Journal of Child Neurology

Brain monoamine vesicular transporter deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the SLC18A2 gene, which encodes vesicular monoamine transporter 2 (VMAT2). VMAT2 is essential for packaging neurotransmitters such as dopamine, serotonin, norepinephrine, and histamine into synaptic vesicles. Its deficiency results in disrupted neurotransmission and a characteristic clinical syndrome involving developmental delay, hypotonia, movement disorders, and autonomic dysfunction. We report a novel homozygous frameshift variant, Chr10:119014792dupC (p.Phe238LeufsTer7), identified in a 5-month-old male from a consanguineous family, who presented with severe hypotonia, oculogyric crises, and developmental delay. This variant expands the known genotypic spectrum of SLC18A2-related disease. Our findings underscore the importance of early genetic testing in infants with unexplained movement disorders and support a multidisciplinary approach to care. We also compare this case to related neurometabolic disorders with overlapping clinical features and with prior SLC18A2 mutation-related disorder.

Limited and variable case exposure during pediatric neurology rotations may leave some clinically important presentations underrepresented within a single rotation window. We evaluated whether augmented reality–supported learning environments (ARLEs) integrated into the rotation improve medical students’ cognitive achievement beyond the standard curriculum. In this prospective cluster-randomized controlled pretest-posttest study, 102 students were allocated by 4 rotation subgroups (clusters) to an intervention group (standard curriculum plus ARLEs delivered via a mobile application; n = 51) or a control group (standard curriculum only; n = 51). Achievement was assessed using a 30-item multiple-choice achievement test and analyzed with a 2 × 2 mixed-design analysis of variance and Welch t test (α=.05). Baseline knowledge did not differ between groups (P = .405). Both groups improved, but posttest scores were higher in the intervention group, t(90.9) = 5.65, P < .001, d = 1.12. The time × group interaction was significant and strong, F(1, 100) = 33.38, P < .001, partial η²=0.250, indicating greater gains with ARLEs. ARLEs integrated into the pediatric neurology rotation may provide a potentially useful short-term adjunct to, rather than a replacement for, face-to-face instruction.

Neonatal hypoxic-ischemic encephalopathy (HIE) contributes to perinatal morbidity and mortality. The influence of racial, ethnic, and socioeconomic factors on long-term outcomes is not well understood. This single-center retrospective study examined associations between these factors and long-term neurodevelopment in infants with HIE. Demographic and clinical data were obtained via chart review. Racial and ethnic minority (REM) status was self-reported. Socioeconomic factors included Social Vulnerability Index (SVI) and insurance type. Motor and language delays were determined by physician assessment or standardized testing. Logistic regressions assessed associations between development, REM, and socioeconomic factors while controlling for clinical covariates. Among 211 infants, 117 (56%) were REM. Motor delay occurred in 49 (23%) and was not associated with REM, SVI, or insurance. Language delay occurred in 59 (28%) and was associated with REM status although the association lessened when insurance was included. These findings suggests that societal factors may underlie language developmental disparities after HIE.

Anxiety commonly co-occurs with childhood epilepsy, yet treatments targeting both are limited. Epidiolex (cannabidiol, CBD) is an FDA-approved treatment for seizures associated with rare pediatric epilepsies and may have anxiolytic effects. We evaluated its effects on seizures and anxiety in pediatric patients with refractory epilepsy, representing diverse seizure etiologies and circulating endocannabinoids and related biomarkers. Twelve participants (12.17 ± 5.17 years; 6 female) initiated Epidiolex for 4-6 weeks. Caregivers completed pre- and post-treatment seizure diaries; validated anxiety and quality-of-life assessments; and plasma endocannabinoids, related lipids, and CBD metabolites—including 7-hydroxycannabidiol (7-OH-CBD)—were measured. Post-treatment, 73% of caregivers reported improvements in anxiety and seizure frequency with minimal side effects and improved sleep. Plasma 2-arachidonoylglycerol increased from baseline to study end, with greater elevations in those with lower baseline concentrations. Plasma 7-OH-CBD increased from baseline to study end, confirming systemic CBD exposure. Epidiolex may provide anxiolytic benefits across pediatric epilepsy, potentially involving endocannabinoids.

