Background Congenital cytomegalovirus (cCMV) infection, caused by a DNA beta-herpesvirus, is the most common congenital infection globally, with significant neurodevelopmental and audiological sequelae. This study aimed to evaluate maternal-to-fetal transmission rates, neonatal outcomes, and the predictive value of clinical and virological markers for adverse outcomes. Methods This prospective longitudinal study enrolled 43 neonates born to mothers with CMV infection during pregnancy (2019–2023). cCMV was diagnosed by CMV DNA detection in urine or saliva within the first two weeks of life. Neuroimaging, audiological evaluations, and neurodevelopmental assessments were conducted during follow-up. Statistical analyses examined associations between maternal infection type, neonatal findings, and clinical outcomes. Results Among 43 neonates, 31 (72%) were diagnosed with cCMV. Primary maternal infection was significantly associated with higher transmission rates (p < 0.01). Twelve infected infants (38.7%) showed neurological symptoms, most commonly of speech and motor delay. SNHL was diagnosed in 2 patients (6.4%). High blood viral load was significantly associated with adverse audiological outcomes (p < 0.05), while intrauterine growth restriction (IUGR) predicted adverse neurological outcomes (p = 0.05). No statistically significant association was found between MRI abnormalities and neurological or audiological outcomes, although a trend toward correlation with adverse outcomes was observed. Conclusions cCMV carries a high risk of neurodevelopmental and auditory sequelae. High blood viral load and IUGR may serve as early predictors of poor outcomes. Early diagnosis, parental counseling, and long-term follow-up remain essential. Larger multicenter studies are needed to validate these findings and refine predictive models.

BACKGROUND:To evaluate the interplay of genetic predispositions and prenatal, perinatal, and postnatal risk factors in children with Level 3 Autism Spectrum Disorder (ASD). METHODS:This retrospective study included 77 children with Level 3-ASD from a Sicilian pediatric cohort. We systematically reviewed medical records to assess prenatal, perinatal, and postnatal risk factors, alongside genetic findings. Genetic testing included chromosomal microarray and next-generation sequencing for the identification of pathogenic or likely pathogenic variants. Statistical analyses were performed to evaluate the correlation between cumulative risk factors and positive genetic findings, focusing on the role of chromosomal copy number variations (CNVs) and point mutations. RESULTS:Of the 77 children included, 54.5% showed a positive genetic finding, including CNVs or pathogenic single-gene variants. All patients had at least one prenatal risk factor, while postnatal complications were present in 48.1%. CNV carriers exhibited a significantly higher burden of both prenatal (mean = 6.70) and neonatal (mean = 2.40) risk factors compared to other groups (P < 0.001). Genetically positive patients had a significantly higher cumulative risk factor load than genetically negative ones (P = 0.0006). Low birth weight, hyperbilirubinemia, and early neurological comorbidities were significantly associated with genetic findings (odds ratio = 10.0, 7.1, and 12.0, respectively). No single risk factor significantly differentiated CNV from single-gene cases. LASSO regression identified neurological comorbidities, hyperbilirubinemia, cesarean delivery, and hypoglycemia as independent predictors of genetic positivity. Overall, genetic predisposition correlated with increased perinatal and neonatal complications. CONCLUSIONS:This study highlights the multifactorial nature of ASD and supports integrating genetic and environmental assessments into early diagnostic strategies. Early genetic screening and targeted interventions in infants with multiple risk factors may aid in reducing ASD risk and improving outcomes.

