuit function. E/I imbalances that result from perturbations in the development of this system, ranging from the generation of inhibitory neurons to the formation of their synaptic connections, have been implicated in several neurodevelopmental disorders. In this review, we discuss how impairments at different stages in GABAergic development can lead to disease states. We also highlight recent studies which show that modulation of the GABAergic system can successfully reverse cognitive deficits in disease models and suggest that therapeutic strategies targeting the GABAergic system could be effective in treating neurodevelopmental disorders.     

Epidemiology of substance use disorders

Epidemiological studies of substance use and substance use disorders (SUDs) have provided an abundance of data on the patterns of substance use in nationally representative samples across the world (Degenhardt et al. in PLoS Med 5(7):e141, 2008; Johnston et al. in Monitoring the future national survey results on drug use, 1975-2010, vol I, secondary school students. Institute for Social Research, Ann Arbor, MI, 2011; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). This paper presents a summary of the goals, methods, and recent findings on the epidemiology of substance use and disorders in the general population of adults and adolescents and describes the methods and findings on the genetic epidemiology of drug use disorders. The high 12-month prevalence rates of substance dependence in US adults (about 12?% for alcohol and 2-3?% for illicit drugs) approximate those of other mental disorders as well as chronic physical disorders with major public health impact. New findings from the nationally representative samples of US youth reveal that the lifetime prevalence of alcohol use disorders is approximately 8?% and illicit drug use disorders is 2-3?% (Merikangas et al. in J Am Acad Child Adolesc Psychiatry 49(10):980-989, 2010; Swendsen et al. in Arch Gen Psychiatry 69(4):390-398, 2012; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, Series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). The striking increase in prevalence rates from ages 13 to 18 highlight adolescence as the key period of development of SUDs. The application of genetic epidemiological studies has consistently demonstrated that genetic factors have a major influence on progression of substance use to dependence, whereas environmental factors unique to the individual play an important role in exposure and initial use of substances. Identification of specific susceptibility genes and environmental factors that influence exposure and progression of drug use may enhance our ability to prevent and treat SUDs.     

Epidemiology of Alzheimer disease and related disorders

Alzheimer's disease and related disorders (dementia) are a major public health problem due to the number of cases in the general population, the projections for the future, and the consequences of these diseases. We can estimate that about 850 000 cases of dementia were present in France in 2005 and this number will increase to 1,200,000 in 2020 and 2,100,000 in 2040 if the incidence and the duration of the disease did not change. The development of prevention is therefore necessary. Four ways of prevention are credible. The most important is the treatment of vascular risk factors and particularly hypertension. Other ways are nutritional factors, stimulating leisure activities and depression.     

Fragile X-related protein family: a double-edged sword in neurodevelopmental disorders and cancer

Abstract

The fragile X-related (FXR) family proteins FMRP, FXR1, and FXR2 are RNA binding proteins that play a critical role in RNA metabolism, neuronal plasticity, and muscle development. These proteins share significant homology in their protein domains, which are functionally and structurally similar to each other. FXR family members are known to play an essential role in causing fragile X mental retardation syndrome (FXS), the most common genetic form of autism spectrum disorder. Recent advances in our understanding of this family of proteins have occurred in tandem with discoveries of great importance to neurological disorders and cancer biology via the identification of their novel RNA and protein targets. Herein, we review the FXR family of proteins as they pertain to FXS, other mental illnesses, and cancer. We emphasize recent findings and analyses that suggest contrasting functions of this protein family in FXS and tumorigenesis based on their expression patterns in human tissues. Finally, we discuss current gaps in our knowledge regarding the FXR protein family and their role in FXS and cancer and suggest future studies to facilitate bench to bedside translation of the findings.     

Modeling human neurodevelopmental disorders in the Xenopus tadpole: from mechanisms to therapeutic targets

The Xenopus tadpole model offers many advantages for studying the molecular, cellular and network mechanisms underlying neurodevelopmental disorders. Essentially every stage of normal neural circuit development, from axon outgrowth and guidance to activity-dependent homeostasis and refinement, has been studied in the frog tadpole, making it an ideal model to determine what happens when any of these stages are compromised. Recently, the tadpole model has been used to explore the mechanisms of epilepsy and autism, and there is mounting evidence to suggest that diseases of the nervous system involve deficits in the most fundamental aspects of nervous system function and development. In this Review, we provide an update on how tadpole models are being used to study three distinct types of neurodevelopmental disorders: diseases caused by exposure to environmental toxicants, epilepsy and seizure disorders, and autism.     

Epidemiology of ADHD in Chilean children and adolescents

ADHD prevalence, associated factors, comorbidity and service use are reported for a sample of 1,558 children and adolescents, belonging to four provinces in Chile. The sample is weighted in each step for selection bias. Psychiatric disorders and impairment are assessed with computerized in-home DISC-IV interviews, and a questionnaire regarding socioeconomic and family variables and service use. Estimates of prevalence rates are obtained by means of STATA 11.0 software, with complex sample design. Multivariate logistic regression is used to determine which factors were the best predictors for mental disorders. Participation rate is 82.4 %. The prevalence of ADHD is 10 %, and the most prevalent subtype is the hyperactive/impulsive, with no gender differences. Both hyperactive/impulsive and combined subtypes are more prevalent in children 4–11 than in adolescents. The most prevalent comorbidities are anxiety disorders and oppositional disorder. Anxiety is the more prevalent comorbid disorder in girls and correlated with a combined subtype. Perception of good family functioning, adolescent age and school dropout have a negative association with ADHD diagnosis, while maltreatment shows a positive correlation. Over 50 % of children and adolescents diagnosed with ADHD have used services in the last year. This is the first comprehensive community study of psychiatric disorders in children and adolescents in a South American country. It yields information for child and adolescent mental health programmes in Chile and contributes to cross-cultural epidemiological research.     

Induction of the GABA cell phenotype: an in vitro model for studying neurodevelopmental disorders

Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD₆₇ (GAD1) expression and may play a role in γ-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD₆₇ regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD₆₇ and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD₆₇-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD₆₇, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of “differentiated” HiB5 neurons. In the presence of Ca²⁺ and K⁺, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD₆₅, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD₆₇ regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD₆₇ regulation in the adult hippocampus.     

A biochemical study on mothers of children with congenital neurodevelopmental abnormalities

A biochemical study has been undertaken on the mothers of children with a major neurodevelopmental disability, without known etiology (study group), and an appropriate control group. Two hundred seventy-four mothers were studied, 137 in each group. Social and environmental details were recorded in each of the two major groups. Biochemical studies included the assay of plasma and urinary amino acids and appropriate screening tests for carbohydrate and organic acid abnormalities. To introduce an element of standardization and also to enhance the opportunities for identifying possible biochemical heterozygote states, a 50-g protein mean was given to all subjects approximately three-quarters of an hour before blood and urine samples were taken. Difference of means tests on 22 amino acids revealed 9 significant t values at the 0.05 level and all means were significantly lower in the study groups. Because of the differences noted a discriminant analysis was carried out which demonstrated an extremely high proportion of correctly classified subjects (98%) when biochemical parameters were used to attempt to classify subjects into the study or control group.