The classic ketogenic diet, a high-fat, adequate-protein, very-low-carbohydrate therapy, is a widely used, mainstream, standard of care in the management of refractory epilepsy. It is difficult to imagine that the first poster presentation in history on this treatment at the American Epilepsy Society Annual Meeting was 30 years ago. This review highlights the resurgence of this nonpharmacologic treatment, invigorated by multicenter, collaborative research into its basic mechanisms of action, ideal clinical indications, flexible methods of initiation and maintenance, and expansion of use to infants, adults, and conditions other than epilepsy.

Dravet syndrome (DS), a severe developmental and epileptic encephalopathy often linked to SCN1A mutations, is defined by a profound thermosensitivity, making fever and hyperthermia potent seizure triggers. This review synthesizes evidence-based strategies and expert consensus for the management of fever and vaccination in children with DS. Management diverges from standard pediatrics, prioritizing aggressive pyrexia control through early antipyretics, physical cooling, and prophylactic benzodiazepines. Proactive strategies are also crucial for non-febrile hyperthermia from triggers like hot baths and overexertion. Although vaccinations can precipitate an initial seizure, they neither cause DS nor worsen its prognosis. Immunization remains strongly recommended, with prophylactic antipyretics advised as a key risk-mitigation measure. Importantly, current management strategies are based primarily on expert consensus rather than controlled clinical trials. Bridging expert consensus with clinical evidence is essential to reduce morbidity and improve long-term quality of life in DS.

Periodic reanalysis of genomic data plays a pivotal role in refining variant interpretation and resolving previously undiagnosed cases, particularly in the context of rare diseases. We report a female patient presenting with global developmental delay, drug-resistant epilepsy, optic atrophy, congenital heart defects, and craniofacial dysmorphism. An initially deprioritized heterozygous NOTCH1 variant (NM_017617.5: c.4787T>C; p.Leu1596Pro), previously associated with isolated cardiac phenotypes, was later reclassified as likely pathogenic following annual reanalysis through our institutional pipeline. Trio-based whole exome sequencing confirmed the variant's de novo origin, and emerging literature published in 2024 expanded the phenotypic spectrum of NOTCH1-related disorders to include neurologic, ocular, musculoskeletal, craniofacial, and integumentary features—closely mirroring the patient's presentation. This diagnostic refinement enabled tailored clinical management and informed genetic counseling. This case underscores the clinical utility of systematic genomic reanalysis in rare disease diagnostics, where evolving knowledge enables reclassification of previously uncertain variants. Moreover, this case adds to the growing body of evidence, broadening the recognized clinical and molecular landscape of NOTCH1-related disorders.

Nonketotic hyperglycinemia (NKH) is a rare genetic disorder with a global incidence of 0.4 to 1.3 per 100 000 live births with regional variation. We sought to estimate the regional birth incidence and describe the clinical and genetic features of NKH in central and Appalachian Kentucky. Fifteen patients met standard diagnostic criteria for NKH; 13 were born in Kentucky, yielding an estimated birth incidence of 2.53 per 100 000 live births (13/513 419; 95% CI 1.35-4.33). Of those with available genetic data (n = 9), 8 carried GLDC variants, with 6 having the c.1166C>T (p.A389V) variant. We found a higher incidence of NKH in central and Appalachian Kentucky compared to global estimates, with local enrichment of the p.A389V variant. These findings highlight the need for clinician awareness and further research to inform regional screening and management.

