Two adolescent female patients, who were referred independently of each other, presented with progressive gait disturbances that worsened over the course of the day. Symptoms began in early childhood with foot instability and progressed to clubfoot, pain, and limping. MRI of the neuroaxis did not reveal any central nervous system abnormalities. Genetic testing identified the same intronic variant of uncertain significance in GCH1 in both individuals. Subsequent investigations uncovered a previously unrecognized familial relationship between the two patients, belonging to an extended family in which six women were affected by a gait disorder. Previous diagnoses within the family included childhood-onset spasticity and psoriatic arthritis. The familial GCH1 variant was confirmed in all symptomatic individuals, as well as in two asymptomatic female carriers. RNA sequencing revealed a splicing defect caused by the GCH1 near splice-site variant. A robust clinical response to L-DOPA therapy confirmed the diagnosis of DOPA-responsive dystonia (DRD) in this family. This case highlights the phenotypic variability of DRD, which frequently leads to misdiagnosis and delays in appropriate treatment. Careful assessment of family history and recognition of diurnal symptom fluctuations are key to identifying this highly treatable condition.

Consensus on the first-line treatment of pediatric-onset multiple sclerosis (POMS) remains unresolved. Recently, dimethyl fumarate (DMF) and anti-CD20 therapies have been among the favorable options for pediatric multiple sclerosis (MS).This study aimed to determine the effectiveness and safety of DMF versus anti-CD20 therapies for POMS.We conducted a retrospective cohort study from July 2012 to July 2022 in the Isfahan MS clinic. MS cases under the age of 18 years old who received DMF or anti-CD20 agents as first-line treatment and were followed for at least 12 months were included.About 124 POMS cases were screened, of which 39 met the inclusion criteria. About 23 patients received DMF, while 16 patients received anti-CD20 (rituximab or ocrelizumab). The median (interquartile range, IQR) annualized relapse rate (ARR) decreased significantly (both with  < 0.0001) from 2.63 (0.68) to 0.0 (1.0) in the DMF group and from 2.89 (1.39) to 0.0 (1.0) in the anti-CD20 group. The median (IQR) expanded disability status score insignificantly changed from 1.0 (1.0) to 1.0 (0.5) in the DMF group, while it changed from 1.25 (1.0) to 1.0 (0.5) in the anti-CD20 group. After 12 months of follow-up, 12/16 in the anti-CD20 group and 17/23 in the DMF group were relapse-free. None of the treatment outcomes were different between the two treatment cohorts. Our study also assessed adverse events (AEs).While subject to replication in future clinical trials, both DMF and anti-CD20 therapies had a significant effect on reducing ARR and disease activity with an acceptable safety profile, but in our study, there were no differences in their efficacy.

Disease-causing variants in are associated with a spectrum of epilepsy and/or movement disorders, often with additional developmental issues or intellectual impairment. Monoallelic gain-of-function variants often lead to paroxysmal nonkinesigenic dyskinesia (PNKD). While the treatment mechanism is unknown, dextroamphetamine and its prodrug lisdexamfetamine have been shown to successfully control the debilitating PNKD with up to several hundred daily incidents in one patient with the (NM_001161352.2) c.1606A > C p.(Asn536His) and six patients with the c.3158A > G p.(Asn1053Ser) variant. Via exome sequencing, a monoallelic c.2367C > A, p.(Asp789Glu) variant was detected in a 7-year-old girl with daily behavioral arrests, tremors, and drop attacks/PNKD occurring every 8 weeks. The girl had moderate difficulties in mainstream school and experienced challenges in her social life as she was easily fatigued. Additionally, she was heat-intolerant and unable to sweat. Lisdexamfetamine treatment led to cessation of the neuro(psycho)logical symptoms, better functioning in daily life and at school during more than 2 years of follow-up. This report illustrates the importance of an exact, genetic diagnosis for successful individual treatment. It adds another previously unreported variant in . Furthermore, this case increases the evidence for a broader treatment effect of lisdexamfetamine for variants beyond its known effects on the control of muscle tone, in this case illustrated by better social interaction, improved attention/school performance, and mood. Finally, the previously unreported findings of heat intolerance and inability to sweat may extend the phenotypic spectrum associated with variants.

The term "neuromonitoring" denotes several methods that are used to monitor the state of the central nervous system. It is mainly used in intensive care units to mitigate the limitations of the clinical neurological examination, which arise in the context of critical illness, sedation, and neuromuscular blockade. In the pediatric intensive care units, neuromonitoring methods are increasingly used across all age groups. This article aims to give an overview of the four most frequently used technical noninvasive neuromonitoring modalities (electroencephalogram, near-infrared spectroscopy, transcranial Doppler, and automated pupillometry) and the evidence for their use in three clinical scenarios: seizures, increased intracranial pressure, and stroke.

