Background/Objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis. Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools. Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype–phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome. Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes.

Electroencephalography (EEG) continues to be a pivotal investigation in children with epilepsy, providing diagnostic evidence and supporting syndromic classification. In the pediatric population, electroencephalographic recordings are frequently performed during sleep, since this procedure reduces the number of artifacts and activates epileptiform abnormalities. To date, no shared guidelines are available for sleep induction in EEG. Among the interventions used in the clinical setting, melatonin and sleep deprivation represent the most used methods. The main purpose of this study is to test the non-inferiority of 3–5 mg melatonin versus sleep deprivation in achieving sleep in nap electroencephalography in children and young adult patients with epilepsy. To test non-inferiority, a randomized crossover trial is proposed where 30 patients will be randomized to receive 3–5 mg melatonin or sleep deprivation. Each enrolled subject will perform EEG recordings during sleep in the early afternoon for a total of 60 EEGs. In the melatonin group, the study drug will be administered a single oral dose 30 min prior to the EEG recording. In the sleep deprivation group, parents will be required to subject the child to sleep deprivation the night before registration. Urinary and salivary concentrations of melatonin and of its main metabolite 6-hydroxymelatonin will be determined by using a validated LC-MS method. The present protocol aims to offer a standardized protocol for sleep induction to be applied to EEG recordings in those of pediatric age. In addition, melatonin metabolism and elimination will be characterized and its potential interference in interictal abnormalities will be assessed.

Objective: Electroencephalography (EEG) plays a fundamental role in the diagnosis and classification of epilepsy, and inducing sleep during EEG can improve patient cooperation and enhance the detection of epileptiform activity. Despite its importance, there is currently no standardized approach for sleep induction in pediatric EEG recordings. Consequently, practices such as melatonin administration and sleep deprivation are commonly utilized. This study aimed to compare the effectiveness of 5 mg melatonin versus partial sleep deprivation in inducing sleep during nap‐time EEGs in children with epilepsy. Methods: A randomized crossover trial was conducted involving 33 participants (mean age 14.5 years), each undergoing EEG following either melatonin administration or partial sleep deprivation. In the melatonin arm, participants received an oral dose 30 min before the recording, while in the sleep deprivation arm, sleep was restricted the previous night. The primary outcome was sleep onset latency, defined as the time from relaxation to non‐REM stage 2 sleep on EEG. Additionally, melatonin and its metabolite, 6‐hydroxy‐melatonin, were measured using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Results: The study showed a mean sleep onset latency of 8.5 min after sleep deprivation and 10.1 min after melatonin administration, with a mean difference of 1.5 min. The analysis of covariance conducted with stratification based on sleep onset latency (five classes) and considering all patients confirmed that melatonin is non‐inferior to sleep deprivation in sleep onset latency, with 97.5% lower confidence limits of −0.37. Melatonin levels in the treated group confirmed adequate absorption, while they were undetectable in the sleep‐deprived group. Significance: Melatonin is non‐inferior to partial sleep deprivation in reducing sleep onset latency, with comparable diagnostic yield and a favorable tolerability profile. The study demonstrates that 5 mg of melatonin is a safe, effective, and well‐tolerated alternative to partial sleep deprivation for sleep induction in pediatric EEG evaluations. Given its ease of use and consistent results, melatonin may be recommended as a practical standard for facilitating EEG recordings in children, particularly those with neurodevelopmental disorders. Plain Language Summary: This randomized crossover trial evaluated the effectiveness and tolerability of melatonin administered before an EEG recording to induce sleep, compared with partial sleep deprivation. The results showed that melatonin helped children achieve sleep and was non‐inferior to sleep deprivation. Moreover, melatonin demonstrated a favorable tolerability profile, representing a safe and easier alternative to support sleep during EEG, particularly in children with neurodevelopmental disorders, and could enhance the efficiency and quality of pediatric EEG recordings.

Background: Idiopathic Generalized Epilepsies (IGEs) are electroclinical syndromes characterized by distinct seizure types, EEG patterns, and presumed polygenic inheritance. While seizure prognosis is often favorable, sleep disturbances, behavioral and emotional difficulties, and executive function impairment are common, especially during adolescence. Objective: To investigate the relationship between subjective sleep quality, emotional–behavioral functioning, and executive functions in adolescents with IGE. Methods: In this single‐center observational study, 28 adolescents (mean age 15.0 ± 2.4 years) with IGE were evaluated with the following standardized measures: PSQI (sleep), BRIEF‐2 (executive functions), CBCL and YSR (emotional–behavioral profile), SAFA‐A/‐D/‐S (internalizing and somatic symptoms). Dream‐related experiences were also collected. Pearson correlations tested behavioral and emotional associations with sleep quality. Results: Poor sleep quality (PSQI ≥5) occurred in 28.6% of patients, although only 14.8% reported sleep problems in their clinical history. Poor sleepers showed significantly higher anxiety, depression, somatic complaints, and stress‐related symptoms ( p < .05). Executive function impairment, particularly in emotional control and cognitive flexibility, was more frequent in this group. Significance: Sleep quality is an under‐recognized but clinically relevant dimension in patients with IGE, closely linked to emotional vulnerability and executive function difficulties. Routine sleep screening and targeted sleep‐focused management should be integrated into pediatric IGE care to support psychological well‐being.

This exploratory cross-sectional multicenter study evaluated the presence of depression and anxiety traits in adolescents with idiopathic generalized epilepsy (IGE) and explored their association with epilepsy-related clinical variables. Sixty-eight patients aged 11-18 years with a confirmed IGE diagnosis participated. Emotional symptoms were assessed using the parent-reported Child Behavior Checklist (CBCL) and the self-reported Psychiatric Scales for Self-Administration for Youths and Adolescents (SAFA). While no clinically significant deficits emerged on the overall CBCL or SAFA scores, 33% of patients showed clinically relevant anxiety traits, 31% showed depressive symptoms, and 19% reported clinically significant somatic complaints. Correlation analyses showed that somatic symptoms were significantly associated with epilepsy-related variables. Higher somatic symptom scores were related to a shorter time since the last seizure and a later age at epilepsy onset, while an inverse association was observed with epilepsy duration. These findings suggest that affective symptoms in adolescents with IGE are linked to specific clinical characteristics of epilepsy. The results highlight the importance of comprehensive emotional assessment and targeted psychological support for this population.