scholarly journals In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Sonia Mayo ◽  
Sandra Monfort ◽  
Mónica Roselló ◽  
Silvestre Oltra ◽  
Carmen Orellana ◽  
...  
Keyword(s):  
Clinical Features ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Epigenetic Mechanisms ◽  
Proof Of Concept ◽  
Partial Loss ◽  
Imprinting Disorders ◽  
Initial Hypothesis ◽  
Definition Of ◽  
Methylation Patterns

Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprintedloci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprintinglociwill indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied:MEG3, H19, KCNQ1OT1, andSNRPN. Remarkably, the cases with partial loss of methylation inKCNQ1OT1andSNRPNpresent clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in knownlociin patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders.

Reconsidering NMIHBA Core Features: Macrocephaly Is Not a So Unusual Sign in PRUNE1-Related Encephalopathy

2020 ◽  
Author(s):  
Roberta Battini ◽  
Enrico Bertini ◽  
Roberta Milone ◽  
Chiara Aiello ◽  
Rosa Pasquariello ◽  
...  
Keyword(s):  
Nervous System ◽  
Differential Diagnosis ◽  
Clinical Features ◽  
Neurodevelopmental Disorder ◽  
Recurrent Mutation ◽  
Clinical Suspicion ◽  
Alexander Disease ◽  
Brain Anomalies ◽  
Progressive Encephalopathy ◽  
Core Features

Abstract PRUNE1-related disorders manifest as severe neurodevelopmental conditions associated with neurodegeneration, implying a differential diagnosis at birth with static encephalopathies, and later with those manifesting progressive brain damage with the involvement of both the central and the peripheral nervous system.Here we report on another patient with PRUNE1 (p.Asp106Asn) recurrent mutation, whose leukodystrophy, inferior olives hyperintensity, and macrocephaly led to the misleading clinical suspicion of Alexander disease. Clinical features, together with other recent descriptions, suggest avoiding the term “microcephaly” in defining this disorder that could be renamed “neurodevelopmental disorder with progressive encephalopathy, hypotonia, and variable brain anomalies” (NPEHBA).

ADHD with Comorbid Bipolar Disorders: A Systematic Review of Neurobiological, Clinical and Pharmacological Aspects Across the Lifespan

2019 ◽  
Vol 26 (38) ◽  
pp. 6942-6969 ◽  
Author(s):  
Federico Mucci ◽  
Maria Teresa Avella ◽  
Donatella Marazziti
Keyword(s):  
Clinical Features ◽  
Adult Adhd ◽  
Neurodevelopmental Disorder ◽  
Bipolar Disorders ◽  
Mood Stabilizers ◽  
Disruptive Behaviour ◽  
Single Individual ◽  
Pharmacological Management ◽  
Long Time ◽  
The Individual

Background: Attention deficit hyperactivity (ADHD) disorder is a neurodevelopmental disorder characterized by inattention, hyperactivity, disruptive behaviour, and impulsivity. Despite considered typical of children for a long time, the persistence of ADHD symptoms in adulthood gained increasing interest during the last decades. Indeed, its diagnosis, albeit controversial, is rarely carried out even because ADHD is often comorbid with several other psychiatric diosrders, in particular with bipolar disorders (BDs), a condition that complicates the clinical picture, assessment and treatment. Aims: The aim of this paper was to systematically review the scientific literature on the neurobiological, clinical features and current pharmacological management of ADHD comorbid with BDs across the entire lifespan, with a major focus on the adulthood. Discussion: The pharmacology of ADHD-BD in adults is still empirical and influenced by the individual experience of the clinicians. Stimulants are endowed of a prompt efficacy and safety, whilst non-stimulants are useful when a substance abuse history is detected, although they require some weeks in order to be fully effective. In any case, an in-depth diagnostic and clinical evaluation of the single individual is mandatory. Conclusions: The comorbidity of ADHD with BD is still a controversial matter, as it is the notion of adult ADHD as a distinct nosological category. Indeed, some findings highlighted the presence of common neurobiological mechanisms and overlapping clinical features, although disagreement does exist. In any case, while expecting to disentangle this crucial question, a correct management of this comorbidity is essential, which requires the co-administration of mood stabilizers. Further controlled clinical studies in large samples of adult ADHD-BD patients appear extremely urgent in order to better define possible therapeutic guidelines, as well as alternative approaches for this potentially invalidating condition.

scholarly journals LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

2021 ◽  
Vol 7 (11) ◽  
pp. eaba1187
Author(s):  
Rina Baba ◽  
Satoru Matsuda ◽  
Yuuichi Arakawa ◽  
Ryuji Yamada ◽  
Noriko Suzuki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Specific Inhibitor ◽  
Autism Spectrum ◽  
Poly I:C ◽  
Control Of Gene Expression ◽  
Epigenetic Machinery ◽  
The Brain

