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Tuberous sclerosis complex (TSC) is a rare autosomal dominant multi-systemic disease, leading to excessive cell proliferation and the formation of hamartomas affecting various organs. International and French national guidelines emphasize the need for regular follow-up by different specialists with regular clinical evaluation, and biological and imaging investigations. This study aims to assess patient follow-up, its cost, and its adherence to the French National follow-up recommendations since the establishment of the day-hospital program tailored for pediatric patients with TSC. Clinical and follow-up data were collected among 81 patients, aged from 3 to 18 years old, from the epilepsy reference center of Necker Hospital in Paris, with a confirmed diagnosis of TSC, retrospectively from January 1st, 2021 to January 1st, 2024. Patients had an average of 9.4 days of pathology-related follow-up events, and an average of 1.1 teleconsultation over 3 years. Patients attended 1.6 day hospital stays over the duration of follow-up. The mean annual cost per patient for consultations and hospitalizations was €1344. The level of disability significantly increases the cost of follow-up. However, home-hospital distance has no significant impact on overall follow-up costs, the number of teleconsultations, or day-hospital visits. While paraclinical imaging and neurological follow-up were consistent with national recommendations, compliance with TSC national guidelines for specialist consultations was more challenging to implement. Our findings suggest that a mixed day hospital model, centered on neuropediatrics and incorporating additional examinations and consultations, would facilitate compliance with follow-up recommendations. Reducing patient travel and optimizing costs should be considered key objectives for improving long-term care.

Pathogenic variants affecting components of the mitochondrial translation machinery lead to various impairments of mitochondrial function and thereby cause a spectrum of multisystem diseases. In an infant with a fatal, metabolic multisystem condition we performed a comprehensive multi-omics approach and detected the intronic biallelic variant NM_014050.4:c.219+6 T > A in MRPL42 (mitochondrial ribosomal protein L42) encoding a component of the large mitochondrial ribosomal subunit. RNA-seq revealed a strong reduction and aberrant splicing of the majority of MRPL42 transcripts leading to a frameshift and thereby to a premature termination codon: p.(Asn46Leufs*18). However, additional use of the canonical splice site led to a low residual expression of the wildtype transcript and MRPL42 protein abundance was consequently strongly reduced. Complex I and IV activity of the oxidative phosphorylation (OXPHOS) system were reduced and a decrease of complex I, III, IV, and mitoribosomal-related proteins was identified by proteomics. Complementation with wildtype MRPL42 corrected most of these phenotypes confirming that they were a direct consequence of the limited availability of MRPL42. Our multi-omics data confirm biallelic MRPL42 loss-of-function as the underlying cause of the fatal mitochondrial disease in our patient. Therefore, we propose MRPL42 deficiency as the cause of a mitochondrial ribosome-related combined OXPHOS-deficiency syndrome.

The onset of epileptic manifestations frequently occurs during childhood and often leads to initial management in pediatric emergency departments. The diagnostic approach is challenging, as epileptic seizures must be distinguished from non-epileptic paroxysmal events and acute symptomatic seizures. Although several national and international recommendations exist, real-world data on the management of first seizures in pediatric emergency settings remain limited. The primary objective of this study was to analyze patient characteristics and management of children presenting to a pediatric emergency department with a first non-febrile convulsive seizure. The secondary objective was to develop a practical management algorithm tailored to pediatric emergency settings. We conducted a retrospective, single-center observational study in a tertiary pediatric hospital in Reims, France. All patients under 18 years of age presenting to the pediatric emergency department with a first non-febrile convulsive seizure between January 1, 2015, and June 30, 2021, were included. Data from 167 children were analyzed and categorized into three groups: epileptic seizure (99, 59.3%), non-epileptic paroxysmal event (64, 38.3%), and acute symptomatic seizure (4, 2.4%). Clinical examination was normal in the majority of cases and did not reliably discriminate between groups. Semiological features such as eye deviation, eye rolling, generalized or focal hypertonia, and postictal confusion were significantly associated with epileptic seizures, whereas stressful or vasovagal situations were more frequent in non-epileptic events. All patients in the epileptic group underwent neuropediatric consultation, and 55 (55.5%) were discharged with antiepileptic treatment. Laboratory investigations were performed in 52 (52.5%) patients, with abnormalities identified in only 4% of cases. Electroencephalography (EEG) was performed in 96 (96.7%) patients and showed abnormalities in 64 (69.8%). In non-epileptic events, the EEG was normal in all cases where it was performed. Brain imaging was selectively performed and identified structural abnormalities in 21 (26.6%) patients who underwent MRI. In children presenting with a first non-febrile convulsive event, epileptic seizures accounted for a substantial proportion of cases, while non-epileptic events remained frequent. Clinical history and witness description were the most informative elements for diagnosis, whereas routine laboratory testing had limited utility. EEG and neuroimaging were valuable in selected cases. The proposed management algorithm provides a pragmatic, emergency-oriented framework to support clinical decision-making and help standardize the evaluation of these patients.

