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Neurodevelopmental disorders (NDDs) cause profound intellectual and physical impairment, yet therapeutic progress remains hindered by the lack of quantitative, unbiased, and non-invasive biomarkers to monitor disease onset and progression. Visual evoked potentials (VEPs) have emerged as promising functional biomarkers for X-linked NDDs, with reduced VEP amplitudes correlating with disease severity. Complementary approaches, like functional Near Infrared Spectroscopy (fNIRS), offer a non-invasive additional tool to assess brain metabolism, monitor disease progression, and evaluate therapeutic responses. This perspective explores the potential of fNIRS in studying visually evoked hemodynamic responses (vHDR) across different age groups, demonstrating its reliability in capturing task-specific cortical activation and tracking brain maturation even in challenging populations. Notably, fNIRS identifies unique vHDR patterns in conditions like optic neuritis, myopia, glaucoma, and migraines, validating its role as a biomarker for disease severity and treatment efficacy. Moreover, fNIRS has proven effective in detecting early neural deficits in high-risk infants, including pre-term newborns. Preclinical studies support that visually induced hemodynamic changes can differentiate healthy from pathological conditions in X-linked NDDs. However, direct evidence from human cohorts with X-linked NDDs remains limited, highlighting the urgent need for further research to validate the potential of visual fNIRS as a reliable functional biomarker in clinical settings. To enhance clinical relevance, the development of standardized protocols, engaging stimuli, and age-stratified analyses is also crucial for improving diagnostic accuracy, tracking neurodevelopmental trajectories, and evaluating therapeutic interventions.

Background Creatine Transporter Deficiency (CTD) is a rare X-linked disorder caused by pathogenic or likely pathogenic variants in the SLC6A8 gene, leading to a deficiency of cerebral Creatine. Clinically, CTD manifests as a complex neurodevelopmental disorder and is associated with Intellectual Disability (ID), language and socio-communicative impairments, behavioral challenges and, often, epilepsy. Methods This study was conducted in two phases: (i) An eSurvey was distributed among major Italian clinics specializing in rare neurometabolic diseases to create a national census of CTD patients, with extensive clinical data; (ii) A retrospective observational study was performed on patients who had undergone regular long-term follow-up using a consistent neuropsychological assessment and treatment protocol. Results We identified 18 CTD male patients, aged 18 months to 32 years at diagnosis. Within this cohort, 3 to 13 years follow-up clinical information was collected for 10 patients. A specific clinical protocol was applied to this subgroup, where a biochemical or 1 H-MRS diagnosis was confirmed in 8 patients (urine Creatine/Creatinine ratio > 1), while in the remaining 2 patients, genetic testing was diagnostic and neurochemical tests followed. 1 H-MRS consistently showed a decreased Creatine peak in all patients. All 10 patients exhibited ID with significant speech disorder, and 6 had epilepsy. The treatment protocol for this cohort involved oral Arginine supplementation. Conclusions Diagnosing CTD remains clinically challenging due to the often negative results from a first tier clinical diagnostic test for intellectual disability (ID) (i.e. family history, cytogenetic testing and Fragile X) and neuroimaging without spectroscopy. CTD should be carefully considered when investigating severe ID with autistic-like traits and significant speech impairment, with or without epilepsy. The Urine Creatine/Creatinine ratio assay is a quick initial diagnostic step, which can be corroborated by a brain MRI/ 1 H-MRS and molecular genetics. Even considering previouis literature findings, it is not yet possible, to demonstrate definite genotype-phenotype correlations, although a milder functional impairment has been suggested for missense SLC6A8 pathogenic or likely pathogenic variants. Treatment strategies supplementation with Creatine and its precursors have provided heterogeneous and inconsistent results. Recently proposed innovative therapeutic strategies such as lipophilic Creatine analogs and betaine supplementation in animal models need validation in human disease.

Background: 47,XYY syndrome is a relatively common sex chromosome aneuploidy that remains largely underdiagnosed. While its somatic phenotype is often mild, growing evidence indicates a substantial burden of neurodevelopmental and psychiatric morbidity. However, the characterization of the neuropsychiatric phenotype across development, particularly during adolescence, and the associated treatment challenges remain incomplete. Objectives: To provide a comprehensive narrative review of the neuropsychiatric phenotype of 47,XYY syndrome and to illustrate clinical complexity and treatment response through a case series of adolescents. Methods: A narrative review of the literature was conducted focusing on genetics, neurodevelopmental and psychiatric features, neuroimaging and neurophysiology findings, clinical course, and management strategies in 47,XYY syndrome. This review is complemented by a case series of adolescents with confirmed 47,XYY karyotype, evaluated for developmental history, psychiatric comorbidity and response to pharmacological and non-pharmacological interventions. Results: The literature consistently describes increased risks of language impairment, executive dysfunction, ADHD, autism spectrum traits, and emotional and behavioral dysregulation in males with 47,XYY syndrome. Psychiatric vulnerability appears to increase during adolescence and adulthood, with elevated rates of mood, psychotic, and substance use disorders. The presented cases illustrate a convergent clinical trajectory marked by early developmental delays, progressive behavioral dysregulation in adolescence and limited or inconsistent response to multiple classes of psychotropic medications, suggesting a pattern of pharmacoresistance in a subset of patients. Conclusions: 47,XYY syndrome is associated with a distinct and heterogeneous neuropsychiatric phenotype that extends beyond early neurodevelopmental disorders. Early diagnosis alone may be insufficient to prevent severe psychiatric outcomes, highlighting the need for long-term monitoring and integrated, multidisciplinary management. Further research is required to identify early predictors of high-risk trajectories and to optimize treatment strategies for this population.

