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Neurodevelopmental Disorders in Pediatrics
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Neurodevelopmental Disorders in Pediatrics

A special issue of Children (ISSN 2227-9067). This special issue belongs to the section "Pediatric Neurology & Neurodevelopmental Disorders".

Deadline for manuscript submissions: 20 October 2024 | Viewed by 31387

Special Issue Editors

Dr. Marco Fiore

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Guest Editor
Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155 Rome, Italy
Interests: neurobiology; endocrinology; neurotrophins; oxidative stress; cancer; toxicology; addiction; antioxidants; polyphenols; alcohol use disorders
Special Issues, Collections and Topics in MDPI journals
Dr. Luigi Tarani

E-Mail Website
Guest Editor
Pediatric Department, “Sapienza” University of Rome, 00185 Rome, Italy
Interests: neurodevelopmental disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodevelopmental diseases in children are disabilities associated mainly with the functioning of the brain and nervous system. Neurodevelopmental disorders can affect a child’s ability to think and function normally. Symptoms of behavior or learning difficulties, autism, brain tumors, or other brain and developmental disorders can appear at birth or in later years. According to recent data, approximately 15% of children in Western countries aged 3 to 17 are affected by neurodevelopmental disorders. Examples of neurodevelopmental disorders in children include attention-deficit/hyperactivity disorder (ADHD), autism (including Asperger’s syndrome), developmental coordination disorders (dyspraxia), communication disorders, neurogenetic conditions and impairments in vision and hearing, intellectual disability (also known as mental retardation), conduct disorders, cerebral palsy, and fetal alcohol syndrome. Children with neurodevelopmental disabilities may experience difficulties with learning, language and speech, behavior, motor skills, memory, or other neurological functions. Though the symptoms and behaviors of neurodevelopmental disabilities often change or evolve as a child grows older, certain incapacities are permanent. Treatment and diagnosis of these diseases can be difficult; treatment often includes a combination of professional therapies, medications, and home- and school-based courses.

Dr. Marco Fiore
Dr. Luigi Tarani
Guest Editors

Manuscript Submission Information

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Keywords

  • neurodevelopment
  • pediatrics
  • brain disorder
  • early disease development
  • therapy and treatment
  • adolescents
  • children
  • central nervous system
  • mental retardation
  • memory and learning
  • motor skill

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Published Papers (10 papers)

