This review provides an updated analysis of the main aspects involving the diagnosis and the management of children with acute ischemic stroke. Acute ischemic stroke is an emergency of rare occurrence in children (rate of incidence of 1/3500 live birth in newborns and 1–2/100,000 per year during childhood with peaks of incidence during the perinatal period, under the age of 5 and in adolescence). The management of ischemic stroke in the paediatric age is often challenging because of pleomorphic age-dependent risk factors and aetiologies, high frequency of subtle or atypical clinical presentation, and lacking evidence-based data about acute recanalization therapies. Each pediatric tertiary centre should activate adequate institutional protocols for the optimization of diagnostic work-up and treatments.Conclusion: The implementation of institutional standard operating procedures, summarizing the steps for the selection of candidate for neuroimaging among the ones presenting with acute neurological symptoms, may contribute to shorten the times for thrombolysis and/or endovascular treatments and to improve the long-term outcome. What is Known:•Acute ischemic stroke has a higher incidence in newborns than in older children (1/3500 live birth versus 1–2/100,000 per year).•Randomized clinical trial assessing safety and efficacy of thrombolysis and/or endovascular treatment were never performed in children What is New:•Recent studies evidenced a low risk (2.1% of the cases) of intracranial haemorrhages in children treated with thrombolysis.•A faster access to neuroimaging and hyper-acute therapies was associated with the implementation of institutional protocols for the emergency management of pediatric stroke.

Background: Sex chromosome aneuploidies (SCAs) are a group of disorders characterised by an abnormal number of sex chromosomes. Collective prevalence rate of SCAs is estimated to be around 1 in 400–500 live births; sex chromosome trisomies (e.g., XXX, XXY, XYY) are most frequent, while tetra- and pentasomies (e.g., XXXX, XXXXX, XXXY, XXXXY) are rarer, and the most common is 48, XXYY syndrome. The presence of additional X and/or Y chromosomes is believed to cause neurodevelopmental differences, with increased risk for developmental delays, language-based learning disabilities, cognitive impairments, executive dysfunction, and behavioural and psychological disorders. Aim of the Study: Our review has the purpose of analysing the neurocognitive, linguistical and behavioural profile of patients affected by sex chromosomes supernumerary aneuploidies (tetrasomy and pentasomy) to better understand the specific areas of weakness, in order to provide specific rehabilitation therapy. Methods: The literature search was performed by two authors independently. We used MEDLINE, PubMed, and PsycINFO search engines to identify sources of interest, without year or language restrictions. At the end of an accurate selection, 16 articles fulfilled the inclusion and exclusion criteria. Results and Conclusions: International literature has described single aspects of the neuropsychological profile of 48, XXYY and 49, XXXXY patients. In 48, XXYY patients, various degrees of psychosocial/executive functioning issues have been reported and there is an increased frequency of behavioural problems in childhood. Developmental delay and behavioural problems are the most common presenting problems, even if anxiety, depression and oppositional defiant disorder are also reported. They also show generalized difficulties with socialization and communication. Cognitive abilities are lower in measures of verbal IQ than in measures of performance IQ. Visuospatial skills are a relative strength compared to verbal skills. In patients with 49, XXXXY, both intellectual and adaptive functioning skills fall into the disability range, with better non-verbal cognitive performance. Speech and language testing reveals more deficits in expressive language than receptive language and comprehension. Anxiety, thought problems, internalizing and externalizing problems, and deficits in social cognition and communication are reported. Behavioural symptoms lessen from school age to adolescence, with the exception of thought problems and anxiety. Individuals affected by sex chromosome aneuploidies show testosterone deficiency, microorchidism, lack of pubertal progression and infertility. Hormone replacement therapy (HRT) is usually recommended for these patients: different studies have found that testosterone-based HRT benefit a wide range of areas initiated in these disorders, affecting not only neuromotor, cognitive and behavioural profile but also structural anomalies of the brain (i.e., increase of volume of grey temporal lobe matter). In conclusion, further studies are needed to better understand the neuropsychological profile with a complete evaluation, including neurocognitive and psychosocial aspects and to establish the real impact of HRT on improving the cognitive and behavioural profile of these patients.

