Epilepsy is characterized by widespread structural brain alterations extending beyond the epileptic zone, involving both cortical and subcortical regions. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy have been seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. Here, we systematically investigated sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multi-center cohort of 1,253 epilepsy patients and 1,077 healthy controls. We studied cortical thickness and subcortical volume in two types of epilepsy: temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Both male and female patients with TLE showed widespread cortical and subcortical thinning compared with controls. In GGE, when compared separately to controls, male patients showed only subtle structural alterations, whereas female patients exhibited more widespread structural alterations. Sex-stratified analyses revealed some variation in the extent and distribution of cortical thickness and subcortical volume alterations between male and female patients in both epilepsy cohorts. Yet, we did not find significant sex-by-diagnosis interaction effects in TLE and GGE. Similarly, no significant interaction effects were observed between sex and age of onset or disease duration in either patient group. Overall, although we observed some differences in regional cortical thickness and subcortical volume between male and female patients with epilepsy, we did not find significant sex-by-diagnosis interactions. Our findings indicate that sex differences in behavioral and clinical outcomes of epilepsy may involve biological or functional processes that require further investigation.

MDGA2 encodes a membrane-associated protein that is critical for regulating glutamatergic synapse development, modulating neuroligins (Nlgns), and maintaining excitatory-inhibitory synaptic balance. While MDGA2 functions have been extensively studied in murine and cellular models, its association with human developmental disorders has yet to be established. Through exome sequencing, we identified seven distinct homozygous loss-of-function variants in MDGA2 in nine individuals from seven consanguineous families, all presenting with developmental and epileptic encephalopathy (DEE). Clinically, these individuals exhibited a consistent phenotype including infantile hypotonia, severe neurodevelopmental delay, intractable seizures, along with distinct dysmorphic features. Neuroimaging findings included delayed/incomplete myelination, early-onset brain atrophy, white-matter thinning, basal ganglia volume loss, and small hippocampi. Functional studies of three representative nonsense variants revealed impaired MDGA2 membrane trafficking, disrupted Nlgn1 interaction, and perturbed MDGA2-mediated excitatory synaptic functions in mammalian expression systems and cultured hippocampal neurons. Our findings support the involvement of MDGA2 in a subtype of autosomal-recessive DEE. This not only underscores a loss-of-function pathogenic mechanism but also highlights the previously unrecognized role of MDGA2 in human synaptic development and regulation, significantly expanding our understanding of the genetic architecture of DEEs.

Background:Preterm birth is a critical period for brain development, as extrauterine factors can impair growth and myelination, thereby increasing the risk of neurodevelopmental impairment. Adequate nutrition and rapid weight gain are associated with better cognitive outcomes, and the choice of lipid emulsion during parenteral nutrition may influence these results. SMOFlipid®, enriched with omega-3 long-chain polyunsaturated fatty acids, could reduce inflammation and oxidative stress, potentially lowering bronchopulmonary dysplasia (BPD) risk. This study compared brain maturation at term-equivalent age (TEA) using MRI and neurodevelopment at 2 years in infants receiving either SMOFlipid® or Intralipid®. Methods:In this single-center retrospective observational cohort study, we included all very low birth weight (VLBW) infants admitted to the NICU of our institution between 2017 and 2021. Infants who underwent brain MRI at term-equivalent age and completed neurodevelopmental assessment at 2 years were included, and those with severe brain lesions were excluded. Patients were categorized into two groups based on the lipid emulsion administered during parenteral nutrition. The primary outcome was neurodevelopment at 24 months of corrected age (CA). The secondary outcome was brain maturation assessed by the total maturation score (TMS) on magnetic resonance imaging (MRI). Results:A total of 121 VLBW infants were included and categorized into two cohorts based on the lipid formulation administered: multi-component lipid emulsion (MLE) in 62 and soybean lipid emulsion (SLE) in 49 infants. TMS showed non-statistically significant differences among infants treated with SLE compared with those treated with MLE, as well as in neurodevelopmental outcomes assessed using Griffith's scales. Conclusion:Despite integrating brain imaging and clinical follow-up data, this study could not determine the optimal lipid emulsion for preterm infants.