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Research

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12 pages, 2193 KiB  
Article
Thirteen New Patients of PPP2R5D Gene Mutation and the Fine Profile of Genotype–Phenotype Correlation Unraveling the Pathogenic Mechanism Underlying Macrocephaly Phenotype
by Yinmo Jiang, Bingbing Wu, Xi Zhang, Lin Yang, Sujuan Wang, Huiping Li, Shuizhen Zhou, Yanyan Qian and Huijun Wang
Children 2024, 11(8), 897; https://doi.org/10.3390/children11080897 - 26 Jul 2024
Viewed by 726
Abstract
Background: Neurodevelopmental disorders (NDDs) are a group of diseases that severely affect the physical and mental health of children. The PPP2R5D gene encodes B56δ, the regulatory subunit of protein phosphatase 2A (PP2A). NDDs related to the PPP2R5D gene have recently been defined as [...] Read more.
Background: Neurodevelopmental disorders (NDDs) are a group of diseases that severely affect the physical and mental health of children. The PPP2R5D gene encodes B56δ, the regulatory subunit of protein phosphatase 2A (PP2A). NDDs related to the PPP2R5D gene have recently been defined as Houge–Janssens syndrome 1. Methods: Clinical/whole exome sequencing was performed on approximately 3000 patients with NDDs from 2017 to 2023. In vitro experiments were performed to assess the impairment of variants to protein expression and the assembly of PP2A holoenzyme. The genetic information and phenotypes of the reported patients, as well as patients in this study, were summarized, and the genotype–phenotype relationship was analyzed. The probability of pathogenic missense variants in PPP2R5D was predicted using AlphaMissense (AM), and the relationship between certain phenotype and 3D protein structural features were analyzed. Results: Thirteen new patients carrying twelve PPP2R5D gene variants were detected, including five novel missense variants and one novel frameshift variant. In vitro experiments revealed that the frameshift variant p.H463Mfs*3 resulted in a ~50 kDa truncated protein with lower expression level. Except for E420K and T536R, other missense variants impaired holoenzyme assembly. Furthermore, we found that pathogenic/likely pathogenic (P/LP) variants that have been reported so far were all missense variants and clustered in three conserved regions, and the likelihood of P/LP mutations located in these conserved regions was extremely high. In addition, the macrocephaly phenotype was related to negatively charged residues involved in substrate recruitment. Conclusions: We reported thirteen new patients with PPP2R5D gene variants and expanded the PPP2R5D variant spectrum. We confirmed the pathogenicity of novel variants through in vitro experiments. Our findings in genotype–phenotype relationship provide inspiration for genetic counseling and interpretation of variants. We also provide directions for further research on the mechanism of macrocephaly phenotype. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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18 pages, 1200 KiB  
Article
Sex Differences in White Matter Diffusivity in Children with Developmental Dyslexia
by Gehna Gupta, C. Nikki Arrington and Robin Morris
Children 2024, 11(6), 721; https://doi.org/10.3390/children11060721 - 13 Jun 2024
Viewed by 890
Abstract
Despite the high prevalence of developmental dyslexia in the U.S. population, research remains limited and possibly biased due to the overrepresentation of males in most dyslexic samples. Studying biological sex differences in the context of developmental dyslexia can help provide a more complete [...] Read more.
Despite the high prevalence of developmental dyslexia in the U.S. population, research remains limited and possibly biased due to the overrepresentation of males in most dyslexic samples. Studying biological sex differences in the context of developmental dyslexia can help provide a more complete understanding of the neurological markers that underly this disorder. The current study aimed to explore sex differences in white matter diffusivity in typical and dyslexic samples in third and fourth graders. Participants were asked to complete behavioral/cognitive assessments at baseline followed by MRI scanning and diffusion-weighted imaging sequences. A series of ANOVAs were conducted for comparing group membership (developmental dyslexia or typically developing), gender status (F/M), and white matter diffusivity in the tracts of interest. The Results indicated significant differences in fractional anisotropy in the left hemisphere components of the inferior and superior (parietal and temporal) longitudinal fasciculi. While males with dyslexia had lower fractional anisotropy in these tracts compared to control males, no such differences were found in females. The results of the current study may suggest that females may use a more bilateral/alternative reading network. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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15 pages, 670 KiB  
Article
Proprioception, Emotion and Social Responsiveness in Children with Developmental Disorders: An Exploratory Study in Autism Spectrum Disorder, Cerebral Palsy and Different Neurodevelopmental Situations
by Inmaculada Riquelme, Samar M. Hatem, Álvaro Sabater-Gárriz, Elisabeth Martín-Jiménez and Pedro Montoya
Children 2024, 11(6), 719; https://doi.org/10.3390/children11060719 - 13 Jun 2024
Viewed by 1024
Abstract
Proprioception has long been linked with emotional dysregulation in neurotypical adults. Neuropediatric disorders such as autism spectrum disorder (ASD) and cerebral palsy (CP) are distinct entities and yet both present with deficits and challenges in sensory processing and the regulation of emotions. This [...] Read more.
Proprioception has long been linked with emotional dysregulation in neurotypical adults. Neuropediatric disorders such as autism spectrum disorder (ASD) and cerebral palsy (CP) are distinct entities and yet both present with deficits and challenges in sensory processing and the regulation of emotions. This study aimed to explore the relationship between proprioception and emotional–social performance in children and to compare proprioception and emotional–social performance in different underlying neurodevelopmental conditions. For this purpose, this cross-sectional study included 42 children with ASD, 34 children with CP and 50 typically developing peers. Proprioceptive acuity, proprioceptive reactive behavior as well as emotion regulation and social responsiveness were assessed. The results show a significant correlation between proprioceptive deficits and emotional difficulties in this pediatric sample, with distinct proprioceptive impairment patterns according to the underlying neurological disorder. Children with CP showed significant emotional knowledge deficits, while children with ASD predominantly showed challenges in social responsiveness. These data thus suggest a differentiated impact of proprioception on emotional–social performance in neurodevelopmental disorders and highlight proprioception as a potential therapeutic target for balancing emotion regulation in children with neurodevelopmental conditions. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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13 pages, 1720 KiB  
Article
Speech Sounds Production, Narrative Skills, and Verbal Memory of Children with 22q11.2 Microdeletion