Lissencephaly (LIS) is a group of malformations of cortical development consisting of a defective neuronal migration that results in lack of formation of the normal cerebral convolutions. It includes a spectrum of defect with varying degrees of severity, from agyria and pachygyria to subcortical band heterotopia. The etiopathogenesis of LIS includes both genetic and environmental factors. Although nongenetic forms of LIS have been reported, genetic causes are certainly more frequent and to date 19 LIS-SBH-associated genes have been identified. Most common mutations involve LIS1 , DCX , ARX , and RELN genes. Clinically affected individuals present with early hypotonia, which can progress to limb spasticity, seizures, and psychomotor retardation. Convulsive episodes usually appear early (first months of life) and include infantile spasms, akinetic or myoclonic seizures, up to the development of complex epileptic syndromes, including atypical absences, myoclonia, and partial or tonic-clonic seizures. Several clinical entities are associated with classical LIS, including the following: isolated lissencephaly sequence (ILS); Miller-Dieker syndrome (MDS; OMIM 247200); subcortical band heterotopia (OMIM 300067); X-linked LIS with abnormal genitalia; and LIS with cerebellar hypoplasia. Diagnosis primarily depends on genetic and neuroimaging. Magnetic resonance imaging (MRI) is the gold standard, and it detects the presence of thick cortical cortex, its location, and the layers' architecture. Based on neuroimaging, it is possible to distinguish six subtypes of gyral malformations. Clinical and therapeutic management of these patients is challenging, considering the necessity to face drug-resistant epilepsy, intellectual disability, spasticity, and dysphagia and feeding problems. At the present moment, no gene-specific treatment for LIS is available.

Background: Middle lobe syndrome (MLS) is a distinct clinical and radiographic entity characterized by recurrent or chronic collapse of the middle lobe of the right lung, but it can also involve the lingula of the left lung. Case Study: This study presents a rare case of MLS caused by a vascular ring never described in the literature until now and provides physicians with the clinical and instrumental tools in order to early recognize and promptly treat this condition. The case report was reported according to CARE guidelines. A literature research on PubMed/MEDLINE was also performed using the MeSH terms “Middle lobe syndrome OR MLS AND double aortic arch” “Middle lobe syndrome OR MLS AND vascular rings”. No case described in the literature was found. In most cases, MLS presents non-specific respiratory symptoms, which unfortunately is responsible for the diagnostic delay that patients with this pathology often suffer. The diagnostic delay is estimated to be 8 months (range 3 to 36 months). A history of dysphagia and regurgitation can be indirect signs of a vascular compression, such as vascular rings, which can cause MLS Conclusion: To date, the reported case is the only case in the literature of MLS caused by double aortic arch. The key point for the diagnosis of MLS is diagnostic suspicion. Early recognition of MLS is essential to quickly start a targeted therapeutic program avoiding the persistence of vicious circle atelectasis-recurrent respiratory infections, and this could significantly improve the long-term outcome of these patients.

Background Cystic Fibrosis (CF), is the most common, life-limiting, single-gene disease affecting the Caucasian population, with a reported incidence of1/3500 births. It is inherited in an autosomal recessive fashion and its diagnosis is notably challenging, since in several cases CF may not be detected by the newborn screening test and the sweat test, which are frequently reported negative of with doubtful results, especially in cases with atypical symptoms at onset or with uncommon mutations or polymorphisms.Case Presentation In this case, we present a case of CF presented with recurrent wheezing, reporting multiple negative or borderline sweat tests. The genetic evaluation revealed delta F508 (CF- causing) and heterozygous poly T5 polymorphism TG11 (TG)11T5.Conclusion The importance of this case lies in the recognition of wheezing as a symptom and not as a disease, thus many conditions such as CF have to be considered in its diagnostic process. Finally, it is of utmost importance to bear in mind that many mutations or polymorphisms might evade newborn screening and sweat tests.