Introduction: Seizures are the most frequent initial symptom of perinatal stroke. Apnea, a less commonly recognized neurological presentation, is a cessation of breathing lasting >15 seconds or shorter if associated with bradycardia. This study explores a monocentric cohort of newborns with perinatal stroke, emphasizing the role of Isolated Central Apnea (ICA) as a potential early indicator of cerebrovascular insult. Methods: A retrospective review was conducted on newborns (>= 36 weeks GA) diagnosed with MRI-confirmed perinatal stroke at our institution between March 2019 and March 2024. Infants with hypoxic-ischemic encephalopathy (HIE), congenital infections, meningoencephalitis, sepsis, or intrauterine stroke were excluded. Clinical data, neuroimaging findings, EEG/aEEG characteristics, and antiepileptic drug (AED) were analyzed. Results: Of 421 newborns who underwent brain MRI, 27 (6%) were diagnosed with perinatal stroke (16 males; median GA 38.5 weeks; mean BW 3137g). Seizures were the presenting symptom in 18 cases (67%), while 8 cases (30%) exhibited ICA as the first sign and an MRI revealing 5 arterial strokes (63%) and 3 venous strokes (37%). EEG abnormalities were detected in 7/8 (88%) cases, while brain ultrasound was abnormal in 5/8 (63%). AED therapy was required in 7/8 (88%) patients. Conclusions: ICA is an early sign of neonatal stroke in approximately one-third of cases. These findings underscore the importance of brain MRI in the diagnostic workup of persistent apnea in term and early-term neonates.

Background: Heterozygosity for pathogenic variants in the ABCC6 gene has been associated with an increased incidence of cerebrovascular diseases. This study aims to characterize the prevalence and clinical and neuroradiological phenotypes associated with monoallelic and biallelic ABCC6 variants in pediatric and adult patients presenting with arterial ischemic stroke or cerebral small vessel disease (CSVD). Methods: We conducted a retrospective observational study on 143 consecutive patients (48 pediatric, 24 juvenile, 71 adult) diagnosed with ischemic stroke or CSVD of unknown etiology. Clinical and neuroradiological data were collected and analyzed in relation to the identified genetic variants through next-generation sequencing. Results: Among the patients, 16 (11.2%) tested positive for causative variants in the ABCC6 gene, with 11 subjects carrying monoallelic variants and 5 carrying biallelic variants. Patients with biallelic variants exhibited severe and complex vasculopathy, with a high incidence of early ischemic events. In contrast, monoallelic carriers predominantly presented with microvascular disease manifestations, including lacunar strokes and signs of CSVD. Conclusions: The results suggest a significant age-dependent phenotypic divergence in patients with ABCC6 variants, highlighting the impact of heterozygosity on cerebrovascular health. Identifying these variants may enhance risk stratification and inform management strategies in patients with traditional vascular risk factors.

EIPR1 (EARP-interacting protein 1, formerly known as tumor suppressing subtransferable candidate 1 or TSSC1) is a WD40-domain protein that interacts with the EARP (endosome-associated recycling protein) and GARP (Golgi-associated retrograde protein) complexes in the process of delivering endosome-derived transmembrane cargos to the plasma membrane and the trans-Golgi network (TGN), respectively. Additionally, EIPR1 cooperates with EARP in the biogenesis of dense core vesicles. While these properties of EIPR1 were established in cultured cells and model organisms, the physiological and pathological importance of EIPR1 in humans remains to be determined. Here, we report the identification of five EIPR1 homozygous missense variants [NM_003310.5:c.835C>G p.(Arg279Gly), NM_003310.5:c.813C>G p.(His271Gln), NM_003310.5:c.694C>T p.(Arg232Trp), NM_003310.5:c.47G>A p.(Arg16His) and NM_003310.5:c.419T>A p.(Val140Asp)] in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies and neutropenia. Cellular studies using a heterologous transfection system demonstrate that these variants reduce EIPR1 protein levels and its physical interaction with EARP and GARP complexes. Furthermore, we show that the Arg279Gly and His271Gln variants reduce the ability of EIPR1 to promote EARP association with endosomes in non-neuronal cells and dense core vesicle biogenesis in induced pluripotent stem cell-derived neurons. Additionally, skin fibroblasts from one of the Arg279Gly affected individuals shows reduced recycling of internalized transferrin to the plasma membrane (an EARP-deficiency phenotype) and impaired retrograde transport of internalized Shiga toxin B-subunit to the TGN (a GARP-deficiency phenotype) compared with fibroblasts from an unaffected parent. Moreover, these patient fibroblasts exhibit enlarged lysosomes, increased levels of the lysosomal membrane protein LAMP1, and increased levels of the autophagic markers LC3B-II and SQSTM1, all phenotypes previously associated with GARP deficiency. Knockout (KO) of the orthologous eipr1 in zebrafish results in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients. Injection of wild-type human EIPR1 mRNA into eipr1 KO zebrafish rescues these defects, whereas mRNAs encoding the human EIPR1 variants Arg279Gly or His271Gln fail to do so, confirming the impaired activity of these variants. These findings identify EIPR1 as a novel genetic locus associated with a neurodevelopmental disorder and underscore its critical role in endosomal recycling and dense core vesicle biogenesis, processes essential for the development and function of the nervous system.