Background Endothelial cell‐selective adhesion molecule (ESAM) is a tight junction protein essential for blood–brain barrier integrity and angiogenesis. Bi‐allelic loss‐of‐function variants in ESAM cause NEDIHSS (“Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity”), a neurodevelopmental/neurovascular disorder with antenatal/neonatal onset, characterized by global developmental delay/intellectual disability (GDD/ID), epilepsy, spasticity, ventriculomegaly, and intracranial hemorrhages. Ocular involvement, particularly retinal vascular anomalies, has been variably reported. Methods A multidisciplinary team of pediatric neurologists, ophthalmologists, and clinical geneticists evaluated the proband through clinical assessment, neuro/ocular imaging, and whole‐exome sequencing. Results We describe a 3‐year‐old male from consanguineous Albanian parents carrying a novel homozygous splice‐site ESAM variant (c.70+1G>T). He presented with GDD, seizures, and brain imaging abnormalities consistent with NEDIHSS. Remarkably, bilateral optic nerve hypoplasia, esotropia, retinal detachment, absent electroretinogram response, and structural eye anomalies, including left eyeball hypoplasia and iris displacement, were observed. Review of our and previous cases indicates that 45% (10/22) of NEDIHSS individuals present ocular manifestations, mainly retinal vascular defects, reinforcing the emerging role of ESAM in retinal endothelial integrity. Conclusions This case broadens the mutational and clinical spectrum of ESAM‐related disease, underscores the need for detailed ocular evaluations in NEDIHSS, and supports inclusion of retinal anomalies within its core phenotype. Overview of neurological, ocular, and genetic findings in individuals with bi‐allelic loss‐of‐function (LoF) ESAM variants. All affected subjects (n = 21) exhibited characteristic neurovascular and neurodevelopmental anomalies, while 45% also showed ocular (mainly retinal) involvement. Exome sequencing identified a novel bi‐allelic splice‐site ESAM variant (c.70+1G>C) in the newly reported individual.

Tankyrases are poly-ADP-ribosyltransferases that regulate many crucial and diverse cellular processes in humans such as Wnt signaling, telomere homeostasis, mitotic spindle formation and glucose metabolism. While tankyrases are present in most animals, functional differences across species may exist. In this work, we confirm the widespread distribution of tankyrases throughout the branches of multicellular animal life and identify the single-celled choanoflagellates as earliest origin of tankyrases. We further show that the sequences and structural aspects of TNKSs are well-conserved even between distantly related species. We also experimentally characterized an anciently diverged tankyrase homolog from the sponge Amphimedon queenslandica and show that the basic functional aspects, such as poly-ADP-ribosylation activity and interaction with the canonical tankyrase binding peptide motif, are conserved. Conversely, the presence of tankyrase binding motifs in orthologs of confirmed interaction partners varies greatly between species, indicating that tankyrases may have different sets of interaction partners depending on the animal lineage. Overall, our analysis suggests a remarkable degree of conservation for tankyrases, and that their regulatory functions in cells have likely changed considerably throughout evolution.

SARS‐CoV‐2 (severe acute respiratory syndrome coronavirus 2), the new coronavirus responsible for the pandemic disease in the last year, is able to affect the central nervous system (CNS). Compared with its well‐known pulmonary tropism and respiratory complications, little has been studied about SARS‐CoV‐2 neurotropism and pathogenesis of its neurological manifestations, but also about postmortem histopathological findings in the CNS of patients who died from COVID‐19 (coronavirus disease 2019). We present a systematic review, carried out according to the Preferred Reporting Items for Systematic Review standards, of the neuropathological features of COVID‐19. We found 21 scientific papers, the majority of which refer to postmortem examinations; the total amount of cases is 197. Hypoxic changes are the most frequently reported alteration of brain tissue, followed by ischemic and hemorrhagic lesions and reactive astrogliosis and microgliosis. These findings do not seem to be specific to SARS‐CoV‐2 infection, they are more likely because of systemic inflammation and coagulopathy caused by COVID‐19. More studies are needed to confirm this hypothesis and to detect other possible alterations of neural tissue. Brain examination of patients dead from COVID‐19 should be included in a protocol of standardized criteria to perform autopsies on these subjects. SARS‐CoV‐2, the new coronavirus responsible for the pandemic disease in the last year, is able to affect the Central Nervous System. However, little has been studied about SARS‐CoV‐2 neurotropism and neuropathogenesis. We present a systematic review of the neuropathological features of COVID‐19. Hypoxic changes, ischemic and hemorrhagic lesions, reactive astrogliosis, and microgliosis are the brain alterations mainly described in the literature. These findings do not seem to be specific to SARS‐CoV‐2 infection, they are more likely due to systemic inflammation and coagulopathy caused by COVID‐19.

