Pituitary adenylate cyclase-activating polypeptide deficient mice show length abnormalities of the axon initial segment.

We previously found that pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP-/-) mice exhibit dendritic spine morphology impairment and neurodevelopmental disorder (NDD)-like behaviors such as hyperactivity, increased novelty-seeking behavior, and deficient pre-pulse inhibition. Recent studies have indicated that rodent models of NDDs (e.g., attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder) show abnormalities in the axon initial segment (AIS). Here, we revealed that PACAP-/- mice exhibited a longer AIS length in layer 2/3 pyramidal neurons of the primary somatosensory barrel field compared with wild-type control mice. Further, we previously showed that a single injection of atomoxetine, an ADHD drug, improved hyperactivity in PACAP-/- mice. In this study, we found that repeated treatments of atomoxetine significantly improved AIS abnormality along with hyperactivity in PACAP-/- mice. These results suggest that AIS abnormalities are associated with NDDs-like behaviors in PACAP-/- mice. Thus, improvement in AIS abnormalities will be a novel drug therapy for NDDs.

Case report: Early use of whole exome sequencing unveils HNRNPU-related neurodevelopmental disorder and answers additional clinical questions through reanalysis.

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient's symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient's life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system.

An Opportunity to Fill a Gap for Newborn Screening of Neurodevelopmental Disorders.

Screening newborns using genome sequencing is being explored due to its potential to expand the list of conditions that can be screened. Previously, we proposed the need for large-scale pilot studies to assess the feasibility of screening highly penetrant genetic neurodevelopmental disorders. Here, we discuss the initial experience from the GUARDIAN study and the systemic gaps in clinical services that were identified in the early stages of the pilot study.

Structure, activity and function of the lysine methyltransferase SETD5.

SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36). These well-characterized functions of SETD5 are transcription regulation, euchromatin formation, and RNA elongation and splicing. SETD5 is frequently mutated and hyperactive in both human neurodevelopmental disorders and cancer, and could be down-regulated by degradation through the ubiquitin-proteasome pathway, but the biochemical mechanisms underlying such dysregulation are rarely understood. Herein, we provide an update on the particularities of SETD5 enzymatic activity and substrate specificity concerning its biological importance, as well as its molecular and cellular impact on normal physiology and disease, with potential therapeutic options.

Review of neurodevelopmental disorders in patients with HNF1B gene variations.

This review investigates the association between neurodevelopmental disorders (NDD) and variations of the gene HNF1B. Heterozygous intragenetic mutations or heterozygous gene deletions (17q12 microdeletion syndrome) of HNF1B are the cause of a multi-system developmental disorder, termed renal cysts and diabetes syndrome (RCAD). Several studies suggest that in general, patients with genetic variation of HNF1B have an elevated risk for additional neurodevelopmental disorders, especially autism spectrum disorder (ASD) but a comprehensive assessment is yet missing. This review provides an overview including all available studies of patients with HNF1B mutation or deletion with comorbid NDD with respect to the prevalence of NDDs and in how they differ between patients with an intragenic mutation or 17q12 microdeletion. A total of 31 studies was identified, comprising 695 patients with variations in HNF1B, (17q12 microdeletion N = 416, mutation N = 279). Main results include that NDDs are present in both groups (17q12 microdeletion 25.2% vs. mutation 6.8%, respectively) but that patients with 17q12 microdeletions presented more frequently with any NDDs and especially with learning difficulties compared to patients with a mutation of HNF1B. The observed prevalence of NDDs in patients with HNF1B variations seems to be higher than in the general population, but the validity of the estimated prevalence must be deemed insufficient. This review shows that systematical research of NDDs in patients with HNF1B mutations or deletions is lacking. Further studies regarding neuropsychological characteristics of both groups are needed. NDDs might be a concomitant of HFN1B-related disease and should be considered in clinical routine and scientific reports.

Rett-like Phenotypes in HNRNPH2-Related Neurodevelopmental Disorder.