From early age in the human brain occurs plasticity process that influences its development. The functioning of the brain is governed by its neuronal connectivity and the synaptic dynamics of these connections. A neuron, over thousands of synapses, can receive a large number of inputs and produce different outputs leading to the consolidation and integration of memory. Synaptic plasticity is the set of experience-dependent changes in neuronal pathways that support acquired habits. It is the ability of the nervous system to reshape connectivity between neurons, changing the functional and structural organization of neuronal circuits that allows us to adapt to the multiple and continuous changes in the environment and leading to processes such as cognitive development and the ability to learn. Synaptic plasticity is mainly due to short- and long-term mechanisms. Short-term synaptic plasticity refers to changes in synaptic strength that occurs very quickly (from one-thousandth of a second to 5minutes) and are temporary and decay over minutes (maximum 30minutes). Long-term synaptic plasticity is defined by a long-lasting, activity-dependent change in synaptic efficacy, last from hours up to a lifetime (from 30minutes to weeks, months, and years) and is thought to constitute the basis of learning and memory. A significant difference occurs in the nature of the change; short-term plasticity adds only a functional change, whereas long-term plasticity causes not only functional but also structural changes. Aside from genetic factors and metabolic processes, brain development is mediated also by environmental factors. Interaction with the environment plays a key role in the development and growth of neural networks and neuroplasticity. Environmental interactions that can modify and increase the development of neural networks and intelligence in children are several and are herein discussed.

Abstract The phenotypic variety associated to mutations in dynamin 1 (DNM1), codifying the presynaptic protein DNM1 has been increasingly reported, mainly related to encephalopathy with intractable epilepsy; currently, it is known the phenotype related to DNM1 gene mutations is relatively homogeneous with developmental delay, hypotonia, and epilepsy characterized by infantile spasms and possible progression to Lennox-Gastaut syndrome. By examining all the papers published until 2020 (18 articles), we compared data from 30 patients (extrapolated from 5 papers) with DNM1 mutations, identifying 26 patients with de novo mutations in DNM1. Nine patients (33.3%) reported the recurrent mutation p.Arg237Trp. A usual phenotype observed comprises severe to deep developmental delay and muscular hypotonia in all patients with epilepsy beginning with infantile spasms, which often evolved into Lennox-Gastaut syndrome. Data about GTPase or central domains mutations, and existing structural modeling and functional suggest a dominant negative effect on DMN1 function. Generally genetic epilepsies consist of a wide spectrum of clinical features, unlike that, DNM1-related CNS impairment phenotype is quite uniform. In up to one third of patients it has been found variant p.Arg237Trp, which is one of the most frequent variant detected in epileptic encephalopathies. The understanding of DNM1 function opens up the chance that this gene would become a new therapeutic target for epilepsies.

The Aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans and are responsible for both malformation (in particular lissencephaly) and nonmalformation complex phenotypes. The epilepsy phenotypes related to ARX mutations are West syndrome and X-linked infantile spasms, X-linked myoclonic epilepsy with spasticity and intellectual development and Ohtahara and early infantile epileptic encephalopathy syndrome, which are related in most of the cases to intellectual disability and are often drug resistant. In this article, we shortly reviewed current knowledge of the function of ARX with a particular attention on its consequences in the development of epilepsy during early childhood.

Objective Hypoxic-ischemic encephalopathy (HIE) is the second cause of neonatal deaths and one of the main conditions responsible for long-term neurological disability. Contrary to past belief, children with mild HIE can also experience long-term neurological sequelae. The aim of this systematic review is to determine the predictive value of long-term neurological outcome of (electroencephalogram) EEG/amplitude-integrated electroencephalogram (aEEG) in children who complained mild HIE. Study Design From a first search on PubMed, Google Scholar, and clinicalTrials.gov databases, only five articles were considered suitable for this study review. A statistical meta-analysis with the evaluation of odds ratio was performed on three of these studies. Results No correlation was found between the characteristics of the electrical activity of the brain obtained through EEG/aEEG in infants with mild HIE and subsequent neurological involvement. Conclusion EEG/aEEG monitoring in infants with mild HIE cannot be considered a useful tool in predicting their neurodevelopmental outcome, and its use for this purpose is reported as barely reliable.

Background Foreign body aspiration is common among older infants and toddlers and is an important cause of morbidity and mortality. It may escape notice by the physicians due to lack of knowledge of the exact history, high variability of clinical presentation, variable latency of the onset of symptoms, and inconclusive radiographical findings.Case Report We present a case series about children diagnosed with foreign body aspiration referred to the Pediatric Respiratory Unit of San Marco Hospital in Catania between January 2018 and November 2022. Data regarding demographic characteristics, symptoms, and type of foreign body were collected and analyzed.Conclusion Early diagnosis is the key to therapeutic success and effective management of foreign body aspiration. We will review the literature to highlight the diagnostic difficulties related to this condition and the useful tools to recognize and manage it. The most essential part of foreign body aspiration treatment is prevention and the need to educate parents and primary care physicians. It is, therefore, of the utmost importance to consider airway foreign bodies as a cause of cough unresponsive to therapy, recurrent wheezing, and relapsing pneumonia.