Over the last decade, the comorbidity between Autism Spectrum Disorder (ASD) and epilepsy has been widely demonstrated, and many hypotheses regarding the common neurobiological bases of these disorders have been put forward. A variable, but significant, prevalence of abnormalities on electroencephalogram (EEG) has been documented in non-epileptic children with ASD; therefore, several scientific studies have recently tried to demonstrate the role of these abnormalities as a possible biomarker of altered neural connectivity in ASD individuals. This narrative review intends to summarize the main findings of the recent scientific literature regarding abnormalities detected with standard EEG in children/adolescents with idiopathic ASD. Research using three different databases (PubMed, Scopus and Google Scholar) was conducted, resulting in the selection of 10 original articles. Despite an important lack of studies on preschoolers and a deep heterogeneity in results, some authors speculated on a possible association between EEG abnormalities and ASD characteristics, in particular, the severity of symptoms. Although this correlation needs to be more strongly elucidated, these findings may encourage future studies aimed at demonstrating the role of electrical brain abnormalities as an early biomarker of neural circuit alterations in ASD, highlighting the potential diagnostic, prognostic and therapeutic value of EEG in this field.

Neurodevelopmental disorders (NDDs) are considered synaptopathies, as they are due to anomalies in neuronal connectivity during development. DLG2 is a gene involved insynaptic function; the phenotypic effect of itsalterations in NDDs has been underestimated since few cases have been thoroughly described.We report on eight patients with 11q14.1 imbalances involving DLG2, underlining its potential effects on clinical presentation and its contribution to NDD comorbidity by accurate neuropsychiatric data collection. DLG2 is a very large gene in 11q14.1, extending over 2.172 Mb, with alternative splicing that gives rise to numerous isoforms differentially expressed in brain tissues. A thorough bioinformatic analysis of the altered transcripts was conducted for each patient. The different expression profiles of the isoforms of this gene and their influence on the excitatory–inhibitory balance in crucial brain structures could contribute to the phenotypic variability related to DLG2 alterations. Further studies on patients would be helpful to enrich clinical and neurodevelopmental findings and elucidate the molecular mechanisms subtended to NDDs.

Neurodevelopmental disorders (NDDs) are considered synaptopathies, as they are due to anomalies in neuronal connectivity during development. DLG2 is a gene involved insynaptic function; the phenotypic effect of itsalterations in NDDs has been underestimated since few cases have been thoroughly described.We report on eight patients with 11q14.1 imbalances involving DLG2, underlining its potential effects on clinical presentation and its contribution to NDD comorbidity by accurate neuropsychiatric data collection. DLG2 is a very large gene in 11q14.1, extending over 2.172 Mb, with alternative splicing that gives rise to numerous isoforms differentially expressed in brain tissues. A thorough bioinformatic analysis of the altered transcripts was conducted for each patient. The different expression profiles of the isoforms of this gene and their influence on the excitatory–inhibitory balance in crucial brain structures could contribute to the phenotypic variability related to DLG2 alterations. Further studies on patients would be helpful to enrich clinical and neurodevelopmental findings and elucidate the molecular mechanisms subtended to NDDs.

In the past, development of tankyrase inhibitors has focused on the ADP-ribosyltransferase domain. Targeting tankyrases ability to interact with protein substrates through their ARC domains represents an alternative strategy to be explored as a therapeutic approach against specific protein-protein interactions. In this paper, we employed a FRET-based assay to identify ARC4-binding compounds by screening the EU-OPENSCREEN Pilot and Commercials Diversity libraries. We discovered an effective series of compounds with the same scaffold and through chemical synthesis we obtained the compound S8 (ARCher-142), which binds selectively to ARC4 with potency of 8 µM. NMR analysis and X-ray crystallography allowed us to identify the binding site in ARC4 and to rationalize the observed selectivity. Despite binding exclusively to ARC4, the inhibitor can attenuate the WNT/β-catenin signaling pathway in cells. Our work demonstrates that targeting single ARC domains is possible, offering an inhibition approach tailored to tankyrase ARC4 inhibition. Tankyrases impact a variety of cellular processes by binding proteins through their ARC domains and the inhibition of these scaffolding functions represents an alternative therapeutic approach to catalytic inhibitors. With a FRET-based high-throughput screening of the EU-OPENSCREEN Pilot and Commercials Diversity libraries we discovered a pyrrolone-based scaffold that is interestingly selective towards ARC4, despite the high conservation of the ARC binding site. Our synthesized compound S8 (ARCher-142) displays an 8 µM potency for TNKS2 ARC4. With NMR and X-ray crystallography we demonstrate that S8 (ARCher-142) competes with the peptide optimized for binding and extends to a unique hydrophobic sub-pocket of ARC4. The compound attenuates the WNT/β-catenin signaling pathway in cells and interestingly offers the possibility to target specific protein-protein interactions mediated by ARC4, paving the way for the development of a pyrrolone-based class of tankyrase scaffolding inhibitors.