Pathogenic KCNC1 mutations (encoding Kv3.1 potassium channels) drive heterogeneous neurological disorders, ranging from progressive myoclonus epilepsy-ataxia (MEAK) to developmental/epileptic encephalopathies (DEE) and global developmental delay. Transmembrane-domain variants predominantly cause MEAK-like phenotypes, whereas cytoplasmic mutations associate with severe DEE characterized by refractory seizures and cognitive impairment. The genotype-phenotype correlation in the currently reported 54 cases remains unclear, particularly for non-transmembrane mutations. This paper describes a novel KCNC1 variant (c.1147 C > T, p.His383Tyr) and utilizes protein modeling to elucidate its structural impact, aiming to advance precision therapy for KCNC1-related channelopathies. An 11-year-old male with normal early development developed febrile convulsions at 19 months, progressing to generalized tonic-clonic seizures and drop attacks by 20 months. Initiated on valproate at age 2 after EEG confirmation of epilepsy, he achieved sustained seizure freedom (> 3 years) with dose optimization. Current assessment shows age-appropriate motor/social function and superior cognition (Raven’s 75-80th percentile) alongside idiopathic short stature (-2.08 SDS height), persistent EEG abnormalities, mega cisterna magna on MRI, and Attention-Deficit/Hyperactivity Disorder-related academic impairment. The whole exome sequencing identified a de novo KCNC1 mutation (c.1147 C > T). Three-dimensional protein modeling demonstrated structural disruption in voltage-sensing domains. Comparative analysis of 54 published cases revealed that transmembrane domain mutations predominantly cause epilepsy-ataxia syndrome, whereas non-transmembrane variants are correlated with developmental encephalopathies. The present study is the first to report a c.1147 C > T KCNC1 mutation and highlights the importance of transmembrane domain integrity for neurological function. The dissociation between seizure control and persistent neurodevelopmental deficits suggests distinct pathomechanisms for epileptic versus cognitive manifestations. These findings emphasize the prognostic value of mutation localization as well as support early genetic testing in neurological disorder patients with subclinical EEG abnormalities. The online version contains supplementary material available at 10.1186/s12883-026-04677-z.

Pathogenic variants in MPDZ are typically associated with congenital hydrocephalus. We report on siblings who present with more complex central nervous system malformations and defects in cardiovascular, ocular, and respiratory systems. Phenotyping of the proband revealed aortic coarctation, bicuspid aortic valve, partial anomalous pulmonary venous return, ventricular septal defect, Dandy-Walker malformation, along with subependymal gray matter heterotopia, megalocornea, and chorioretinal punctate lesions. Prenatal phenotyping of the proband's now deceased brother noted left-sided diaphragmatic hernia, a single cardiac ventricle of right ventricular morphology, aortic and mitral valve hypoplasia with aortic coarctation, ventriculomegaly, and mega cisterna magna. Whole genome sequencing identified a homozygous likely pathogenic canonical splice site variant in MPDZ, c.2650-1G>A in both siblings. These siblings present with features suggesting that MPDZ pathogenicity may be associated with a more complex syndromic neurodevelopmental phenotype with both central nervous system and non-central nervous system features. We speculate that MPDZ influences common morphogenetic pathways underlying these relationships.

Congenital arachnoid cysts (ACs) are cerebrospinal fluid collections resulting from abnormal splitting of the arachnoid membrane during embryogenesis. They may occur as isolated lesions or in association with other central nervous system (CNS) malformations. Congenital cytomegalovirus (cCMV) infection is a leading infectious cause of neurodevelopmental impairment and may contribute to complex CNS anomalies. A term male infant was diagnosed prenatally at 30 weeks with midline cystic lesions, ventriculomegaly, and absent corpus callosum. Postnatal magnetic resonance imaging confirmed a large left temporal interhemispheric AC with complete agenesis of the corpus callosum, colpocephaly, absent cavum septi pellucidi, subcortical heterotopia, and mega cisterna magna. Maternal serology indicated past CMV infection, and postnatal urine PCR confirmed congenital CMV infection. Despite progressive cyst enlargement, he remained asymptomatic until neurosurgical fenestration at 5 months, after which imaging showed good decompression and neurodevelopment remained normal. The coexistence of a large AC with multiple major structural brain anomalies and cCMV exposure is exceptionally rare and typically portends a poor prognosis. This case demonstrates that even in the presence of several high-risk features, favorable early neurodevelopmental outcomes are possible. Early detection through prenatal imaging, close postnatal monitoring, and timely surgical intervention were critical to this outcome. A large AC with multiple associated CNS anomalies does not invariably lead to severe neurodevelopmental impairment. This case reinforces the heterogeneity of outcomes, especially the early ones, and shows the importance of early diagnosis, tailored multidisciplinary management, and long-term developmental follow-up to guide family counseling and clinical decision-making.