Epileptic encephalopathy is a condition in which seizures, electroencephalographic epileptiform abnormalities lead to a progressive deterioration of brain functions causing a significant psychomotor delay. One of the typical features of this heterogeneous and large group of severe disorders is the extremely early onset of seizures. The main causes of the epileptic encephalopathies include structural brain defects, inherited metabolic disorders; in this aspect, more than 100 genetic defects, including mutations in the solute carrier family 25 (SLC25A22 ) gene which encodes a mitochondrial glutamate carrier. To date, the main clinical phenotypes related to mutations of this gene are Ohtahara syndrome (or early infantile epileptic encephalopathy), early myoclonic encephalopathy and migrating partial seizures in infancy. In all the cases, prognosis is poor and no disease-modifying treatment is available in the present days.

Abstract MECP2 (methyl-CpG binding protein-2) gene, located on chromosome Xq28, encodes for a protein particularly abundant in the brain that is required for maturation of astrocytes and neurons and is developmentally regulated. A defective homeostasis of MECP2 expression, either by haploinsufficiency or overexpression, leads to a neurodevelopmental phenotype. As MECP2 is located on chromosome X, the clinical presentation varies in males and females ranging from mild learning disabilities to severe encephalopathies and early death. Typical Rett syndrome (RTT), the most frequent phenotype associated with MECP2 mutations, primarily affects girls and it was previously thought to be lethal in males; however, MECP2 duplication syndrome, resulting from a duplication of the Xq28 region including MECP2, leads to a severe neurodevelopmental disorder in males. RTT and MECP2 duplication syndrome share overlapping clinical phenotypes including intellectual disabilities, motor deficits, hypotonia, progressive spasticity, and epilepsy. In this manuscript we reviewed literature on epilepsy related to MECP2 disorders, focusing on clinical presentation, genotype–phenotype correlation, and treatment.

PRRT2 encodes for proline-rich transmembrane protein 2 involved in synaptic vesicle fusion and presynaptic neurotransmitter release. Mutations in human PRRT2 have been related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis, benign familial infantile epilepsies, and hemiplegic migraine. PRRT2 mutations cause neuronal hyperexcitability, which could be related to basal ganglia or cortical circuits dysfunction, leading to paroxysmal disorders. PRRT2 is expressed in the cerebral cortex, basal ganglia, and cerebellum. Approximately, 90% of pathogenic variants are inherited and 10% are de novo. Paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and ballismus. In the benign familial infantile epilepsy (BFIE), seizures are usually focal with or without generalization, usually begin between 3 and 12 months of age and remit by 2 years of age. In 30% of cases of PRRT2-associated PKD, there is an association with BFIE, and this entity is referred to as PKD with infantile convulsions (PKD/IC). PRRT2 mutations are the cause of benign family childhood epilepsy and PKD/IC. On the other hand, PRRT2 mutations do not seem to correlate with other types of epilepsy. The increasing incidence of hemiplegic migraine in families with PRRT2-associated PKD or PKD/IC suggests a common disease pathway, and it is possible to assert that BFIE, paroxysmal kinesigenic dyskinesia, and PKD with IC belong to a continuous disease spectrum of PRRT2-associated diseases.