Knowledge in the spectrum of epidermal nevi and epidermal nevus syndrome has been elaborated on and expanded rapidly through the years. In this review, we provide a comprehensive overview of the neurologic manifestations of epidermal nevus syndromes (ENS), with a particular focus on epilepsy, which represents one of the most disabling and frequent systemic complications. Although ENS comprises a heterogeneous group of neurocutaneous syndromes unified by the presence of epidermal hamartomas and extracutaneous involvement, the relationship between genotype, cutaneous phenotype, and seizure phenotype remains incompletely understood. We systematically outline the epileptogenic potential of the 10 well-characterized ENS subtypes, highlighting the distinct seizure types, electroencephalographic findings, and associated structural brain anomalies such as hemimegalencephaly, cortical dysplasia, and neuronal heterotopias. Particular emphasis is placed on subtypes with a high seizure burden, including keratinocytic epidermal nevus syndrome, nevus sebaceus syndrome, phakomatosis pigmentokeratotica, nevus comedonicus syndrome, and angora hair nevus syndrome. For each, we examine the available evidence on seizure semiology, electroencephalographic correlates, radiologic features, and outcomes. Additionally, we review current management strategies, including both medical and surgical approaches to epilepsy in ENS, and discuss the emerging role of molecular targeted therapies. Through this review, we aim to underscore the importance of early diagnostic evaluation in patients presenting with epidermal nevi and to support multidisciplinary approaches for seizure control and long-term neurologic outcomes.

Prechtl's General Movement Assessment (GMA) and the Hammersmith Infant Neurological Exam (HINE) are recommended for early detection of cerebral palsy (CP) in high-risk infants. These tools are well validated in premature infants but less well studied in the high-risk term population. We sought to determine the added prognostic value of incorporating GMA and HINE assessment in term- and near-term infants with hypoxic ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). In this retrospective and prospective pilot case series of 20 neonates with HIE that were treated with TH, we analyzed the associations between HIE severity, early clinical course, electroencephalography (EEG) background, and magnetic resonance imaging (MRI) injury pattern, with performance on the GMA and HINE. Absence of fidgety movements was significantly associated with severity of EEG background and was most concordant with gray matter injury score on MRI. There were no significant associations between 3-month HINE scores and any clinical measure. Three-month HINE scores were overall lower than published norms for age and tended to normalize over time in patients that had normal fidgety movements. Although the generalizability of these findings is limited because of the small sample size and lack of long-term outcomes, they support incorporation of the GMA as an early outcome in the follow-up of this population for accurate early identification of CP, which is complemented by longitudinal HINE scores for further delineation of severity and topography.

Nearly one-third of patients with epilepsy are unable to achieve adequate seizure control with medication alone. Responsive neurostimulation (RNS) of thalamic nuclei is a relatively new option for the treatment of drug-resistant epilepsy (DRE). Here the authors present a complex case of a pediatric patient with DRE secondary to left hemimegencephaly after anatomic hemispherectomy and vagal nerve stimulation. One year after undergoing right centromedian (CM) and anterior nucleus (ANT) thalamic RNS, the patient achieved a greater than 50% seizure frequency reduction. The technical challenges of targeting of the CM and ANT nuclei due to the lack of contralateral hemisphere and thalamus are discussed. Ultimately, the use of direct targeting with advanced MRI sequences allowed for successful targeting despite the challenges posed by the patient's unique anatomy.

SHQ1-related neurodevelopmental disorder is a rare autosomal recessive condition linked to disrupted ribosome biogenesis, telomerase activity, and RNA modification. Among the few reported cases, typical clinical presentations consist of early-onset hypotonia, seizures, movement disorders, and progressive neurologic impairment. We present a male patient who, at 4 months, displayed global developmental delay, hypotonia, feeding difficulties, and impaired cervical motor control. He progressed to exhibit choreiform movements and oromotor hypotonia. Extensive metabolic and genetic workup was unrevealing; whole exome sequencing (WES) in 2022 was nondiagnostic, and supportive measures were continued. In 2024, WES reanalysis identified compound heterozygous variants in SHQ1, NM_018130.4:c.523G>T (p.Gly175Cys) and NM_018130.4:c.828_831del (p.Glu276fs*12), both now recognized as pathogenic. Brain MRI was normal, and cerebrospinal fluid neurotransmitter analysis revealed reduced homovanillic acid, suggesting dopaminergic pathways. This case expands the clinical spectrum of SHQ1-related disorder by illustrating a milder phenotype with functional developmental gains and emphasis on the diagnostic value of WES reanalysis.