Genetic variants in RNU4-2, which is transcribed into the U4 small nuclear RNA component of the major spliceosome, were recently shown to cause ReNU syndrome, a prevalent dominant neurodevelopmental disorder (NDD). These variants almost exclusively arise de novo and cluster within 18 nucleotides of RNU4-2. Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2. We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. We characterize the clinical phenotype in 31 individuals, demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Finally, we find reduced RNU4-2 transcript levels in individuals with the recessive disorder, suggesting a loss-of-function disease mechanism that is distinct from the mechanism underlying ReNU syndrome. Together, these findings expand the genotypic and phenotypic spectrum of RNU4-2-associated NDDs.

Currently, no standardized anatomic magnetic resonance (MR) imaging protocol exists for detecting parathyroid adenomas. We analyzed various MR pulse sequences to evaluate their performance in visualizing histopathologically confirmed parathyroid adenomas in patients with primary hyperparathyroidism (pHPT) undergoing [18F]fluorocholine positron emission tomography (PET)/MR. This retrospective study included 128 adenomas in 110 patients with biochemically confirmed pHPT who underwent [18F]fluorocholine PET/MR at our institution between December 2020 and October 2023. Two radiologists independently characterized the lesions (as upper pole, lower pole, or ectopic adenomas). Surgical reports and histopathology served as reference standard. Lesion conspicuity, delineation, and size were compared on axial T1-weighted fast spin echo sequence (T1w FSE) and axial T2-weighted iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) sequence with water image reconstruction (T2w FSE flex water). Interreader agreement was determined using Cohen's kappa; differences were analyzed using Wilcoxon signed-rank test. Parathyroid adenomas had significantly higher conspicuity, superior delineation, and were larger (p&#x2009;<&#x2009;0.001) on T2w FSE flex water images compared to T1w FSE images. While these differences were maintained in the subgroup analysis for upper and lower pole adenomas, ectopic adenomas were of similar size on both MR pulse sequences (p&#x2009;=&#x2009;0.646). T2w FSE flex water offers significantly better visualization of parathyroid adenomas compared to T1w FSE, especially in orthotopic lesions. These results support the targeted use of such a limited MR protocol as part of PET/MR in the preoperative assessment of patients with pHPT.

Despite growing interest in music therapy (MT) as a supportive intervention in neonatal intensive care units (NICUs), strong evidence for its long-term efficacy remains scarce. This perspective article explores the multifaceted challenges of implementing and evaluating MT in NICUs, particularly for preterm infants. These challenges include (1) limited understanding of premature auditory development, (2) environmental acoustics, (3) methodological inconsistencies in MT delivery, and the complex medical (4) and psychosocial (5) context of the NICU. Further compounding this issue is the underappreciation of parental involvement and the perception of MT among healthcare professionals. Addressing these gaps is essential for establishing standardized, effective MT protocols tailored to this vulnerable population.