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

scholarly journals A Low-Cost Assistive Robot for Children with Neurodevelopmental Disorders to Aid in Daily Living Activities

2021 ◽  
Vol 18 (8) ◽  
pp. 3974
Author(s):  
Roberto J. López-Sastre ◽  
Marcos Baptista-Ríos ◽  
Francisco Javier Acevedo-Rodríguez ◽  
Soraya Pacheco-da-Costa ◽  
Saturnino Maldonado-Bascón ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Low Cost ◽  
Children And Youth ◽  
Proof Of Concept ◽  
Robotic Platform ◽  
Assistive Robot ◽  
Technical Details ◽  
The Impact ◽  
Near Future ◽  
Everyday Living

In this paper, we present a new low-cost robotic platform that has been explicitly developed to increase children with neurodevelopmental disorders’ involvement in the environment during everyday living activities. In order to support the children and youth with both the sequencing and learning of everyday living tasks, our robotic platform incorporates a sophisticated online action detection module that is capable of monitoring the acts performed by users. We explain all the technical details that allow many applications to be introduced to support individuals with functional diversity. We present this work as a proof of concept, which will enable an assessment of the impact that the developed technology may have on the collective of children and youth with neurodevelopmental disorders in the near future.

scholarly journals Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph J. Rossi ◽  
Jill A. Rosenfeld ◽  
Katie M. Chan ◽  
Haley Streff ◽  
Victoria Nankivell ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Function ◽  
Transcriptional Activity ◽  
Neurodevelopmental Disorder ◽  
Complete Loss ◽  
Loss Of Function ◽  
Targeted Disruption ◽  
Clinical Exome Sequencing ◽  
Partner Protein ◽  
The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

scholarly journals DNA methylation patterns–based subtype distinction and identification of soft tissue sarcoma prognosis

2020 ◽  
Author(s):  
Zhengyuan Wu ◽  
Miao Yu ◽  
Jing-yuan Fan ◽  
Zhen-pei Wen ◽  
Tian-yu Ren ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Soft Tissue ◽  
Clinical Features ◽  
Soft Tissue Sarcomas ◽  
Survival Prediction ◽  
Biological Functions ◽  
Promoter Regions ◽  
Patient Prognosis ◽  
Selection Operator ◽  
Methylation Patterns

Abstract Background: Soft tissue sarcomas (STSs) are heterogeneous at the clinical with a variable tendency of aggressive behavior. Methods: In this study, we constructed a specific DNA methylation-based classification to identify the distinct prognosis-subtypes of STSs based on the DNA methylation spectrum from the TCGA database.Results: Eventually, samples were clustered into four subgroups, and their survival curves were distinct from each other. Meanwhile, the samples in each subgroup reflected differentially in several clinical features. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was also conducted on the genes of the corresponding promoter regions of the above‐described specific methylation sites, revealing that these genes were mainly concentrated in certain cancer‑associated biological functions and pathways. In addition, we calculated the differences among clustered methylation sites and performed the specific methylation sites with LASSO algorithm. The selection operator algorithm was employed to derive a risk signature model, and a prognostic signature based on these methylation sites performed well for risk stratification in STSs patients. At last, a nomogram consisted of clinical features and risk score was developed for the survival prediction. Conclusion: In conclusion, this study declares that DNA methylation-based STSs subtype classification is highly relevant for future development of personalized therapy as it identifies the prediction value of patient prognosis.

scholarly journals Parental infections disrupt clustered genes encoding related functions required for nervous system development in newborns

2018 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Dna Sequences ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Gene Clusters ◽  
Nervous System Development ◽  
Driver Mutations ◽  
Large Chromosome ◽  
Chromosomal Anomalies ◽  
Chromosome Anomalies ◽  
Human Dna

AbstractThe purpose of this study was to understand the role of infection in the origin of chromosomal anomalies linked to neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared to viruses and bacteria including known teratogens. Results support the explanation that parental infections disrupt elaborate multi-system gene coordination needed for neurodevelopment. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, and chromatin activity were all found close together in polyfunctional clusters that were deleted in neurodevelopmental disorders. These deletions account for immune, circulatory, and structural deficits that accompany neurologic deficits. In deleted gene clusters, specific and repetitive human DNA matched infections and passed rigorous artifact tests. In some patients, epigenetic driver mutations were found and may be functionally equivalent to deleting a cluster or changing topologic chromatin interactions because they change access to large chromosome segments. In three families, deleted DNA sequences were associated with intellectual deficits and were not included in any database of genomic variants. These sequences were thousands of bp and unequivocally matched foreign DNAs. Analogous homologies were also found in chromosome anomalies of a recurrent neurodevelopmental disorder. Viral and bacterial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with highly active break repair during meiosis; sometimes delete polyfunctional clusters, and disable epigenetic drivers. Mis-repaired gametes produce zygotes containing rare chromosome anomalies which cause neurologic disorders and accompanying non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA with some infections more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology.Graphic Abstract

scholarly journals Neurodevelopmental Trajectories and Clinical Profiles in a Sample of Children and Adolescents With Early- and Very-Early-Onset Schizophrenia