by Marijana Rakonjac, Goran Cuturilo, Natasa Kovacevic-Grujicic, Ivana Simeunovic, Jovana Kostic, Milena Stevanovic and Danijela Drakulic
Children 2024, 11(4), 489; https://doi.org/10.3390/children11040489 - 19 Apr 2024
Viewed by 1007
Abstract
22q11.2 deletion syndrome (22q11.2DS), the most frequent microdeletion syndrome in humans, is related to a high risk of developing neurodevelopmental disorders. About 95% of patients with 22q11.2DS have speech and language impairments. Global articulation, story generation, and verbal memory tests were applied to [...] Read more.
22q11.2 deletion syndrome (22q11.2DS), the most frequent microdeletion syndrome in humans, is related to a high risk of developing neurodevelopmental disorders. About 95% of patients with 22q11.2DS have speech and language impairments. Global articulation, story generation, and verbal memory tests were applied to compare articulatory characteristics of speech sounds, spontaneous language abilities, and immediate verbal memory between four groups of Serbian-speaking children: patients with 22q11.2DS, children with clinical presentation of 22q11.2DS that do not have the microdeletion, children with non-syndromic congenital heart defects, and their peers with typical speech–sound development. The obtained results showed that children with this microdeletion have impaired articulation skills and expressive language abilities. However, we did not observe weaker receptive language skills and immediate verbal memory compared to healthy controls. Children with 22q11.2DS should be considered a risk category for the development of speech–sound pathology and expressive language abilities. Since speech intelligibility is an instrument of cognition and adequate peer socialization, and language impairment in school-aged children with 22q11DS might be an indicator of increased risk for later psychotic symptoms, patients with 22q11.2 microdeletion should be included in a program of early stimulation of speech–language development immediately after diagnosis is established. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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18 pages, 552 KiB  
Article
Comorbidities and Disease Duration in Tourette Syndrome: Impact on Cognition and Quality of Life of Children
by Giulia Conte, Carola Costanza, Maria Novelli, Veronica Scarselli, Elena Arigliani, Francesca Valente, Valentina Baglioni, Arianna Terrinoni, Flavia Chiarotti and Francesco Cardona
Children 2024, 11(2), 226; https://doi.org/10.3390/children11020226 - 9 Feb 2024
Viewed by 1522
Abstract
Background: Cognitive functions represent foundational factors for mental health and quality of life (QoL). In Tourette syndrome (TS), psychiatric comorbidities are common and have been inconsistently reported to affect the cognition and QoL of patients, while the role of tic disorder duration has [...] Read more.
Background: Cognitive functions represent foundational factors for mental health and quality of life (QoL). In Tourette syndrome (TS), psychiatric comorbidities are common and have been inconsistently reported to affect the cognition and QoL of patients, while the role of tic disorder duration has not been yet explored. Methods: To examine how comorbidities and TS duration may influence cognition and QoL, N = 80 children with TS (6–16 years) were evaluated using the Wechsler Intelligence Scale for Children (WISC-IV). Standardized questionnaires were used to assess the presence and severity of TS main comorbidities and QoL. Data were interpreted using linear correlations, regression, and mediation analysis. Results: Depression and attention-deficit/hyperactivity disorder (ADHD) symptoms accounted for poorer cognitive performance. Anxiety oppositely predicted better cognitive performance, while no significant role for obsessive compulsive disorder (OCD) was observed. Disease duration was associated with lower total IQ, verbal reasoning, and working memory abilities. Depression, anxiety, and TS duration also deeply influenced QoL measures. Conclusions: TS common comorbidities have a differential impact on the cognitive abilities of children and adolescents, which translates into a complex influence on their perceived QoL. A longer clinical history of tics was related to worse cognitive outcomes, which prompts further consideration of disease duration in both clinical and research settings involving children and adolescents. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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11 pages, 976 KiB  
Article
Predictors of Neurodevelopment in Microcephaly Associated with Congenital Zika Syndrome: A Prospective Study
by Adriana M. Mattos, Valmir N. Rastely-Junior, Matheus M. Pires, Juan P. Aguilar, Millani S. A. Lessa, Clarina Regis, Mariana Wanderley, Julio Leony, Joseane Bouzon, Verena Ballalai, Carina Vieira, Gustavo B. S. Carvalho, João R. M. Almeida, Nivison Nery, Jr., Rodrigo Leal, Federico Costa, Albert I. Ko, Mitermayer G. Reis and Jamary Oliveira-Filho
Children 2023, 10(12), 1831; https://doi.org/10.3390/children10121831 - 21 Nov 2023
Cited by 1 | Viewed by 1199
Abstract
The municipality of Salvador, situated in Brazil, distinguished itself as the epicenter of the emergence of microcephaly related to congenital manifestations of Zika syndrome. Despite the anticipated significant developmental setbacks in these children, research has indicated a varied range of outcomes, with certain [...] Read more.
The municipality of Salvador, situated in Brazil, distinguished itself as the epicenter of the emergence of microcephaly related to congenital manifestations of Zika syndrome. Despite the anticipated significant developmental setbacks in these children, research has indicated a varied range of outcomes, with certain instances even reflecting minimal developmental delay. Our objective was to pinpoint determinants that could forecast developmental anomalies in children diagnosed with microcephaly associated with congenital Zika syndrome (CZS). Methodology: A forward-looking clinical and neurodevelopmental examination was conducted focusing on neonates diagnosed with microcephaly with CZS, birthed between September 2015 and April 2016 at the Hospital Geral Roberto Santos, in Salvador city. That infants were monitored up to their third year by a multiprofessional team. Child development was assessed using the composite Bayley III score. Undertaken by two blinded experts, cranial CT scan analysis was performed during the neonate period for the detection of brain abnormalities and to quantify ventricle enlargement, measured by Evans’ index (EI). Results: Fifty newborns were evaluated with a median head circumference of 28 cm (interquartile range 27–31 cm). EI was associated with neurodevelopmental delay at three years and remained significant after adjustment for head circumference. A 0.1-point increase in EI was associated with a delay of 3.2 months in the receptive language (p = 0.016), 3.4 months in the expressive language (p = 0.016), 3.4 months in the cognitive (p = 0.016), 2.37 months in the gross motor (p = 0.026), and 3.1 months in the fine motor (p = 0.021) domains. Conclusions: EI predicted neurodevelopmental delay in all Bayley domains in children with microcephaly associated with CZS. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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Review