The clinical utility of the comprehensive laboratory and medical investigations currently recommended for children with pediatric acute-onset neuropsychiatric syndrome (PANS) remains unclear. Notably, comparisons with relevant psychiatric control patients without suspected immunologic pathogenesis are lacking. To evaluate whether currently recommended laboratory investigations differentiate children with PANS from children with idiopathic obsessive-compulsive disorder (OCD) and/or tic disorders and whether the full set of recommended medical investigations identify underlying somatic conditions in children with PANS. This case-control study recruited children (aged 4-18 years) with PANS and children with idiopathic OCD and/or tic disorders (control group) from specialist PANS and OCD clinics in Stockholm, Sweden, between January 1, 2020, and September 19, 2023. The data analyses were performed between June 16, 2024, and August 19, 2025. Following published PANS guidelines, assessments included 56 laboratory variables from blood and throat cultures. Additional data from cerebrospinal fluid analysis, brain magnetic resonance imaging, and electroencephalography were available for a subsample of the PANS group. Laboratory findings were compared between the PANS and control groups. Among 109 participants, the PANS group included 51 children (mean [SD] age, 10.2 [3.4] years; 34 boys [66.7%], and the control group included 58 children (mean [SD] age, 13.6 [3.1] years; 29 boys [50.0%]). Nearly all participants had at least 1 abnormal laboratory finding (44 [86.3%] in the PANS group, 56 [96.6%] in the control group), with no significant between-group differences. Most participants in the PANS group had 3 or more abnormal laboratory findings, while most in the control group had 4 or more. One participant with PANS was diagnosed with celiac disease; another showed electroencephalographic signs of neuroinflammatory activity without a definite diagnosis prior to the PANS assessment. Incidental, nonactionable findings were frequent. In this case-control study of children with PANS and idiopathic OCD and/or tic disorders, abnormal laboratory findings were common in both groups and did not differ significantly. The full set of recommended medical investigations rarely identified underlying somatic conditions in children with PANS. These findings question the clinical utility of the comprehensive and costly medical investigations currently recommended for children with suspected PANS.

Autosomal recessive Limb-Girdle Muscular Dystrophy type R28 (LGMDR28; OMIM #620375) is one of the most recently identified subtypes of recessive LGMD. To date, 17 affected individuals from eight unrelated families have been reported to harbor biallelic variants in the HMGCR gene. Here, we report eleven individuals from six unrelated Middle Eastern families diagnosed with LGMDR28 and carrying homozygous variants in HMGCR. Our cohort recapitulated most of the previously described clinical features of the HMGCR-related phenotype. In addition, we also report a family with congenital onset of the condition as well as two affected individuals with liver failure. Through genome and exome sequencing, we identified three novel homozygous missense variants; c.2519G&#x2009;>A, p.(Arg840Gln), c.1784G&#x2009;>A, p.(Arg595His), and c.1783C>T, p.(Arg595Cys) and a homozygous in-frame deletion (c.1522_1524del, p.(Ser508del)) previously reported in compound heterozygous state with a second relevant variant and very recently as homozygous in an unrelated proband. This study consolidates the pathogenic role of HMGCR in LGMDR28 while expanding the phenotypic and mutations spectrum of LGMDR28.

Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.

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This study aimed to assess the availability of national transition guidelines in paediatric neurology across Europe and to provide a review of the existing literature. A mixed-methods descriptive study was conducted, combining a survey of national representatives of the European Paediatric Neurology Society and a scoping literature review. The survey, performed in 2021 with an update in 2026, assessed the existence of national or officially endorsed transition guidelines. The literature review (2002-2025) followed the Arksey and O'Malley framework and PRISMA-ScR recommendations. Thirty-six of 42 representatives responded to the 2021 survey; 66.7% reported no national transition guidelines in paediatric neurology, while 16.7% reported officially endorsed guidance. The literature search identified 23372 records, of which 132 publications were included in the final analysis. Most described centre-based transition models or general recommendations, while formal guidelines were rare. Drawing on the gaps identified through literature review and survey findings, this paper proposes a series of targeted recommendations to enhance the transition process in paediatric neurology. Transition guidance in paediatric neurology remains limited and heterogeneous across Europe. Specific recommendations are needed to provide guidance and enhance the effectiveness of this process. An EPNS-EAN Transition Task Force is currently developing a transition framework.