BORCS5 encodes a subunit of the BLOC-One-Related Complex (BORC), which is known to promote anterograde movement and fusion of lysosomes. We identified 16 individuals from 9 families with bi-allelic BORCS5 variants, revealing a spectrum of neurodevelopmental and neurodegenerative phenotypes. Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 KO in zebrafish resulted in microcephaly, motor deficits, and increased seizure susceptibility, mirroring the patients' clinical presentation. At the cellular level, only BORCS5 PTVs, but not missense variants, led to perinuclear lysosomal clustering and impaired lysosomal axonal trafficking in induced pluripotent stem cell-derived forebrain neurons. However, PTVs and missense variants were associated with reduced lysosomal proteolysis and activity of lysosomal hydrolases glucocerebrosidase and cathepsin B, indicating lysosomal dysfunction. Our study reveals a role for BORCS5 in modulation of lysosomal function, in addition to its known role in lysosome movement and fusion, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.

Aicardi-Goutières syndrome (AGS) and genes-related interferonopathies are a group of multisystem disorders involving the central nervous system, caused by pathogenic variants in genes regulating nucleic acid metabolism and type I interferon signaling, leading to chronic interferon overproduction.This retrospective multicenter study analyzed the efficacy and safety of Janus kinase 1/2 (JAK1/2) inhibitors in 12 patients treated with Baricitinib or Ruxolitinib, compared with 20 untreated patients.Treatment showed improvement in immunological and dermatological symptoms, while the impact on neurological manifestations was limited and heterogeneous, with greater benefits in patients with mild or intermediate phenotypes and earlier treatment initiation. Neuroroimaging analyses in untreated patients showed radiological improvements equal to or greater than those treated, raising doubts about the true impact of JAK 1/2 inhibitors on the neuroradiological course. Adverse events were rare and mild, confirming the favorable safety profile of this treatment. The results suggest that the pathogenetic complexity of AGS goes beyond the JAK-STAT pathway, highlighting the need for larger prospective studies to identify subgroups most likely to benefit from this therapeutic approach and to refine treatment strategies.

Sphingolipids are integral components of cell membranes and modulate cell survival, proliferation, and apoptosis. ASAH2 is a brain-and gut-enriched gene encoding the neutral N-acylsphingosine amidohydrolase 2, a poorly characterized member of the human ceramidase family. This enzyme plays a pivotal role in maintaining the sphingolipid homeostasis, which is crucial for neurogenesis and synaptic function in the central and peripheral nervous systems. In fact, a dysregulated sphingolipid metabolism is associated with progressive neurological conditions, including Alzheimer disease and Parkinson disease. Here, we report the identification of biallelic ASAH2 variants in an individual with a neurodevelopmental condition featuring cognitive impairment, neuropathy, ophthalmoplegia, and progressive cerebellar and extraocular muscles atrophy. Through exome sequencing, we identified very rare missense ASAH2 variants, predicted to be deleterious by in silico analyses. Muscle biopsy histopathologic evaluation revealed features suggestive of neuropathic damage. Lipidomic profiling revealed a hyper-accumulation of glucosylceramide in the subject's cells. Then, the functional investigation of the ASAH2 variants in Drosophila showed the production of an unstable protein and consistent loss-of-function neuromotor phenotypes. Our findings support ASAH2 as a candidate gene for a previously uncharacterized neurodevelopmental disorder with neuropathic features and progressive cerebellar atrophy, underscoring the important role of this ceramidase in human nervous systems.

