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Brain Sciences
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Neuro-Developmental Disorders: Bench-to-Bedside
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Neuro-Developmental Disorders: Bench-to-Bedside

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Developmental Neuroscience".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 21892

Special Issue Editor

Dr. Constance Smith-Hicks

E-Mail Website
Guest Editor
1. The Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA
2. Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA
3. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Interests: Rett syndrome; SYNGAP1; biomarkers and outcome measures; genetics of neurodevelopmental disorders.

Special Issue Information

Dear Colleagues,

The increased availability of next-generation sequencing has led to greater insight into the etiology of neurodevelopmental disorders (NDD) and the subsequent expansion of the clinical features of monogenetic disorders. Disorders that were previously grouped on the basis of their clinical manifestations are now determined to have different etiologies and offer the promise for targeted therapies. This is not altogether surprising since the brain’s function is mediated by integration across diverse genes, molecular pathways, cellular networks, and functional circuits.

This Special Issue seeks to advance our understanding of disease variants and to showcase efforts directed at translating between the bench and the bedside. I hope this topic will facilitate communication and collaboration between researchers and will advance our understanding and treatment of neurodevelopmental disorders.

 Original research articles, review articles, and clinical case series that address the following topics are being solicited:

  • Broadening of the clinical phenotype of monogenetic disorders
  • Genotype-phenotype correlations
  • Research focused on the development of biomarkers and outcome measures
  • Advancements in the biology of neurodevelopmental disorders related genes with a focus on molecular pathways and networks.
  • Translational research using preclinical model systems
  • Discuss challenges translating preclinical studies to the clinic

Dr. Constance Smith-Hicks
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodevelopment
  • epilepsy
  • autism
  • intellectual disability
  • cerebral palsy
  • neurogenetics
  • biomarkers
  • outcome measures
  • molecular pathways
  • circuits
  • pre-clinical
  • genes

Published Papers (6 papers)

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Research

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10 pages, 1008 KiB  
Article
Sleep Abnormalities in the Synaptopathies—SYNGAP1-Related Intellectual Disability and Phelan–McDermid Syndrome
by Constance Smith-Hicks, Damien Wright, Aisling Kenny, Robert C. Stowe, Maria McCormack, Andrew C. Stanfield and J. Lloyd Holder, Jr.
Brain Sci. 2021, 11(9), 1229; https://doi.org/10.3390/brainsci11091229 - 17 Sep 2021
Cited by 20 | Viewed by 3690
Abstract
Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated [...] Read more.
Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children’s Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies—Phelan–McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1–46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1–64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1–17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Neuro-Developmental Disorders: Bench-to-Bedside)
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8 pages, 422 KiB  
Article
Sleep, Behavior, and Adaptive Function in KAT6A Syndrome
by Clay Smith and Jacqueline Harris
Brain Sci. 2021, 11(8), 966; https://doi.org/10.3390/brainsci11080966 - 23 Jul 2021
Cited by 10 | Viewed by 3084
Abstract
KAT6A syndrome is a Mendelian Disorder of the Epigenetic Machinery characterized by intellectual disability and profound expressive language impairment. This study aimed to further characterize behavior and sleep in this syndrome. 26 participants between the ages of 3 and 35 years with KAT6A [...] Read more.
KAT6A syndrome is a Mendelian Disorder of the Epigenetic Machinery characterized by intellectual disability and profound expressive language impairment. This study aimed to further characterize behavior and sleep in this syndrome. 26 participants between the ages of 3 and 35 years with KAT6A syndrome were assessed via parental informant using the Adaptive Behavior Assessment System version 3 (ABAS-3), Achenbach Child or Adult Behavior Checklist (CBCL/ABCL), and a Modified Simonds and Parraga Sleep Questionnaire (MSPSQ). The ABAS reports conceptual, social, and practical domains of adaptive function as well as a general composite score for adaptive function. The CBCL/ABCL is an inventory that measures internalizing, externalizing, and DSM-oriented problem domains. The MSPSQ is a mix of qualitative and quantitative sleep information that includes behavioral and medical sleep problems. Mean values for all domains of the ABAS-3 were in the extremely low range. Additionally, sleep was very dysfunctional in this cohort. Sixty percent of respondents reported feeling there was a sleep problem, 64% take medication for sleep, and 68% have sought treatment or advice for sleep. Only 12% of these participants have sleep apnea suggesting that sleep problems in this disorder are unrelated to sleep-disordered breathing. Interestingly, there were extremely low rates of all types of behaviors reported among participants on the CBCL/ABCL. No significant differences were seen based on genotype grouping in adaptive function, sleep, or behavior. This study further delineates the phenotype of the KAT6A syndrome and emphasizes the need for supports for adaptive functioning as well as detailed attention to the behavioral aspects of sleep in this condition. Full article
(This article belongs to the Special Issue Neuro-Developmental Disorders: Bench-to-Bedside)
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10 pages, 637 KiB  
Article
Expansion of the Genotypic and Phenotypic Spectrum of WASF1-Related Neurodevelopmental Disorder
by Siddharth Srivastava, Erica L. Macke, Lindsay C. Swanson, David Coulter, Eric W. Klee, Sureni V. Mullegama, Yili Xie, Brendan C. Lanpher, Emma C. Bedoukian, Cara M. Skraban, Laurent Villard, Mathieu Milh, Mary L. O. Leppert and Julie S. Cohen
Brain Sci. 2021, 11(7), 931; https://doi.org/10.3390/brainsci11070931 - 14 Jul 2021
Cited by 6 | Viewed by 2469
Abstract
In humans, de novo truncating variants in WASF1 (Wiskott–Aldrich syndrome protein family member 1) have been linked to presentations of moderate-to-profound intellectual disability (ID), autistic features, and epilepsy. Apart from one case series, there is limited information on the phenotypic spectrum and genetic [...] Read more.
In humans, de novo truncating variants in WASF1 (Wiskott–Aldrich syndrome protein family member 1) have been linked to presentations of moderate-to-profound intellectual disability (ID), autistic features, and epilepsy. Apart from one case series, there is limited information on the phenotypic spectrum and genetic landscape of WASF1-related neurodevelopmental disorder (NDD). In this report, we describe detailed clinical characteristics of six individuals with WASF1-related NDD. We demonstrate a broader spectrum of neurodevelopmental impairment including more mildly affected individuals. Further, we report new variant types, including a copy number variant (CNV), resulting in the partial deletion of WASF1 in monozygotic twins, and three missense variants, two of which alter the same residue, p.W161. This report adds further evidence that de novo variants in WASF1 cause an autosomal dominant NDD. Full article
(This article belongs to the Special Issue Neuro-Developmental Disorders: Bench-to-Bedside)
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8 pages, 681 KiB  
Communication
Sleep Duration in Mouse Models of Neurodevelopmental Disorders
by Rachel Michelle Saré, Abigail Lemons, Alex Song and Carolyn Beebe Smith
Brain Sci. 2021, 11(1), 31; https://doi.org/10.3390/brainsci11010031 - 30 Dec 2020
Cited by 12 | Viewed by 2205
Abstract
Sleep abnormalities are common in patients with neurodevelopmental disorders, and it is thought that deficits in sleep may contribute to the unfolding of symptoms in these disorders. Appreciating sleep abnormalities in neurodevelopmental disorders could be important for designing a treatment for these disorders. [...] Read more.
Sleep abnormalities are common in patients with neurodevelopmental disorders, and it is thought that deficits in sleep may contribute to the unfolding of symptoms in these disorders. Appreciating sleep abnormalities in neurodevelopmental disorders could be important for designing a treatment for these disorders. We studied sleep duration in three mouse models by means of home-cage monitoring: Tsc2+/− (tuberous sclerosis complex), oxytocin receptor (Oxtr) knockout (KO) (autism spectrum disorders), and Shank3 e4-9 KO (Phelan–McDermid syndrome). We studied both male and female mice, and data were analyzed to examine effects of both genotype and sex. In general, we found that female mice slept less than males regardless of genotype or phase. We did not find any differences in sleep duration in either Tsc2+/− or Oxtr KO mice, compared to controls. In Shank3 e4-9 KO mice, we found a statistically significant genotype x phase interaction (p = 0.002) with a trend that Shank3e4-9 KO mice regardless of sex slept more than control mice in the active phase. Our results have implications for the management of patients with Phelan–McDermid syndrome. Full article
(This article belongs to the Special Issue Neuro-Developmental Disorders: Bench-to-Bedside)
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Review