Three disease-modifying therapies are approved for individuals with spinal muscular atrophy (SMA); however, data concerning the combination of these therapies remain limited. This study aimed to evaluate the safety and efficacy of add-on risdiplam in children who had experienced clinical deterioration despite gene therapy with onasemnogene abeparvovec. This is a retrospective case series study at two centers of children treated with risdiplam who had previously received onasemnogene abeparvovec. Therapy was evaluated by clinical examination, standardized physiotherapeutic assessments, and parent perspectives. Five patients with SMA (four male and one female), diagnosed between 0 and 8&#x2009;months, were included in the study. All had 2 SMN2 copies and were started on risdiplam between five and 48&#x2009;months after onasemnogene abeparvovec. Risdiplam was added due to motor regression, dysphagia, new onset of respiratory insufficiency, and/or recurrent pneumonias. Four children showed improvements in motor development, swallowing, and respiratory function. One child remained stable. Parents perceived a significant improvement in general impression, motor, and respiratory function. The add-on therapy was well tolerated without adverse events. Our results indicate an improvement in most children in a case series through add-on risdiplam. Evaluating clinical outcome parameters in clinical practice may prove challenging and should be complemented by the parental perspective. The decision regarding the use of add-on therapy in children with SMA who receive one line of treatment but show a clinical deterioration should be considered on an individual level, and assessments of predefined therapeutic goals are recommended.

This study was undertaken to test whether arterial spin labeling (ASL) performs comparably to 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the mainstay functional imaging technique, in pediatric lesional epilepsy, while avoiding radiotracer exposure and additional sedation. We retrospectively included children with epilepsy due to focal cortical dysplasia, low-grade epilepsy-associated tumors, or hippocampal sclerosis who underwent standardized magnetic resonance imaging (MRI; including single-delay ASL) and FDG-PET during presurgical evaluation. Lesions, perilesional perfusion, and metabolic abnormalities were segmented and coregistered. Spatial overlap was quantified using DICE scores to compare functional modalities with each other (perfusion-to-metabolism: DICEP-to-M), with the lesion (metabolism-to-lesion: DICEM-to-L; perfusion-to-lesion: DICEP-to-L), and, in seizure-free children, with the resection cavity (lesion-, metabolism-, perfusion-to-resection cavity: DICEL-/M-/P-to-Post). We also assessed the temporal stability of perilesional ASL abnormalities and the presence of remote ipsilateral/contralateral abnormalities. Equivalence testing used the Wilcoxon signed-rank equivalence test with FDG-PET as reference; Cohen &#x3ba; quantified agreement for remote abnormalities. Fifteen children were included; median ages at FDG-PET and ASL were 7.7 and 7.5&#x2009;years; 53% required sedation. Median perilesional volumes were 11&#x2009;339&#x2009;mm3 (FDG-PET) and 10&#x2009;791&#x2009;mm3 (ASL); both were larger under sedation (p&#x2009;<&#x2009;.001). Perilesional volumes were equivalent (p&#x2009;=&#x2009;.037). Median DICEM-to-L and DICEP-to-L were .3 and .4; equivalence was confirmed (p&#x2009;<&#x2009;.001). Median DICEP-to-M was .7, indicating strong ASL-FDG-PET concordance. In seizure-free children following surgery, DICEM-to-Post and DICEP-to-Post were both .6 and equivalent (p&#x2009;=&#x2009;.01). ASL findings were stable over time (DICE = .27-.75; n&#x2009;=&#x2009;4 with repeat ASL). Remote ipsilateral abnormalities were common (ASL 73%, FDG-PET 67%; &#x3ba;&#x2009;=&#x2009;.53), with poor contralateral agreement (&#x3ba;&#x2009;=&#x2009;.12). ASL yielded perilesional findings equivalent to FDG-PET and showed comparable overlap with the resection cavity in seizure-free children. As a radiation-free technique embedded into routine MRI, ASL reduces logistics and avoids an additional sedation session. These findings support ASL as a practical alternative to FDG-PET for presurgical workup, especially when FDG-PET access is limited.