(nitrogen permease regulator-like 3) variants are associated with focal epilepsy syndromes, including sleep-related hypermotor epilepsy (SHE) and familial focal epilepsy with variable foci (FFEVF), with or without focal cortical dysplasia (FCD). The gene encodes a protein that forms the GATOR1 complex, which regulates the mTOR signaling pathway.To characterize the epilepsy phenotype associated with , assess treatment strategies, and evaluate patient prognosis.We conducted a multicenter, retrospective study using an online questionnaire to collect clinical data on seizure onset, crisis-like seizure exacerbations, MRI findings, neuropsychological assessment, treatment, and genetic variants. Variants were classified per ACMG guidelines. The study was part of the Network for Therapy in Rare Epilepsies (NETRE).Data from 37 patients with -associated epilepsy were analyzed. Mean age at seizure onset was 3.7 years (median with interquartile range [IQR] 1.3-4.9). Over 1 to 45 years of follow-up (mean 13.6, IQR 5.4-18), 21/37 (57%) experienced crisis-like seizure exacerbations. MRI abnormalities were present in 10/36 (28%) cases: 8 FCD, 1 hippocampal sclerosis, and 1 hippocampal asymmetry. Persistent focal epileptiform discharges were present on serial EEGs in 20/37 patients (54%). Highest drug response rates were seen with lacosamide, followed by clobazam, carbamazepine/oxcarbazepine, and lamotrigine. Epilepsy surgery ( = 8) led to seizure freedom in four and significant reduction in one case.Crisis-like seizure exacerbations were common in NPRL3-associated epilepsy. Sodium channel blockers showed notable efficacy. Epilepsy surgery was beneficial even in MRI-negative cases. No distinct genotype-phenotype correlation was identified.

The elucidation of the molecular basis of monogenic epilepsies is advancing rapidly. For clinicians, knowing not only the affected gene, but also the patient's exact genetic variant and gaining insight into its effect on RNA, protein, cell, and organism level is becoming increasingly important. As different variants in the same gene can lead to opposing functional effects, an understanding of their nature is crucial for informed treatment choices. Correctly counseling patients, parents, and families regarding the patient's prognosis and the risk to other family members of being affected or having an affected child is only possible with detailed knowledge of the genetic and functional alterations underlying the condition. This review aims to provide a comprehensive overview of genetic variants and their effects, following them from the DNA to the organism level. Protein-level outcomes, such as gain- and loss-of-function mechanisms as well as dominant-negative effects, will be illustrated using examples from monogenic epilepsies. Their downstream impact on cellular function and phenotype will be traced to shed light on the mechanisms by which different variants in the same gene can result in diverging clinical presentations. In doing so, we illustrate key genetic concepts relevant to clinical practice to help inform clinical interpretation of genetic variants and facilitate therapeutic decision-making.

We report the clinical course of a 13-year-old male patient with a history of focal structural epilepsy starting at the age of 18 months due to focal cortical dysplasia (FCD) IIa and undetected genetic arrhythmia syndrome due to a pathogenic variant in sodium voltage-gated channel alpha subunit 5 (SCN5A) gene at that time.High-resolution MRI detected FCD in the left suprabasal margin matching the EEG focus. At the age of 12 years, epileptological-surgical evaluation led to lesionectomy, which resulted in seizure freedom postoperatively. Months later, the patient experienced an episode of leg pain, increased tone of the upper body, and subsequent cardiac arrest. Resuscitation efforts were successful, leading to survival with hypoxic brain injury. Unexpected cardiac arrest not in line with the previous seizure semiology led to further cardiological examinations including electrophysiology and genetic testing, revealing a pathogenic SCN5A variant associated with arrhythmia syndromes. A two-chamber implantable cardioverter defibrillator (ICD) was implanted. To our knowledge, this combination of diseases has not been reported yet, a causal relationship stays speculatively. Nevertheless, it highlights the complexity of coexisting structural and genetic conditions that can only be detected in alertness to uncommon conditions and via an interdisciplinary approach.

To analyze the association between the growth of the central and peripheral nervous systems (PNS) in children aged 0 to 3 years.A total of 40 participants were included in this cross-sectional study to analyze the association between the growth and development of the peripheral and central nervous system (CNS). Using high-resolution ultrasound, the cross-sectional area (CSA) of the median nerve was measured at three locations (wrist, forearm, and upper arm) representing the development of the PNS and then compared with the head circumference (HC) as a proxy for the CNS development.There was a significant correlation between HC and the CSA of the median nerve at the three measured locations. When looking at adjusted linear regression models, HC appeared to be a stronger predictor of nerve CSA size than age.The observed association between nerve CSAs and HC growth indicates a parallel size increase. This association may have clinical relevance because both HC and nerve CSA could potentially serve as complementary markers for neurodevelopmental monitoring, that is, myelination, and may contribute to the early identification of atypical developmental patterns, though confirmatory longitudinal data are required.