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14 pages, 623 KiB  
Review
Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Immunological Features Underpinning Controversial Entities
by Lucia Leonardi, Camilla Perna, Irene Bernabei, Marco Fiore, Meiqian Ma, Jennifer Frankovich, Luigi Tarani and Alberto Spalice
Children 2024, 11(9), 1043; https://doi.org/10.3390/children11091043 - 27 Aug 2024
Viewed by 1674
Abstract
Pediatric acute-onset neuropsychiatric syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), represent an overlapping group of disorders which is characterized by acute-onset obsessive compulsive disorders, eating restriction, tics, cognitive and behavioral deterioration which typically follows a relapsing-remitting course but [...] Read more.
Pediatric acute-onset neuropsychiatric syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), represent an overlapping group of disorders which is characterized by acute-onset obsessive compulsive disorders, eating restriction, tics, cognitive and behavioral deterioration which typically follows a relapsing-remitting course but some patients have a primary or secondary persistent progress. This condition is likely caused by heterogeneous inflammatory mechanisms (autoantibodies, complement activation, pro-inflammatory cytokine production) involving the basal ganglia as evidenced by imaging studies (patients vs. controls), sleep studies that found movements and/or atonia during REM sleep, and neurological soft signs that go along with basal ganglia dysfunction. The condition causes significant psychiatric and behavioral symptoms, caregiver burden and sleep abnormalities. Autoantibodies resulting from molecular mimicry of infectious agents (namely group A Streptococcus) and neuronal autoantigens that map to the basal ganglia play also a subtle role. This narrative review aims to describe the key immunological features documented thus far and that likely play a role in the pathogenesis and clinical manifestations of this disorder. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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33 pages, 2178 KiB  
Review
The Fetal Alcohol Spectrum Disorders—An Overview of Experimental Models, Therapeutic Strategies, and Future Research Directions
by Magdalena Król, Paweł Skowron, Kamil Skowron and Krzysztof Gil
Children 2024, 11(5), 531; https://doi.org/10.3390/children11050531 - 28 Apr 2024
Viewed by 1709
Abstract
Since the establishment of a clear link between maternal alcohol consumption during pregnancy and certain birth defects, the research into the treatment of FASD has become increasingly sophisticated. The field has begun to explore the possibility of intervening at different levels, and animal [...] Read more.
Since the establishment of a clear link between maternal alcohol consumption during pregnancy and certain birth defects, the research into the treatment of FASD has become increasingly sophisticated. The field has begun to explore the possibility of intervening at different levels, and animal studies have provided valuable insights into the pathophysiology of the disease, forming the basis for implementing potential therapies with increasingly precise mechanisms. The recent reports suggest that compounds that reduce the severity of neurodevelopmental deficits, including glial cell function and myelination, and/or target oxidative stress and inflammation may be effective in treating FASD. Our goal in writing this article was to analyze and synthesize current experimental therapeutic interventions for FASD, elucidating their potential mechanisms of action, translational relevance, and implications for clinical application. This review exclusively focuses on animal models and the interventions used in these models to outline the current direction of research. We conclude that given the complexity of the underlying mechanisms, a multifactorial approach combining nutritional supplementation, pharmacotherapy, and behavioral techniques tailored to the stage and severity of the disease may be a promising avenue for further research in humans. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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20 pages, 1033 KiB  
Review
The Dangers of Acetaminophen for Neurodevelopment Outweigh Scant Evidence for Long-Term Benefits
by William Parker, Lauren G. Anderson, John P. Jones, Rachel Anderson, Lauren Williamson, Dillan Bono-Lunn and Zacharoula Konsoula
Children 2024, 11(1), 44; https://doi.org/10.3390/children11010044 - 29 Dec 2023
Cited by 2 | Viewed by 17687
Abstract
Based on available data that include approximately 20 lines of evidence from studies in laboratory animal models, observations in humans, correlations in time, and pharmacological/toxicological considerations, it has been concluded without reasonable doubt and with no evidence to the contrary that exposure of [...] Read more.
Based on available data that include approximately 20 lines of evidence from studies in laboratory animal models, observations in humans, correlations in time, and pharmacological/toxicological considerations, it has been concluded without reasonable doubt and with no evidence to the contrary that exposure of susceptible babies and children to acetaminophen (paracetamol) induces many, if not most, cases of autism spectrum disorder (ASD). However, the relative number of cases of ASD that might be induced by acetaminophen has not yet been estimated. Here, we examine a variety of evidence, including the acetaminophen-induced reduction of social awareness in adults, the prevalence of ASD through time, and crude estimates of the relative number of ASD cases induced by acetaminophen during various periods of neurodevelopment. We conclude that the very early postpartum period poses the greatest risk for acetaminophen-induced ASD, and that nearly ubiquitous use of acetaminophen during early development could conceivably be responsible for the induction in the vast majority, perhaps 90% or more, of all cases of ASD. Despite over a decade of accumulating evidence that acetaminophen is harmful for neurodevelopment, numerous studies demonstrate that acetaminophen is frequently administered to children in excess of currently approved amounts and under conditions in which it provides no benefit. Further, studies have failed to demonstrate long-term benefits of acetaminophen for the pediatric population, leaving no valid rationale for continued use of the drug in that population given its risks to neurodevelopment. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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Other