Congenital melanocytic nevus syndrome is a disorder characterized by postzygotic, mosaic NRAS Proto-Oncogene, GTPase mutations. Clinical manifestations include melanotic skin lesions and, optionally, central nervous system melanosis typically noted during early infancy. Affected individuals have an increased risk of developing malignant melanomas at an early age. We report a child with neurocutaneous melanosis due to this syndrome, who had innumerable nevi at birth and diffuse leptomeningeal thickening. He developed increased intracranial pressure at 4&#xa0;weeks of age. The nucleoside analogue azacitidine and the Mitogen-Activated Protein Kinase, Kinase inhibitor trametinib were started at 6&#xa0;weeks of age resulting in rapid reduction of leptomeningeal thickening. At 53&#xa0;months of age, the patient still takes trametinib and has met all developmental milestones. There has been no evidence of melanoma, and he exhibits minimal residual leptomeningeal changes. To our best knowledge, this is the first child with this syndrome who has undergone successful therapy to reduce leptomeningeal thickening.

Renal artery stenosis is an uncommon cause of secondary hypertension in infants and is rarely related to infectious etiologies such as cytomegalovirus (CMV). We report a 5-month-old infant who was admitted for afebrile status epilepticus and found to have severe hypertension. Imaging revealed focal stenosis of the right renal artery. Virological investigations confirmed active CMV infection. The patient was treated with intravenous ganciclovir, leading to normalization of blood pressure and complete radiological resolution of the stenosis within 6 weeks. CMV has a known endothelial tropism and may induce inflammatory vascular lesions. Renal artery involvement outside the transplant setting is exceptionally rare. This case highlights a reversible inflammatory vasculopathy related to CMV infection. CMV infection should be considered in infants presenting with unexplained renal artery stenosis. Early antiviral therapy may lead to complete reversibility without invasive intervention.

Growing evidence for reperfusion therapies in pediatric acute ischemic stroke (AIS) increases the importance of timely diagnosis within treatment windows. We therefore aimed to describe 24-year trends and associated factors of diagnostic delay. We conducted a nationwide retrospective cross-sectional study including 314 children aged 28 days to 16 years from the Swiss Neuropediatric Stroke Registry (2000-2023). The primary outcome was time from stroke onset to diagnosis (TOD). Trends for diagnoses beyond intravenous thrombolysis (&#x2265;4.5 hours) and thrombectomy (&#x2265;24 hours) windows were assessed with multivariable logistic regression, and for continuous TOD with robust linear regression. Prespecified covariates were retained in multivariable models if associated with the outcome in univariable analyses. Analyses were stratified by AIS onset location (out-of-hospital and in-hospital). Median TOD was 26.9 hours (interquartile range, 10.1-91.5) between 2000 and 2023. During this period, the proportion diagnosed beyond the thrombolysis window decreased significantly in the overall cohort from 90.9% to 77.5% (adjusted odds ratio per calendar year 0.94 [95% CI, 0.88-1.00]) and in out-of-hospital AIS from 88.1% to 74.1% (adjusted odds ratio, 0.91 [0.84-1.00]). No significant change was observed beyond the thrombectomy window diagnoses. Continuous TOD decreased significantly only in in-hospital AIS (&#x3b2;=-4.3 [-7.2 to -1.5]). Older age (&#x3b2;=-1.8 [-2.9 to -0.8]), higher pedNIHSS (&#x3b2;=-1.2 [-2.1 to -0.4]), and facial palsy (&#x3b2;=-19.4 [-30.2 to -8.5]) were associated with shorter TOD, and nonspecific symptoms (&#x3b2;=110.0 [72.5-147.5]) with longer TOD. Out-of-hospital TOD was shorter when patients presented to a stroke center compared with other presentation sites. Posterior-stroke symptoms were associated with diagnoses beyond the thrombolysis window. Despite decreasing proportions of beyond-thrombolysis window diagnoses in out-of-hospital AIS and decreasing TOD in in-hospital AIS, most diagnoses occur beyond reperfusion windows. Goals to decrease delay include raising awareness of posterior-stroke signs and AIS in younger children, and strengthening direct-to-stroke center pathways.

