Lissencephaly (LIS) is a spectrum of cortical malformations including agyria, pachygyria and subcortical band heterotopia, which arises from aberrant neuronal migration and is associated with severe neurodevelopmental impairments. Despite advancements in prenatal imaging, diagnosing LIS remains challenging. Genetic factors play a crucial role in LIS, involving multiple genes and signalling pathways, yet research on prenatal diagnosis and the genetic basis is still limited. This study aimed to assess the diagnostic yield of whole exome sequencing (WES) in LIS and to examine genotype-phenotype correlations, addressing the challenge of 'phenotype lag' in prenatal LIS diagnosis. This study included 20 fetuses with LIS suggested by prenatal imaging and 20 children with LIS diagnosed after birth; all cases were diagnosed by magnetic resonance imaging and underwent genetic testing. In addition, a literature review was conducted and 80 studies were included, of which 1 was used to compare detection efficacy and 79 studies totalling 210 cases were used to assess genotype-phenotype correlation. In the prenatal cohort, 85.0% (17/20) of cases exhibited concurrent anomalies, predominantly ventriculomegaly (50.0%) and microcephaly (25.0%). In the postnatal cohort, the most common phenotypes were epilepsy (80.0%, 16/20) and global developmental delay (65.0%, 13/20), with half of the cases (10/20) showing no abnormalities in the prenatal period. The diagnostic yields were 55.0% (11/20) and 65.0% (13/20), respectively, with PAFAH1B1 point mutations or 17p13.3 microdeletions being the predominant genetic variant in both cohorts, accounting for 31.3% (prenatal) and 25.5% (postnatal) of cases, respectively. DARS2 and NPRL3 were reported to be associated with LIS for the first time in this study. Literature synthesis revealed an overall diagnostic yield of 79.04%, dominated by PAFAH1B1 (26.3%), DYNC1H1 (11.9%), and DCX (10.2%). By reviewing the prenatal images, up to 48.05% (74/154) of the cases had no specific findings in the prenatal period, and the most common presentations were ventriculomegaly/hydrocephalus (52.63%) and head circumference anomalies (29.82%). This study highlights the significant genetic heterogeneity, phenotypic complexity and diagnostic challenges of LIS by integrating data from our cohort and the published literature. We developed a comprehensive genetic aetiology classification framework for LIS and identified novel associations with non-canonical genes such as NPRL3 and DARS2. With a high molecular diagnostic yield of 79.04%, we recommend WES as the first-line genetic test. Furthermore, the establishment of an integrated prenatal imaging-molecular diagnostic system, along with a postnatal multidisciplinary model, is crucial for improving prognosis assessment, clinical decision-making and genetic counselling.

Subcortical band heterotopia (SBH), also known as "double cortex" syndrome, is a rare neuronal migration disorder characterized by symmetric bands of heterotopic gray matter located between the cerebral cortex and lateral ventricles. It predominantly affects females and typically presents in childhood or adolescence with epilepsy and variable cognitive or motor impairment. We report a 9-year-old girl with normal antenatal, perinatal, developmental, and academic history who presented with a one‑month history of frequent generalized tonic-clonic seizures accompanied by new onset generalized limb weakness. Neurological examination revealed mild, symmetric weakness with brisk deep tendon reflexes but preserved cranial nerve and sensory function. Routine laboratory tests and electroencephalography were unremarkable. Brain magnetic resonance imaging demonstrated classic features of SBH, including bilateral, well-defined bands of gray matter deep to and paralleling the cortical surface, separated from the overlying cortex by intervening white matter and isointense to normal cortex on all sequences. A diagnosis of SBH was made based on these characteristic imaging findings. The patient was started on phenytoin, reflecting local prescribing practices and formulary availability in resource‑limited settings, resulting in effective seizure control and clinical stability on follow‑up; genetic testing for DCX or other implicated genes was not performed due to resource limitations. This case highlights that SBH can present in a developmentally normal child with new-onset generalized seizures and limb weakness, underscores the crucial role of MRI in diagnosis where genetic testing is unavailable, and emphasizes the importance of early recognition and tailored antiepileptic therapy to optimize long‑term neurological outcomes.