Introduction Brain structural differences consistent with an older-appearing brain have been reported in people with epilepsy, but the extent to which these differences reflect clinical characteristics vs broader socioeconomic context is unclear. We investigated whether country-level socioeconomic factors are associated with neuroanatomical differences in adults with epilepsy using MRI-based age prediction, along with epilepsy subtype, sex, and clinical factors. Methods Structural MRI and clinical data were collected from 26 epilepsy centres across 12 countries in the Americas, Australia, Europe, Asia and Africa. MRI-based age estimates were estimated using a previously developed prediction model trained on 29,175 healthy subjects. Brain predicted age difference (BrainPAD) was calculated as the difference between MRI-predicted brain age and chronological age. National gross domestic product (GDP) per capita and income inequality (Gini index) were obtained from the World Bank. Associations between BrainPAD and epilepsy subtype (temporal lobe epilepsy, extratemporal epilepsy, and genetic generalised epilepsy), national socioeconomic context (GDP per capita and Gini index), age and sex were assessed using regression models. Results We analyzed 2,109 individuals with epilepsy and 1,041 healthy non-epilepsy controls (57% female; median age = 35; range 17-83). BrainPAD was higher in epilepsy than controls (β 4.2 years, SE 0.4; t=10.6), with increases ranging from 2.5 to 6 years across subtypes. Male sex was associated with 1 year higher BrainPAD relative to females (SE 0.33, t=3.12). There were no main effects of GDP or Gini index; however, significant interactions between were observed. The effect of epilepsy on BrainPAD was greater in countries with lower GDP per capita (t=-2.74) and higher income inequality (t=2.72). Conclusions Clinical factors and socioeconomic context both influence brain structural ageing in epilepsy. These findings highlight the importance of geographic and economic diversity in neuroimaging research and underscore the relevance of global socioeconomic context when interpreting brain health measures.

Cerebral perfusion abnormalities often represent an early and dynamic marker in pediatric neurological emergencies, preceding structural changes detectable by conventional MRI. Arterial Spin Labeling (ASL), a noninvasive and contrast-free perfusion MRI technique, allows for quantitative assessment of cerebral blood flow and is gaining relevance in acute neuroimaging protocols. This review discusses the diagnostic and prognostic utility of ASL across a range of acute conditions including ischemic stroke, encephalopathies, and seizures. Technical principles, typical perfusion patterns, and clinical implications are outlined, highlighting ASL’s potential to improve diagnostic confidence and optimize care in pediatric emergency neuroradiology.

COL18A1 encodes the α1 chain of collagen type XVIII, a non-fibrillar collagen expressed in vascular and epithelial basement membranes. Biallelic pathogenic variants in COL18A1 have been associated with Knobloch syndrome, a condition defined by ophthalmologic abnormalities, though patients often have some or all of brain malformations, epilepsy, and intellectual disability. We reviewed our research and clinical databases for patients with seizures and biallelic COL18A1 variants suspected to be pathogenic. Three patients were identified, all of whom had epilepsy and global development impairment, with two having had developmental regression and drug-resistant seizures. None of the patients had severe ophthalmologic disease. All three patients had one heterozygous likely pathogenic frameshift COL18A1 variant on one allele, with the other allele carrying a rare heterozygous missense COL18A1 variant of less certain pathogenicity. These data raise the possibility that COL18A1 disruption could produce phenotypes without severe eye abnormalities, but significant neurologic dysfunction.

Herpes simplex virus 1 encephalitis (HSE) is the most common sporadic infectious encephalitis in Western countries, with a 70

Seizures and apneas are always concerning symptoms in near-term and term newborns, but finding a clear explanation is not always easy. In addition, it is not always clear which investigations should be promptly conducted. We aimed to evaluate the relationship (or lack thereof) between apneas and seizures and the role of MRI and EEG in their investigation. We conducted a retrospective analysis including infants born at ≥ 36 + 0 weeks of gestational age who presented with seizures or apneas soon after birth and underwent brain magnetic resonance imaging (MRI) during their stay at a tertiary-level academic Neonatal Intensive Care Unit (NICU) in Italy between January 2016 and July 2024. Brain MRI was systematically planned for to all term infants with clinical presentations of seizures, recurrent unexplained apneas, or abnormal aEEG/EEG. Our inclusion criteria were met by 58 (18