Leigh syndrome (Leigh) is an untreatable mitochondrial disorder characterized by lactic acidosis and basal ganglia and midbrain pathology, leading to psychomotor regression and early death. We previously uncovered impaired neuronal morphogenesis in Leigh cerebral organoids carrying SURF1 gene variants. Leveraging this phenotype, we here develop a deep learning algorithm tailored for cell type-specific drug repurposing screening. In parallel, we perform a survival drug screen in a yeast model of Leigh. The two approaches independently converge on azole compounds, two of which - talarozole and sertaconazole - rescue neuronal morphogenesis in Leigh neurons and lower lactate release and improve growth rate in Leigh midbrain organoids. Mechanistically, these compounds modulate the retinoic acid pathway and membrane-associate lipid metabolism. The findings highlight azoles as promising candidates for Leigh and demonstrate the potential of combining in silico screens with human brain organoids as new approach methodologies (NAMs) to advance&#xa0;the discovery of therapeutics addressing rare neurodevelopmental disorders.

Magnetic resonance imaging (MRI) is the imaging of choice to diagnose brain injury and prognosticate long-term neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy (HIE). Independent scoring from Neuroradiology and Neonatology fellows was obtained for 97 brain MRIs for HIE after teaching. Analysis for reliability was compared against a gold standard of an experienced Neuroradiologist. There was good (intraclass correlation coefficient: 0.87) reliability for the Neonatology fellow and excellent (intraclass correlation coefficient: 0.94) reliability for the Neuroradiology fellow compared with the Neuroradiologist. This suggests that the scoring system used has good interobserver reliability between less experienced readers compared with an experienced reader.

Neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis (NDEEMA) represents the most severe end of the gain-of-function (GOF) SCN1A disorder spectrum. Sporadic cases of congenital arthrogryposis have also been reported in individuals with SCN2A-, SCN3A-, and SCN8A-related developmental and epileptic encephalopathy. Here, we investigated whether NDEEMA occurs in other brain-expressed sodium channelopathies and characterized its features. Individuals with the clinical phenotype of NDEEMA were identified through internal databases, an international network of epileptologists and geneticists, and the literature. Their clinical and genetic information was analyzed. A literature survey was conducted to review studies describing the functional effects of the pathogenic variants. Of 46 NDEEMA individuals, 25 harbored variants in SCN1A, 13 in SCN2A, one in SCN3A, and seven in SCN8A. Thirty-five different pathogenic/likely pathogenic missense variants were identified, all of which clustered in evolutionary conserved paralogous NaV positions. Five individuals died in utero. Thirty-nine of 41 (95%) liveborn individuals developed neonatal epilepsy with tonic seizures and/or apnea. Thirty-one individuals tried sodium channel blockers, of whom 21 (68%) experienced seizure reduction. All individuals for whom information was available developed movement disorders, with myoclonus, dystonia, and tremor being the most common features. Literature review of functional studies revealed that nine NDEEMA variants, and the corresponding paralogues of 16 additional NDEEMA variants, have been biophysically characterized as GOF. This study expands the phenotype of NDEEMA from SCN1A to its paralogue sodium channel genes expressed in the brain: SCN2A, SCN3A, and SCN8A.