Rett Syndrome (RTT) is a neurodevelopmental disorder with a prevalence of 1:10,000 to 15,000 females worldwide. Classic Rett Syndrome presents in early childhood with a period of developmental regression, loss of purposeful hand skills along with hand stereotypies, gait abnormalities, and loss of acquired speech. Atypical RTT is diagnosed when a child shows some but not all the phenotypes of classic RTT, along with additional supporting criteria. Over 95% of classic RTT cases are attributed to pathogenic variants in Methyl-CpG Binding Protein 2 (MECP2), though additional genes have been implicated in other RTT cases, particularly those with the atypical RTT clinical picture. Other genetic etiologies have emerged with similar clinical characteristics to RTT Syndrome. Our team has characterized HNRNPH2-related neurodevelopmental disorder (HNRNPH2-RNDD) in 33 individuals associated with de novo pathogenic missense variants in the X-linked HNRNPH2 gene, characterized by developmental delay, intellectual disability, seizures, autistic-like features, and motor abnormalities. We sought to further characterize RTT clinical features in this group of individuals by using caregiver report. Twenty-six caregivers completed electronic surveys, with only 3 individuals having previously received an atypical RTT diagnosis, and no individuals with a typical RTT diagnosis. Caregivers reported a high number of behaviors and/or phenotypes consistent with RTT, including the major criteria of the syndrome, such as regression of developmental skills and abnormal gait. Based on the survey results, 12 individuals could meet the diagnostic clinical criteria for atypical RTT Syndrome. In summary, individuals with HNRNPH2-RNDD exhibit clinical characteristics that overlap with those of RTT, and therefore, HNRNPH2-RNDD, should be considered on the differential diagnosis list with this clinical picture.

Prenatal Diagnosis of PPP2R1A-Related Neurodevelopmental Disorders Using Whole Exome Sequencing: Clinical Report and Review of Literature.

PPP2R1A-related neurodevelopmental disorder (NDD) is expressed with autosomal dominant inheritance and is typically caused by a pathogenic de novo PPP2R1A mutation. It is characterized by the predominant features of hypotonia, developmental delay, moderate-to-severe intellectual disability, agenesis of corpus callosum (ACC), ventriculomegaly, and dysmorphic features; however, none of these anomalies have been diagnosed prenatally. We report on the prenatal diagnosis of PPP2R1A-related NDD in two fetuses by whole exome sequencing. Fetus 1 had partial ACC and severe lateral ventriculomegaly; the pathogenic heterozygous c.544C > T (p. Arg182Trp) de novo missense variant in PPP2R1A was detected. Fetus 2 had severe enlargement of the lateral and third ventricles and macrocephaly; they showed a heterozygous likely pathogenic mutation in PPP2R1A gene (c.547C > T, p. Arg183Trp). Both variants were de novo. This was the first study to use trio WES to prenatally analyze fetuses with PPP2R1A variants. Prenatal diagnosis will not only expand the fetal phenotype of this rare genetic condition but also allow for an appropriate counseling of prospective parents regarding pregnancy outcomes.

Synapse-specific roles for microglia in development: New horizons in the prefrontal cortex.

Dysfunction of both microglia and circuitry in the medial prefrontal cortex (mPFC) have been implicated in numerous neuropsychiatric disorders, but how microglia affect mPFC development in health and disease is not well understood. mPFC circuits undergo a prolonged maturation after birth that is driven by molecular programs and activity-dependent processes. Though this extended development is crucial to acquire mature cognitive abilities, it likely renders mPFC circuitry more susceptible to disruption by genetic and environmental insults that increase the risk of developing mental health disorders. Recent work suggests that microglia directly influence mPFC circuit maturation, though the biological factors underlying this observation remain unclear. In this review, we discuss these recent findings along with new studies on the cellular mechanisms by which microglia shape sensory circuits during postnatal development. We focus on the molecular pathways through which glial cells and immune signals regulate synaptogenesis and activity-dependent synaptic refinement. We further highlight how disruptions in these pathways are implicated in the pathogenesis of neurodevelopmental and psychiatric disorders associated with mPFC dysfunction, including schizophrenia and autism spectrum disorder (ASD). Using these disorders as a framework, we discuss microglial mechanisms that could link environmental risk factors including infections and stress with ongoing genetic programs to aberrantly shape mPFC circuitry.

Case Report: Novel Biallelic Null Variants of SMPD4 Confirm Its Involvement in Neurodevelopmental Disorder With Microcephaly, Arthrogryposis, and Structural Brain Anomalies.

The SMPD4 gene encodes sphingomyelin phosphodiesterase 4, which preferentially hydrolyzes sphingomyelin over other phospholipids. The biallelic loss-of-function variants of SMPD4 have been identified in a group of children with neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA). Here, we report a girl of Chinese ancestry with intrauterine growth restriction, microcephaly, postnatal developmental delay, arthrogryposis, hypertonicity, seizure, and hypomyelination on brain magnetic resonance imaging; biallelic null variants (c.1347C > G [p.Tyr449*]; Chr2 [GRCh37]: g.130877574_131221737del [whole-gene deletion]) were detected by whole-exome sequencing. Our case is the first report of NEDMABA of Chinese ancestry, confirming the involvement of SMPD4 in NEDMABA and expanding the mutation spectrum of this syndrome.