The diagnosis of peripheral polyneuropathy in children and the differential diagnosis among its various forms often present a challenge, also because electrodiagnostic studies can be painful and sometimes yield inconclusive results. This systematic review examines the role of nerve ultrasound (-US) in the diagnosis and follow-up of pediatric polyneuropathies. We searched PubMed and Embase from 1975 to April 1, 2025. Included studies assessed patients aged ≤ 18 years with clinically and neurophysiologically confirmed polyneuropathy, providing pediatric-specific qualitative or quantitative -US findings. Eighteen studies met the inclusion criteria. Six focused on acquired inflammatory polyneuropathies (three on Guillain-Barré Syndrome [GBS], three on Chronic Inflammatory Demyelinating Polyneuropathy [CIDP]), eight on Charcot-Marie-Tooth disease (CMT), two on lysosomal storage disorders, one on Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), and one on mixed etiologies. Most ( = 7) were case reports. Cross-sectional area and nerve enlargement (NE) distribution were the main parameters evaluated. Marked, diffuse NE was found in demyelinating CMT and lysosomal disorders; CIDP showed diffuse and multifocal NE; GBS presented mild and proximal NE. No NE was reported in axonal CMT or ARSACS. Few studies assessed echogenicity or fascicular structure; none evaluated vascularization. -US shows promise in differentiating demyelinating conditions such as CMT, CIDP, GBS, and certain metabolic syndromes in children. However, further age-matched control studies are needed, given that nerve growth and myelination peak between 15 and 17 years. Future research should explore -US as an early diagnostic, screening, and follow-up tool.

Prevalence of seizures is 1 to 5/1,000 neonates. The most common causes of neonatal seizures are hypoxic-ischemic encephalopathy (HIE), vascular events (hemorrhages, stroke), and infections. We assessed prevalence and etiology of seizures defined according to the recent Brighton and International League of Epilepsy (ILAE) criteria in a neonatology monocenter cohort.In a retrospective cross-sectional cohort study of all 12,154 neonates born in our three maternities from January 1, 2022 to December 31, 2023 seizures were categorized by frequency, etiology, risk profile, semiology, and EEG. A total of 19 neonates (male:  = 11 [57.9%]; full-term:  = 11 [57.9%]; preterm very low birth weight [VLBW]:  = 6 [31.6%]; preterm >1,500 g birth weight:  = 2 [10.5%]) were identified.In 19/12,154 neonates, seizures were confirmed by application of the ILAE criteria. Preterm VLBW was found in 174 neonates with birth weight <1,500 g. Seizure incidence was 1.6/1,000 in all neonates and 3.4% in VLBW infants. HIE was the most frequent etiology in term infants (30.8%), followed by vascular events in preterm >1,500 g and term infants (30.8%). Vascular events were the most common cause in preterm VLBW infants (83.3%). Whole exome sequencing (WES) was performed in four cases (21.1% of neonates with seizures).Incidence of neonatal seizures in our center is in the lower range and leading seizure etiologies are comparable to the literature. Early recognition of neonatal seizures including the detection of electrographic-only seizures and early WES to identify rare genetic defects possibly offering tailored treatment options have the potential to further raise the standard of neonatal care and improve neurodevelopmental outcome.

The congenital disorders of glycosylation (CDG) encompass >190 multiorgan disorders with predominantly neurodevelopmental phenotypes with no causative treatment available. The glycoprotein biotinidase (BTD) provides biotin, an essential cofactor for carboxylases in ubiquitous metabolic pathways. Individuals with (partial) BTD deficiency (BTDD) and CDG patients show overlapping phenotypes like movement disorders, seizures, and neurodevelopmental issues. Biotin is a water-soluble, inexpensive, and safe food supplement. Patients with primary BTDD respond well to oral biotin supplement. We here explore secondary BTDD and the effect of biotin supplementation in PMM2-CDG in an initial open-label study.BTD activity in dried blood spots from 29 individuals with PMM2-CDG indicated a mean reduction to 27% (range: 23.0-40.5%) at group level. Patients (mean: 19.6 ± 11.9 years) were supplemented with 10 mg biotin daily for 12 months. The parents/caretaker reported positive responses in 62 to 69% of patients across seven (performance, social, at home, self-control, self-care, leisure, health) of the nine categories covered by the Adaptive Behavior Assessment System-II (ABAS-II) questionnaires. The reported positive effect of biotin supplementation differed between age groups, ranging from 54% (16-43 years) via 62% (2-5 years) to 80% (6-13 years). Its effect was reported to be the highest in the moderate to severely affected patient subgroups, with significant improvements in home functioning, health, performance, leisure, self-control. No adverse effects were reported.Given the absence of other treatments, the supportive effect of Biotin in PMM2-CDG deserves further exploration.