Abstract KCNT1 gene encodes the sodium-dependent potassium channel reported as a causal factor for several different epileptic disorders. The gene has been also linked with cardiac disorders and in a family to sudden unexpected death in epilepsy. KCNT1 mutations, in most cases, result in a gain of function causing a neuronal hyperpolarization with loss of inhibition. Many early-onset epileptic encephalopathies related to gain of function of KCNT1 gene have been described, most often associated with two phenotypes: malignant migrating focal seizures of infancy and familial autosomal-dominant nocturnal frontal lobe epilepsy; however, there is no clear phenotype–genotype correlation, in fact same mutations have been represented in patients with West syndrome, Ohtahara syndrome, and early myoclonic encephalopathy. Additional neurologic features include intellectual disability, psychiatric disorders, hypotonia, microcephaly, strabismus, and movement disorders. Conventional anticonvulsant, vagal stimulation, and ketogenic diet have been used in the absence of clinical benefit in individuals with KCNT1-related epilepsy; in some patients, quinidine therapy off-label has been practiced successfully. This review aims to describe the characteristics of the gene, the phenotypes related to genetic mutations with the possible genotype–phenotype correlations and the treatments proposed to date, discussing the comorbidities reported in the literature.

Although rare, ischemic lesions in neonates may occur in Neonatal Intensive Care Units (NICUs) secondary to routine procedures and/or medicaments. We present double-center case series, reporting three preterm neonates with ischemic lesions following cardiac arrest and radial blood sampling. The overall outcome after treatment with 2% nitroglycerine (NTG) ointment showed optimal results with no adverse events. The most frequent causes responsible for the onset of such lesions are peripheral arterial catheterization procedures and dopamine extravasation. Our series describe the cardiac arrest as an underestimated cause of onset. Despite the optimal results emerging from the treatment of such lesions with NTG ointment, both in our experience and in the scientific literature, a defined protocol for its use in NICUs is not currently available, hence the need for further studies.

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated ( ATM ) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype–phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.

Neonatal seizures (NS) occur in the first 28 days of life; they represent an important emergency that requires a rapid diagnostic work-up to start a prompt therapy. The most common causes of NS include: intraventricular haemorrhage, hypoxic-ischemic encephalopathy, hypoglycemia, electrolyte imbalance, neonatal stroke or central nervous system infection. Nevertheless, an Inborn Error of Metabolism (IEM) should be suspected in case of NS especially if these are resistant to common antiseizure drugs (ASDs) and with metabolic decompensation. Nowadays, Expanded Newborn Screening (ENS) has changed the natural history of some IEMs allowing a rapid diagnosis and a prompt onset of specific therapy; nevertheless, not all IEMs are detected by such screening (e.g. Molybdenum-Cofactor Deficiency, Hypophosphatasia, GLUT1-Deficiency Syndrome) and for this reason neonatologists have to screen for these diseases in the diagnostic work-up of NS. For IEMs, there are not specific semiology of seizures and EEG patterns. Herein, we report a systematic review on those IEMs that lead to NS and epilepsy in the neonatal period, studying only those IEMs not included in the ENS with tandem mass, suggesting clinical, biochemical features, and diagnostic work-up. Remarkably, we have observed a worse neurological outcome in infants undergoing only a treatment with common AED for their seizures, in comparison to those primarily treated with specific anti-convulsant treatment for the underlying metabolic disease (e.g.Ketogenic Diet, B6 vitamin). For this reason, we underline the importance of an early diagnosis in order to promptly intervene with a targeted treatment without waiting for drug resistance to arise.

One of the first reported genes associated with epilepsy was SCN1B, which encodes for beta-subunit of voltage-gated sodium channel of excitable cells and it is critical for neuronal function in both central and peripheral nervous system. beta-subunits modulate the expression levels and functional properties of sodium channels and though their immunoglobulin domains may mediate interactions between channels and other proteins. Traditionally, SCN1B mutations were associated with generalized epilepsy with febrile seizures plus, a familial epilepsy syndrome characterized by heterogeneous phenotypes including febrile seizures (FS), febrile seizures plus (FSthorn), mild generalized epilepsies, and severe epileptic encephalopathies. Throughout the years, SCN1B mutations have been also associated with Dravet syndrome and, more recently, with developmental and epileptic encephalopathies, expanding the spectrum associated with this gene mutations to more severe phenotypes.