Corrigendum: Palmitoylethanolamide attenuates neurodevelopmental delay and early hippocampal damage following perinatal asphyxia in rats.

[This corrects the article DOI: 10.3389/fnbeh.2022.953157.].

Palmitoylethanolamide attenuates neurodevelopmental delay and early hippocampal damage following perinatal asphyxia in rats.

Impaired gas exchange close to labor causes perinatal asphyxia (PA), a neurodevelopmental impairment factor. Palmitoylethanolamide (PEA) proved neuroprotective in experimental brain injury and neurodegeneration models. This study aimed to evaluate PEA effects on the immature-brain, i.e., early neuroprotection by PEA in an experimental PA paradigm. Newborn rats were placed in a 37°C water bath for 19 min to induce PA. PEA 10 mg/kg, s.c., was administered within the first hour of life. Neurobehavioral responses were assessed from postnatal day 1 (P1) to postnatal day 21 (P21), recording the day of appearance of several reflexes and neurological signs. Hippocampal CA1 area ultrastructure was examined using electron microscopy. Microtubule-associated protein 2 (MAP-2), phosphorylated high and medium molecular weight neurofilaments (pNF H/M), and glial fibrillary acidic protein (GFAP) were assessed using immunohistochemistry and Western blot at P21. Over the first 3 weeks of life, PA rats showed late gait, negative geotaxis and eye-opening onset, and delayed appearance of air-righting, auditory startle, sensory eyelid, forelimb placing, and grasp reflexes. On P21, the hippocampal CA1 area showed signs of neuronal degeneration and MAP-2 deficit. PEA treatment reduced PA-induced hippocampal damage and normalized the time of appearance of gait, air-righting, placing, and grasp reflexes. The outcome of this study might prove useful in designing intervention strategies to reduce early neurodevelopmental delay following PA.

Case Report: A Case of Epileptic Disorder Associated With a Novel CNTN2 Frameshift Variant in Homozygosity due to Maternal Uniparental Disomy.

Background: Contactin 2, encoded by CNTN2 on chromosome 1q32.1, is a neural-specific glycoprotein and plays important roles in neurodevelopment. A deleterious homozygous variant in the CNTN2 gene was previously reported to cause autosomal recessive cortical myoclonic tremor and epilepsy. Since then, there has been no further report confirming the association of CNTN2 and epilepsy. Here, we reported one new case, who presented with epilepsy, carrying a novel homozygous frameshift variant in CNTN2. The clinical and genetic features of the patient were reviewed. Case presentation: The male patient presented with preschool age-of-onset neurodevelopmental impairment and focal seizures of temporal origin, and responded to valproate. A trio-whole exome sequencing revealed a novel homozygous frameshift variant in CNTN2 (c.2873_c.2874delCT, p.Thr958Thrfs). The patient's mother was a heterozygous carrier while his father was wild-type; they were both unaffected and non-consanguineous. Further study revealed that maternal uniparental disomy (1q32.1) unmasked the heterozygous variant of CNTN2 in the proband. Conclusions: This case enhanced the gene-disease relationship between CNTN2 and epilepsy, which will help to further understand this emerging disorder.

Sensitive and critical periods during neurotypical and aberrant neurodevelopment: a framework for neurodevelopmental disorders.

During sensitive and critical periods, the brain undergoes significant plasticity from the level of individual synapses and neuronal networks up to the level of behaviour. Both sensitive and critical periods during neurotypical development of the young animal provide a framework to the early temporally-regulated modifications that occur in the nervous system. In neurodevelopmental disorders (NDD), notably autistic syndromes and intellectual disability, children exhibit developmental delays in motor, social and sensory processes and often miss key developmental milestones. In corresponding genetic NDD mouse models, recent data reveal temporally-regulated and in some cases, transient impairments in many neuronal and behavioural phenotypes during development. However, the mechanisms underlying these impairments in NDDs and their potential links with neurobiological mechanisms governing neurotypical development are not fully investigated. This article highlights the potential for the use of known critical and sensitive periods during vertebrate development to investigate and advance our understanding of the neural bases underlying impairments in these developmental disorders of the nervous system.