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14 pages, 2557 KiB  
Review
The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders
by Boudewien A Brand, Alyssa E Blesson and Constance L. Smith-Hicks
Brain Sci. 2021, 11(7), 904; https://doi.org/10.3390/brainsci11070904 - 09 Jul 2021
Cited by 17 | Viewed by 4269
Abstract
Nearly 20% of genes located on the X chromosome are associated with neurodevelopmental disorders (NDD) due to their expression and role in brain functioning. Given their location, several of these genes are either subject to or can escape X-chromosome inactivation (XCI). The degree [...] Read more.
Nearly 20% of genes located on the X chromosome are associated with neurodevelopmental disorders (NDD) due to their expression and role in brain functioning. Given their location, several of these genes are either subject to or can escape X-chromosome inactivation (XCI). The degree to which genes are subject to XCI can influence the NDD phenotype between males and females. We provide a general review of X-linked NDD genes in the context of XCI and detailed discussion of the sex-based differences related to MECP2 and FMR1, two common X-linked causes of NDD that are subject to XCI. Understanding the effects of XCI on phenotypic expression of NDD genes may guide the development of stratification biomarkers in X-linked disorders. Full article
(This article belongs to the Special Issue Neuro-Developmental Disorders: Bench-to-Bedside)
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15 pages, 330 KiB  
Review
Behavior Testing in Rodents: Highlighting Potential Confounds Affecting Variability and Reproducibility
by Rachel Michelle Saré, Abigail Lemons and Carolyn Beebe Smith
Brain Sci. 2021, 11(4), 522; https://doi.org/10.3390/brainsci11040522 - 20 Apr 2021
Cited by 43 | Viewed by 5200
Abstract
Rodent models of brain disorders including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases are essential for increasing our understanding of underlying pathology and for preclinical testing of potential treatments. Some of the most important outcome measures in such studies are behavioral. Unfortunately, reports from different [...] Read more.
Rodent models of brain disorders including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases are essential for increasing our understanding of underlying pathology and for preclinical testing of potential treatments. Some of the most important outcome measures in such studies are behavioral. Unfortunately, reports from different labs are often conflicting, and preclinical studies in rodent models are not often corroborated in human trials. There are many well-established tests for assessing various behavioral readouts, but subtle aspects can influence measurements. Features such as housing conditions, conditions of testing, and the sex and strain of the animals can all have effects on tests of behavior. In the conduct of behavior testing, it is important to keep these features in mind to ensure the reliability and reproducibility of results. In this review, we highlight factors that we and others have encountered that can influence behavioral measures. Our goal is to increase awareness of factors that can affect behavior in rodents and to emphasize the need for detailed reporting of methods. Full article
(This article belongs to the Special Issue Neuro-Developmental Disorders: Bench-to-Bedside)
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