This study aimed to investigate whether the site of gene mutations is linked to motor functions in children with Duchenne muscular dystrophy (DMD).A total of 58 children with DMD, aged between 7 and 16 years, were divided into two groups according to the site of mutation (proximal or distal). Motor functions of the groups were compared.The physical and demographic characteristics of two groups were similar ( > 0.05). Distal group had significantly worser Brooke Lower Extremity Functional Classification (BLEFC) (median 3) and D2 score of Motor Function Measure (MFM-32/D2) (mean 86.78 ± 19.83) than proximal group [BLEFC, median 1; MFM-32/D2, mean 93.77 ± 14.89] ( ≤ 0.05). There was no difference in timed performance tests and Four Square Step Test between two groups ( > 0.05).Considering that mutations in the distal site of the DMD gene may lead to poorer motor function, performance outcomes, dynamic balance and functional status compared to proximal mutations, it is important to take the mutation site into account in the evaluation and intervention of children with DMD. Early recognition of the mutation site may help professionals implement timely and proactive strategies to maintain motor functional abilities for a longer duration.

Epilepsy significantly impacts the health-related quality of life (HRQoL) of children and adolescents (CaA). This study aimed to assess HRQoL in pediatric epilepsy patients compared to their healthy peers, using both self- and proxy-reports, and to identify specific HRQoL domains affected by epilepsy.A single-center, cross-sectional study was conducted in Munich between October 2021 and June 2023. HRQoL was assessed in 139 patients aged 3 to 17 years with medically diagnosed epilepsy using age-adapted, validated KINDL© questionnaires, completed by the patients and one caregiver. The questionnaire comprised six subscales: "Physical Well-being," "Emotional Well-being," "Self-Esteem," "Family," "Friends," and "Everyday Functioning." Control values from healthy CaA aged 7 to 17 were drawn from the BELLA and KiGGS studies. Welch tests and Wilcoxon signed-rank tests were used for statistical comparisons.Compared to their healthy peers, CaA with epilepsy reported significantly lower HRQoL overall, particularly in the subscales "Physical Well-being," "Emotional Well-being," and "Friends." No significant differences were observed in the "Family" subscale. Interestingly, self-reports revealed a trend toward higher "Self-Esteem" scores among CaA with epilepsy, though this did not reach statistical significance. No significant differences emerged between self- and proxy-reported total HRQoL scores.Epilepsy in CaA is associated with reduced HRQoL, especially in physical, emotional, and social domains. Stable family support can cushion some negative effects. In particular, the unexpectedly high results in the area of self-confidence should be the subject of future research.

The timing and indications for endoscopic third ventriculostomy (ETV) in pediatric hydrocephalus are debated. We evaluated head circumference growth as a predictor of ETV success in children with posthemorrhagic hydrocephalus (PHH).We conducted a retrospective review of 303 patients who underwent ETV from 2012 to 2021, focusing on those with intraventricular hemorrhage (IVH) and PHH. Data were collected from electronic medical records. A univariate logistic regression analyzed predictors of ETV failure, with head circumference growth rate calculated from preoperative occipito-frontal circumference measurements.Among the 303 patients, 24 had IVH and PHH. Mean gestational age was 30 weeks, with 58% male, and a mean weight of 4.48 kg at surgery. Notably, 96% ( = 23) had choroid plexus cauterization, and 46% ( = 11) underwent ventriculosubgaleal shunt. Of the 24, 67% ( = 16) required eventual ventriculoperitoneal shunt (VPS) placement, indicating ETV failure. Corrected age at ETV was younger in the failure group (0.69 months) than in the success group (2.56 months,  = 0.020, odds ratio [OR]: 1.04). Mean weight at surgery was lower for the failure group (3.85 kg vs. 5.75 kg,  = 0.036). Duration of preoperative surveillance was 1.94 months for the failure group and 5.25 months for the success group ( = 0.004). Head circumference growth rate was 1.57 mm/day in the failure group compared to 0.85 mm/day in the success group ( = 0.009, OR: 39.9).Younger corrected age, lower weight at surgery, shorter preoperative surveillance time, and faster head circumference growth rate were associated with ETV failure and ultimately VPS placement. Further analysis with a larger cohort may enhance predictions of ETV success rates.