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9 pages, 396 KiB  
Brief Report
Atomoxetine Treatment of Attention Deficit/Hyperactivity Disorder Symptoms in 3–6-Year-Old Children with Autism Spectrum Disorder: A Retrospective Cohort Study
by Hamza A. Alsayouf, Osama Alsarhan, Wael Khreisat and Azhar Daoud
Children 2024, 11(2), 163; https://doi.org/10.3390/children11020163 - 26 Jan 2024
Cited by 2 | Viewed by 2959
Abstract
Atomoxetine is indicated for the management of attention deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 to 18 years. Few studies have assessed the safety and tolerability of atomoxetine in younger patients. This retrospective cohort study included 133 children aged 3–6 years [...] Read more.
Atomoxetine is indicated for the management of attention deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 to 18 years. Few studies have assessed the safety and tolerability of atomoxetine in younger patients. This retrospective cohort study included 133 children aged 3–6 years who were diagnosed with ADHD comorbid with autism spectrum disorder (ASD). The primary endpoint was the evaluation of the safety profile of atomoxetine. In total, 50 patients (37.6%) experienced adverse events (AEs), which led to treatment discontinuation in 23 patients (17.3%). The most common AEs were gastrointestinal (24.1%), aggression or hostility (12.8%), and increased hyperactivity (9.0%). In the 23 patients who discontinued treatment, all the AEs resolved after treatment ceased. Among the 110 patients who completed at least 6 months’ treatment, atomoxetine titrated to a dose of 1.2–1.8 mg/kg/day appeared to be well tolerated and effective. The Clinical Global Impression—Improvement score improved to 1 (“very much improved”) and 2 (“much improved”) in 62.4% and 20.3% of children, respectively, at their last visit. Overall, atomoxetine appeared to be well tolerated in younger children with comorbid ADHD and ASD. Nevertheless, close patient monitoring remains essential, and the study limitations necessitate caution in generalizing these findings to broader populations. Long-term prospective studies are required. Full article
(This article belongs to the Special Issue Neurodevelopmental Disorders in Pediatrics)
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