Background Foramen magnum stenosis (FMS) is a serious complication in children with achondroplasia that may necessitate cervicomedullary decompression (CMD). It is unclear how FMS and CMD influence growth in these children. This study aimed to assess the effects of FMS and CMD on the growth of children with achondroplasia. Methods Eighty-seven children (45 males, 42 females) with achondroplasia, aged 4 to 6 years, were evaluated. Height, weight, head circumference, and body mass index were expressed as standard deviation scores (SDS) according to Merker et al., while sitting height SDS was derived using Tanner's methods. FMS was graded on magnetic resonance imaging using Fornarino's score. Results Fifty-two patients (26 males, 26 females) underwent CMD at a median age of 0.95 years (IQR 0.52;1.50). Of these, 28 (53.8%) were under one year old at the time of CMD, with a median age of 0.6 years (0.4;0.7). The remaining 24 children had CMD after their first year of life, with a median age of 1.6 years (1.3;2.8). The median age at anthropometric assessment was 5.16 years (4.74;5.50). Children who underwent CMD showed significantly lower median height SDS, particularly among males compared to females (p=0.026). Conclusions Impaired growth in children with foramen magnum stenosis requiring cervicomedullary decompression may primarily reflect greater disease severity, while the potential contribution of surgery remains uncertain.

Background and ObjectivesThe ABCC9 gene encodes the widely expressed SUR2 subunit of ATP-sensitive potassium (KATP) channels. Autosomal recessive loss-of-function variants in ABCC9 cause ABCC9-related Intellectual disability and Myopathy Syndrome (AIMS). Here, we sought to compile multiple case reports from previously unidentified individuals with the primary objective of further establishing the clinical consequences of ABCC9 variants.MethodsWe combine multiple case reports with genetic diagnoses and functional tests of recombinant KATP channels.ResultsWe report 5 cases of AIMS, including a neonate, and a woman who presented as a sexagenarian with signs of dementia. All variants are predicted to lead to nonsense mediated decay of ABCC9 transcripts and/or drastic truncation of SUR2. Functional tests of recombinant channels confirm that disease-associated SUR2 truncations cause a complete loss-of-function. These new cases further demonstrate the prominence of white matter abnormalities resembling periventricular leukomalacia or small vessel disease as a key hallmark of the disorder, alongside developmental delay, intellectual impairment, seizures, and fatigability. These latest findings also highlight neonatal presentation of disease, deterioration following surgical procedures, and the potential for motor and cognitive decline, which should be monitored in older individuals.DiscussionThese findings provide new insights into the spectrum of pathology and natural history of AIMS. This new cohort underscores that AIMS is characterized by the combination of periventricular leukomalacia, developmental delay and intellectual disability, and muscle weakness and fatigability - and is driven by biallelic loss-of-function variants in ABCC9.

Background:Familial cerebral cavernous malformations (fCCMs) are a rare genetic autosomal dominant cerebrovascular disease characterized by multiple cerebral and spinal angiomas. The condition is caused by mutations in KRIT1 (CCM1), CCM2 (malcavernin), or PDCD10 (CCM3) and may lead to intracerebral hemorrhage (ICH) or non-hemorrhagic focal neurological deficits (FNDs), potentially leading to severe disability and even death. To date, little is known about disease progression, and tools to identify patients at higher risk are lacking. Methods:Pediatric and adult fCCM patients, whether symptomatic or asymptomatic, will be enrolled and followed annually over a 2-year period. Participants will undergo clinical assessments, blood sampling, and 3 T brain MRI scans at baseline, 12 months, and 24 months. The primary outcome is the new occurrence of symptomatic ICH or FNDs attributable to CCMs over 24 months. Patient characteristics will be assessed for the primary and secondary endpoints and illustrated using Kaplan-Meier curves and Cox proportional hazard regressions. This trial is registered with ClinicalTrials.gov, NCT06983132 and is currently recruiting participants. Discussion/conclusion:Despite increasing efforts in basic and clinical research and an improved understanding of the pathogenic mechanisms underlying fCCM, tools to predict disease progression, identify at-risk individuals, and pinpoint effective therapeutic targets are still lacking. This study aims to create the largest Italian cohort of fCCM patients, who will be monitored closely over time to collect data that may help identify risk factors and disease trajectories. The collection of standardized information on clinical and radiological evolution, along with results from circulating biomarkers, will help address the complexities of the disease and may suggest potential reliable markers of disease progression. Clinical trial registration:ClinicalTrials.gov, identifier NCT06983132.