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Pontillo ◽  
Roberto Averna ◽  
Maria Cristina Tata ◽  
Fabrizia Chieppa ◽  
Maria Laura Pucciarini ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Neurodevelopmental Disorders ◽  
Early Onset ◽  
Social Role ◽  
Treatment Plan ◽  
Neurodevelopmental Disorder ◽  
Communication Disorders ◽  
Autism Spectrum ◽  
Early Onset Schizophrenia ◽  
Assessment And Treatment

Schizophrenia before the age of 18 years is usually divided into two categories. Early-onset schizophrenia (EOS) presents between the ages of 13 and 17 years, whereas very-early-onset schizophrenia (VEOS) presents at or before the age of 12 years. Previous studies have found that neurodevelopmental difficulties in social, motor, and linguistic domains are commonly observed in VEOS/EOS patients. Recent research has also shown a high prevalence of neurodevelopmental disorders (e.g., intellectual disability, communication disorders, autism spectrum disorder, neurodevelopmental motor disorders) in VEOS/EOS patients, indicating genetic overlap between these conditions. These findings lend support to the neurodevelopmental continuum model, which holds that childhood neurodevelopmental disorders and difficulties and psychiatric disorders (e.g., schizophrenia) fall on an etiological and neurodevelopmental continuum, and should not be considered discrete entities. Based on this literature, in this study we focused on the overlap between neurodevelopmental disorders and schizophrenia investigating, in a large sample (N = 230) of VEOS/EOS children and adolescents, the clinical differences, at the onset of psychosis, between VEOS/EOS with neurodevelopmental disorder or neurodevelopmental difficulties and VEOS/EOS with no diagnosed neurodevelopmental disorder or neurodevelopmental difficulties. The findings showed that, in children and adolescents with a neurodevelopmental disorder or neurodevelopmental difficulties, psychosis onset occurred at an earlier age, was associated with more severe functional impairment (e.g., global, social, role), and was characterized by positive symptoms (e.g., grandiose ideas, perceptual abnormalities, disorganized communication) and disorganized symptoms (e.g., odd behavior or appearance, bizarre thinking). Instead, in children and adolescents without a neurodevelopmental disorder or neurodevelopmental difficulties, psychosis onset was mainly characterized by negative symptomatology (e.g., social anhedonia, avolition, expression of emotion, experience of emotions and self, ideational richness). Given these differences, the presence of a neurodevelopmental disorder or neurodevelopmental difficulties should be carefully investigated and integrated early into the assessment and treatment plan for VEOS/EOS patients.

scholarly journals Intergenerational epigenetic inheritance in reef-building corals

2018 ◽  
Author(s):  
Yi Jin Liew ◽  
Emily J. Howells ◽  
Xin Wang ◽  
Craig T. Michell ◽  
John A. Burt ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Intergenerational Transmission ◽  
Epigenetic Inheritance ◽  
Cpg Methylation ◽  
Epigenetic Mechanisms ◽  
Transgenerational Inheritance ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Hypermethylated Genes

MainThe notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants1,2and metazoans1,3. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations1–4. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals)4. Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

scholarly journals Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings

2018 ◽  
Vol 49 (1) ◽  
pp. 84-91 ◽  
Author(s):  
Elina Jokiranta-Olkoniemi ◽  
Keely Cheslack-Postava ◽  
Petteri Joelsson ◽  
Auli Suominen ◽  
Alan S. Brown ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Population Based ◽  
Autism Spectrum ◽  
Schizophrenia Spectrum Disorders ◽  
Hyperactivity Disorder ◽  
Increased Risk ◽  
Spectrum Disorders

AbstractBackgroundProbands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort.MethodsEvery child born in Finland in 1991–2005 and diagnosed with ADHD in 1995–2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981–2007 and diagnosed in 1981–2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations.Results44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0–2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1–6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5–4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3–4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4–3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4–2.8), and intellectual disability (RR = 2.4; 95% CI 2.0–2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases.ConclusionsThe results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies.

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