Subcortical band heterotopia (SBH) is a neuronal migration disorder within the agyria-pachygyria spectrum, ranging from subtle thin bands to diffuse lissencephaly. Adult presentations and prognostic factors remain poorly defined. To characterize the clinical, electrophysiological, radiological features, and long-term outcomes of adults with epilepsy and SBH. We retrospectively reviewed 16 adults diagnosed between 2000 and 2024. Demographics (including age at seizure onset), epilepsy risk factors, seizure semiology, treatment histories, and follow-up durations were obtained from hospital records. Interictal and ictal EEG data were gathered from epilepsy center archives and PACS, and MRI studies were analyzed for lesion distribution. All 16 patients (12 females; mean age 40 years, range 25-55) remained alive at last follow-up. Seizure onset occurred between 6 months and 15 years of age. Developmental delay was noted in 7 patients (44%). All exhibited pharmacoresistant epilepsy. Interictal EEGs demonstrated focal (predominantly temporal in 11/16, 69%), multifocal, combined focal/multifocal, and generalized epileptiform discharges. Seven underwent video-EEG monitoring, revealing predominantly extratemporal seizure semiology in 6/7 (86%). Levetiracetam and carbamazepine were the most frequently employed antiseizure medications. Four patients received vagus nerve stimulation for drop attacks and generalized seizures; three experienced ≥ 50% seizure reduction. The SBH in adults typically manifests as refractory focal epilepsy with frequent developmental delays. Given the absence of pathognomonic semiology, comprehensive evaluation-including multimodal EEG, high-resolution neuroimaging, and genetic testing when available-is essential for accurate diagnosis and tailored management.

Microtubule-associated protein EML1 is an important member of the EML family and plays a key role in cytoskeleton regulation and neural development. During neural development, EML1 expression is spatiotemporally specific, and its functional abnormalities are closely associated with neural developmental disorders such as subcortical band heterotopia. This article systematically reviews the structural characteristics and biological functions of EML1. Structural studies have shown that EML1 contains unique HELP-WD and TAPE domains, which underlie its binding to microtubules and functional performance. Functionally, EML1 regulates microtubule stability through multiple mechanisms. Moreover, EML1 is also involved in regulating intracellular material transport-maintaining the stability of transport tracks, coordinating the function of motor proteins, and regulating Golgi-related transport. These findings reveal the multiple roles of EML1 in cellular physiological processes and provide a new perspective for understanding the pathogenesis of related diseases. Future research should focus on elucidating the precise EML1 action mechanisms and its potential as a therapeutic target.

Holoprosencephaly (HPE) is a well-described forebrain patterning disorder in mid-late gestation fetuses and infants. Here, we used a novel, whole-brain multimodal approach (ultrasonography, magnetic resonance imaging, and histology with 3-dimensional [3D] reconstructions with cell mapping) in earlier-gestation specimens than previously reported. In one 13- and two 22-gestational week fetuses and age-matched controls, we elucidated heretofore underappreciated HPE findings of (1) abnormal clustering of immature (doublecortin-immunoreactive) cells in the midline and paramedian forebrain, (2) linear arrays of cells in the intermediate zone of the cerebral mantle (reminiscent of subcortical band heterotopia, but possibly transient), (3) "reactive"-appearing glial fibrillary acidic protein-immunoreactive cortical cells, and (4) apparent "midline fusion" of rostral ganglionic eminences. We observed disorganization of orbitofrontal cortices and midline structures, rostral subarachnoid (marginal zone) heterotopia, and lateral displacement of the hippocampal formations utilizing multiscale multimodal 3D analytics. These findings shed light on the temporal evolution of HPE at earlier gestational ages. Moreover, this approach is scalable to include the wide range of phenotypes of HPE and is applicable to other neurologic disorders, including developmental as well as adult vascular, infectious, neoplastic, and degenerative conditions for which spatial analyses permit a fuller understanding of their pathologic spectrum.