CONTEXT:Neuroradiological findings in Noonan syndrome (NS) remain insufficiently characterized. OBJECTIVE:To characterize neuroimaging abnormalities in children with genetically confirmed NS and evaluate their associations with clinical phenotype. DESIGN, SETTING, AND PARTICIPANTS:In this multicenter retrospective study, brain MRI scans and longitudinal clinical and genetic data were reviewed from children with genetically confirmed NS evaluated between 2008 and 2023 at seven pediatric endocrinology centers. MAIN OUTCOME MEASURES:Prevalence and spectrum of neuroimaging abnormalities and their associations with genotype and clinical features. RESULTS:The cohort included 130 individuals with NS (71 males; mean age at MRI, 9.7 years), most carrying PTPN11 variants (69.2%). Structural brain abnormalities were identified in 84.7% and included midbrain-hindbrain malformations (69.2%), callosal anomalies (52.3%), cortical malformations (50%), white matter abnormalities (48.4%), and cranio-cervical junction anomalies (40%). Brain tumors and Chiari I malformation were present in 12.3% and 10.7%, respectively. Seizures were associated with cortical tumors (p = 0.02) and callosal anomalies (p = 0.03), whereas developmental delay was associated with callosal anomalies (p = 0.02) and microcephaly (p < 0.01). Follow-up MRI, available in 41 patients over a mean duration of 6.3 years, showed interval changes in 48.7%, including tumor progression, progressive tonsillar descent, odontoid retroversion, and newly detected lesions. CONCLUSIONS:In this selected cohort of children with NS who underwent brain MRI as part of routine clinical care, structural brain abnormalities were frequent and were associated with neurological manifestations. These findings support a role for RAS/MAPK pathway dysregulation in brain development and highlight the clinical value of MRI in selected patients with NS.

BACKGROUND AND PURPOSE:VPS11-related Hypomyelinating Leukodystrophy (VPS11-HLD), also named HLD12, is an ultrarare lysosomal-autophagic disorder characterized by severe, early-onset neurodevelopmental disability and diffuse hypomyelination. The neuroimaging spectrum of VPS11-HLD had not been systematically studied. We aimed to characterize the MRI phenotype of VPS11-HLD and identify reproducible imaging features that may aid in distinguishing it from other hypomyelinating leukodystrophies. MATERIALS AND METHODS:Patients with VPS11-HLD from two tertiary centers were retrospectively identified between 2019 and 2025. Clinical and genetic data were retrieved from medical records. Brain MRIs were independently reviewed by two pediatric neuroradiologists, and inter-rater agreement was assessed. Imaging features and biometric measurements were compared with those of 21 individuals with other genetically confirmed HLDs using Mann-Whitney U and Fisher's exact tests. A systematic literature review was conducted to identify previously reported cases and provide clinical and neuroimaging data. RESULTS:Six patients (four unrelated boys and two sisters; age range 8 months to 10 years) diagnosed with a homozygous VPS11 c.2536T>G (p.Cys846Gly) variant were identified. The first MRI, obtained at a median age of 9 months (IQR 7.5,13.75), demonstrated the following findings in all patients: 1) a distinct cerebellar signature characterized by focal absence of the cerebellar cortex in the middle-anterior hemispheric portions; 2) diffuse hypomyelination; 3) a periventricular leukomalacia (PVL)-like pattern; 4) short corpus callosum with marked thinning of the posterior portion, 5) hypoplasia of the anterior commissure and 6) mild pontine volume reduction. Inter-rater agreement for MRI feature assessment was high. In a comparative analysis with 21 patients with other HLDs, the cerebellar signature was observed exclusively in VPS11-HLD (6/6 vs. 0/21, respectively, p < .001). CONCLUSION:VPS11-HLD demonstrates a reproducible MRI pattern combining a novel, peculiar cerebellar anomaly, hypomyelination with PVL-like pattern, and extremely thin and short corpus callosum.In the context of an ultra-rare disorder, this pattern may represent a candidate neuroradiologic phenotype that could support diagnostic stratification, guide targeted genetic evaluation, and provide insight into the role of autophagy-lysosome dysfunction in myelin and cerebellar development.

This article reviews the key concepts in pediatric headaches and provides a guide for neuroimaging assessment of children (≥ 2 years) and adolescents presenting with this chief complaint in both emergent and non-emergent settings. Contemporary imaging approaches (such as upfront utilization of abbreviated brain MR imaging) have been incorporated in the provided flow charts whenever appropriate. Our aim is to improve patient care and clinical outcomes by identifying the cases that need additional examinations and rapidly depicting any underlying serious disease (especially those requiring acute interventions) while at the same time reducing overuse of neuroimaging (especially irradiating CT) and associated risks and costs, thereby contributing to health system efficiency.