Neurodevelopmental disorders (NDDs) are often the results of genetic factors, whose identification and key role in their etiology may be elusive. Despite advancements in genetic testing, many cases remain unsolved. Single-nucleotide variants in a critical 18-bp region of the noncoding gene RNU4-2, a crucial component of the spliceosome complex, have been recently recognized as being responsible for ReNU syndrome, also known as NDD with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA). The aim of this study was to investigate the prevalence of RNU4-2 variants within a cohort of unsolved patients exhibiting NDDs from the Telethon Undiagnosed Disease Program (TUDP). We conducted a reanalysis of genomic data using bioinformatic tools, followed by direct sequencing to identify variants in the RNU4-2 critical region. Causative variants were detected in 11 of 375 tested individuals, allowing us to diagnose 2.93% of our unsolved cohort. All heterozygous variants in RNU4-2 occurred de novo, including 10 with the recurrent n.64_65insT insertion and 1 with n.77_78insT. Structural modeling suggested that these variants disrupt the U4/U6 snRNA interaction, potentially impairing spliceosome function. Our findings reinforce the critical role of RNU4-2 variants in syndromic NDDs and underscore the importance of noncoding regions in genetic diagnoses. These findings show that RNU4-2 variants account for approximately 2.9% of the patients with TUDP in this study and highlight the need for integrating advanced molecular techniques and data sharing to refine diagnoses and enhance our understanding of rare genetic disorders.

Autosomal recessive DNAJC12 disease, the most recently identified disorder of biogenic amine synthesis, presents with a broad clinical spectrum and variable outcomes, ranging from asymptomatic patients to early-onset parkinsonism. This study aimed to better outline the clinical phenotype and outcomes of DNAJC12 disease, the prognostic value of the metabolic and genetic biomarkers, and the treatment response. We systematically collected clinical, biochemical, and genetic data from 56 patients with DNAJC12 disease in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines: 51 from the literature since the disease was first described and 5 unpublished personal cases. Three prevalent clinical patterns of presentation and outcome were identified: (1) asymptomatic condition, (2) neurodevelopmental disorders (NDD) leading to intellectual disability with psychiatric issues and dystonia-parkinsonism (D-P) during the second decade of life in some patients, and (3) early-onset static l-dopa–responsive parkinsonism in previously asymptomatic adult patients. Hyperphenylalaninemia was the most consistent metabolic alteration. CSF depletion of homovanillic acid (HVA) and 5-HIAA was detected in 18 and 20 of 29 symptomatic patients, respectively. Three stepwise regression analyses identified significant predictors of clinical outcomes in patients with phenylketonuria (PKU). CSF HVA levels and phenylalanine levels at diagnosis predicted the occurrence of D-P, while 26% of intellectual disability variability was explained by CSF HVA at diagnosis, and 31% of psychiatric disorder variability by later age at diagnosis. The phenotype was consistently associated with only a few DNAJC12 pathogenic variants, primarily for phenotypes A and C. Movement disorders responded positively to the various therapies in all symptomatic patients. The preventive effects on NDD and psychiatric problems were less clear. DNAJC12 disease is a new metabolic neurodevelopmental disorder linked to parkinsonism. The combined effects of neurotransmitter depletion and disrupted enzyme proteostasis in dopaminergic and serotoninergic neurons may underlie the early neurodevelopmental presentation and subsequent neurologic and psychiatric disorders.

Objectives: To investigate the clinical value of cerebrospinal fluid (CSF) testing for biogenic amine, pterins, amino acids, and folates in paediatric onset epilepsies. Methods: Retrospective clinical and biochemical phenotyping of patients with epilepsy who underwent diagnostic CSF measurement of monoamine neurotransmitters, pterins, folates, and amino acids between 2009 and 2022. Results: The studied cohort included 123 patients with epilepsy (mean age at the procedure: 4.54 ± 3.65 years). The diagnostic yield for primary neurotransmitter disorders was 1.68% and zero for inherited amino acid and folate metabolism disorders. Patients with higher seizure frequency showed higher levels of CSF homovanillic acid (HVA) and HVA/5-hydroxyindolacetic acid (5HIAA) ratio. Lower levels of 3-O-methyldopa (3-OMD) were found in patients with co-occurring neurodevelopmental disorders, and lower levels of biopterin, 3-methoxy-4-hydroxyphenylglycol (3-MHPG) and 5-methyltetrahydrofolate (5-MTHF) in those with movement disorders. Significantly lower CSF glutamine levels were found in patients receiving antiseizure medications as polytherapy. Patients with a history of status epilepticus had significantly lower levels of CSF aspartic acid, glycine, leucine, ornithine, and valine, and higher levels of CSF serine. Conclusions: CSF analysis disclosed differences in the concentrations of various metabolites that might be related to the severity of the epilepsy, the presence of comorbid conditions, and medications.