Introduction Quadrigeminal cistern arachnoid cysts (QACs) represent a rare subgroup of arachnoid cysts. Patients may present with headache, visual disturbances, gait imbalance, or nausea, typically secondary to obstructive hydrocephalus. Hydrocephalus is frequently assessed using the Evans Index (EI). Vertebral artery hypoplasia (VAH) is generally defined as a decrease in the diameter of the vertebral artery. It has been associated with posterior circulation ischemia, vertebrobasilar insufficiency (VBI), vertigo, and headache. However, the relationship between QAC-related mass effect and vascular variants such as VAH has not been systematically evaluated. Mega cisterna magna (MCM) represents another posterior fossa cerebrospinal fluid variant relevant to the differential diagnosis. Objective To evaluate the relationship between QAC dimensions, EI, vertebral artery diameters, and clinical symptoms, and to assess the coexistence of MCM. Methods Seventy-three patients (36 females, 37 males; mean age 52.4 ± 19.0 years) with radiologically confirmed QAC were retrospectively reviewed. Clinical symptoms, including headache and VBI, were recorded. Imaging parameters included QAC anteroposterior (AP) diameter, quadrigeminal cistern diameter, EI, vertebral artery diameters, and the presence of MCM. Multivariable logistic regression analysis was performed to identify imaging predictors of clinical symptoms (odds ratio (OR) and confidence interval (CI)). Results Headache was present in 67.1% of patients, VBI in 31.5%, and MCM in 21.9%. Mean QAC AP diameter was 16.9 ± 4.8 mm, quadrigeminal cistern diameter 23.1 ± 5.2 mm, and EI 0.24 ± 0.08. Mean right and left vertebral artery diameters were 2.46 ± 0.83 mm and 2.36 ± 0.73 mm, respectively. Headache showed no independent association with any imaging parameter (p-value > 0.05). VBI was significantly associated with a smaller left vertebral artery diameter (OR 0.32; 95% CI 0.16-0.64; p-value = 0.001). Conclusion In patients with QAC, headache did not correlate with radiologic measurements, whereas VBI was strongly associated with reduced vertebral artery diameter, particularly on the left side. These findings highlight the importance of incorporating vascular assessment when evaluating symptomatic QAC patients.

Axenfeld-Rieger syndrome/anomaly (ARS) is a rare genetic disorder with an autosomal dominant inheritance pattern, characterized by dysgenesis of the anterior segment of the eye. It may present with systemic anomalies (Axenfeld-Rieger syndrome) or without (Axenfeld anomaly) and may sometimes be associated with multiple congenital malformations. The estimated prevalence ranges from 1 in 50,000 to 1 in 200,000 live births, with an approximate rate of 1 in 100,000, but no epidemiological studies have been conducted to date. A clinical diagnosis of Axenfeld-Rieger syndrome requires the presence of both Axenfeld and Rieger ocular anomalies, accompanied by extraocular systemic features. Ocular manifestations include iris abnormalities, posterior embryotoxon, juvenile-onset glaucoma (a common complication), and dysgenesis of the iridocorneal angle with iridocorneal adhesions. The most commonly observed systemic anomalies include: umbilical defects; craniofacial dysmorphism; dentofacial abnormalities, such as Class III malocclusion due to maxillary hypoplasia, oligodontia, dental malformations (taurodontism, root dysplasia), microdontia, hypodontia, and anodontia; hearing impairment (partial or complete sensorineural hearing loss); and cardiac anomalies, including non-congenital heart disease and mitral valve insufficiency. Additional anomalies may include hypospadias in males, anal stenosis, endocrine disorders (notably growth retardation) secondary to pituitary dysfunction, psychomotor delay, and various neurological malformations such as Dandy-Walker malformation, mega cisterna magna, posterior fossa cysts, cerebellar vermis hypoplasia, ventriculomegaly, aprosencephaly, cerebral atrophy, microcephaly, arteriovenous malformations (AVM), and digital anomalies such as camptodactyly. Diagnosis is typically made in infancy, based on iris anomalies such as corectopia (displacement of the pupil), polycoria (multiple pupils), and iris hypoplasia. Posterior embryotoxon is frequently observed upon slit-lamp examination. Given the clinical variability, a comprehensive pediatric assessment is essential to identify systemic anomalies and distinguish Axenfeld-Rieger syndrome from the isolated Axenfeld anomaly.