Subcortical Heterotopia Research Articles

Forebrain Eml1 depletion reveals early centrosomal dysfunction causing subcortical heterotopia.

Subcortical heterotopia is a cortical malformation associated with epilepsy, intellectual disability, and an excessive number of cortical neurons in the white matter. Echinoderm microtubule-associated protein like 1 (EML1) mutations lead to subcortical heterotopia, associated with abnormal radial glia positioning in the cortical wall, prior to malformation onset. This perturbed distribution of proliferative cells is likely to be a critical event for heterotopia formation; however, the underlying mechanisms remain unexplained. This study aimed to decipher the early cellular alterations leading to abnormal radial glia. In a forebrain conditional Eml1 mutant model and human patient cells, primary cilia and centrosomes are altered. Microtubule dynamics and cell cycle kinetics are also abnormal in mouse mutant radial glia. By rescuing microtubule formation in Eml1 mutant embryonic brains, abnormal radial glia delamination and heterotopia volume were significantly reduced. Thus, our new model of subcortical heterotopia reveals the causal link between Eml1's function in microtubule regulation and cell position, both critical for correct cortical development.

ILAE neuroimaging task force highlight: Subcortical laminar heterotopia.

The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational mission. Subcortical laminar heterotopia, also known as subcortical band heterotopia (SBH) or "double cortex," is an intriguing and rare congenital malformation of cortical development. SBH lesions are part of a continuum best designated as agyria-pachygyria-band-spectrum. The malformation is associated with epilepsy that is often refractory, as well as variable degrees of developmental delay. Moreover, in an increasing proportion of cases, a distinct molecular-genetic background can be found. Diagnosing SBH can be a major challenge for many reasons, including more subtle lesions, and "non-classic" or unusual MRI-appearances. By presenting an illustrative case, we address the challenges and needs of diagnosing and treating SBH patients in epilepsy, especially the value of high-resolution imaging and specialized MRI-protocols.

Disrupted neurogenesis, gliogenesis, and ependymogenesis in the Ccdc85c knockout rat for hydrocephalus model

Coil-coiled domain containing 85c (Ccdc85c) is a causative gene for congenital hydrocephalus and subcortical heterotopia with frequent brain hemorrhage. We established Ccdc85c knockout (KO) rats and investigated the roles of CCDC85C and intermediate filament protein expression, including nestin, vimentin, GFAP, and cytokeratin AE1/AE3 during the lateral ventricle development in KO rats to evaluate the role of this gene. We found altered and ectopic expression of nestin and vimentin positive cells in the wall of the dorso-lateral ventricle in the KO rats during development from the age of postnatal day (P) 6, whereas both protein expression became faint in the wild-type rats. In the KO rats, there was a loss of cytokeratin expression on the surface of the dorso-lateral ventricle with ectopic expression and maldevelopment of ependymal cells. Our data also revealed disturbed GFAP expression at postnatal ages. These findings indicate that lack of CCDC85C disrupts the proper expression of intermediate filament proteins (nestin, vimentin, GFAP, and cytokeratin), and CCDC85C is necessary for normal neurogenesis, gliogenesis, and ependymogenesis.

Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRASG12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRASG12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRASG12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRASG12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRASG12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.

The analysis of 18 F-FDG PET/MRI, electroencephalography, and semiology in patients with gray matter heterotopia: A pilot study.

To describe 18 F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18 F-FDG PET/MRI) along with semiology and electroencephalography (EEG) in patients with gray matter heterotopia (GMH); to evaluate the concordance between 18 F-FDG PET/MRI and clinical epileptogenic zone (EZ). GMH (subcortical heterotopia [SCH] and periventricular nodular heterotopia [PNH]) patients with epilepsy who underwent 18 F-FDG PET/MRI were retrospectively enrolled. Two radiologists evaluated brain MRI, while two nuclear medicine specialists assessed the 18 F-FDG PET. The SUVmax values of visually hypometabolic cortical areas were compared to the contralateral cortex using a SUVmax threshold value of 10%; the SUVmax values of GMH lesions were compared with that of the right precentral gyrus. The cortex or GMH with hypometabolism on 18 F-FDG PET/MRI was considered representative of the EZ. The clinical EZ was identified using EEG and semiology. Thirty patients (19 PNH; 11 SCH) with a mean age of 28.46 ± 9.52 years were enrolled. The heterotopic nodules were ametabolic in 3 patients (10%), hypometabolic in 16 (33.33%), isometabolic in 13 (26.66%), and hypermetabolic in 4 (10%). 18 F-FDG PET/MRI demonstrated hypometabolism in the cortex and GMH in 22/30 (73.33%) and 16/30 (53.33%). We could identify a clinical EZ in 18 patients, and 15 out of 18 (83.33%) had concordant 18 F-FDG PET/MRI findings. Heterotopic nodules in GMH patients show different metabolic patterns on 18 F-FDG PET/MRI, with nearly three-quarters of the patients having cortical hypometabolism. 18 F-FDG PET/ MRI findings are mostly concordant with the clinical EZ.

Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development

Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.

Genetic causes underlying grey matter heterotopia.

Grey matter heterotopia (GMH) can cause of seizures and are associated with a wide range of neurodevelopmental disorders and syndromes. They are caused by a failure of neuronal migration during fetal development, leading to clusters of neurons that have not reached their final destination in the cerebral cortex. We have performed an extensive literature search in Pubmed, OMIM, and Google scholar and provide an overview of known genetic associations with periventricular nodular heterotopia (PNVH), subcortical band heterotopia (SBH) and other subcortical heterotopia (SUBH). We classified the heterotopias as PVNH, SBH, SUBH or other and collected the genetic information, frequency, imaging features and salient features in tables for every subtype of heterotopia. This resulted in 105 PVNH, 16 SBH and 25 SUBH gene/locus associations, making a total of 146 genes and chromosomal loci. Our study emphasizes the extreme genetic heterogeneity underlying GMH. It will aid the clinician in establishing an differential diagnosis and eventually a molecular diagnosis in GMH patients. A diagnosis enables proper counseling of prognosis and recurrence risks, and enables individualized patient management.

Expression of CCDC85C, a causative protein for hydrocephalus, and intermediate filament proteins during lateral ventricle development in rats.

Coiled-coil domain containing 85c (Ccdc85c) is a causative gene for genetic hydrocephalus and subcortical heterotopia with frequent brain hemorrhage. In the present study, we examined the expression pattern of CCDC85C protein and intermediate filament proteins, such as nestin, vimentin, GFAP, and cytokeratin AE1/AE3, during lateral ventricle development in rats. CCDC85C was expressed in the neuroepithelial cells of the dorsal lateral ventricle wall, diminishing with development and almost disappearing at postnatal day 20. By immunoelectron microscopy, CCDC85C was localized in the cell-cell junction and apical membrane. The expression of nestin and vimentin was decreased in the wall of the lateral ventricle in manner similar to CCDC85C, but GFAP expression started immediately after birth and became stronger with age. Moreover, cytokeratin expression was found at postnatal day 13 and increased at postnatal day 20 in conjunction with the disappearance of CCDC85C expression. Taken together, CCDC85C is expressed in the cell-cell junctions lining the wall of the lateral ventricle and plays a role in neural development with other intermediate filaments in the embryonic and postnatal periods. Our chronological study will help to relate CCDC85C protein with intermediate filaments to elucidate the detailed role of CCDC85C protein during neurogenesis.

Gray matter heterotopia: clinical and neuroimaging report on 22 children

ObjectiveTo investigate the clinical characteristics and neuroimaging features of childhood presenting with gray matter heterotopia observed in a single tertiary Pediatric Department in Catania and compare the data with those reported in the literature.MethodsA retrospectively review of the history, clinical findings, electrophysiological features and magnetic resonance images of 22 children presenting with gray matter heterotopia observed from January 2010 to January 2020.ResultsAmong the 22 children included in the study, 17 presented with periventricular heterotopia (PVNH), two with Subcortical Band Heterotopia (SBH), and three with other subcortical heterotopia (SUBH). In the affected children, the ages at first diagnosis ranged from 3 months to 16 years with a mean age of 8.2 years (± 5.4); twelve (54.5%) suffered by developmental delay and intellectual deficit; eleven children (50%) complained of epileptic seizures, mostly focal to bilateral tonic–clonic seizure. In addition, in the periventricular heterotopia group (PVNH), cerebral and systemic malformations were reported in twelve (70%) and in ten (58%) children, respectively, out of seventeen. In the SBH plus SUBH group, epileptic seizures were recorded in 3 (60%) out of 5 children, cerebral malformations in one child and systemic malformations in two children.ConclusionsHeterotopic gray matter malformations include a group of disorders that manifest with a variety of neurological implications, such as cognitive impairment and epilepsy, and often related with epilepsy, other cerebral malformations and systemic anomalies.

Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias.

Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive, given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic KOs, we report here that — whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild MCPH during development — lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs). Our mouse model of MCPH8 suggests that loss of CEP135 results in centriole duplication defects, TP53 activation, and cell death of NPs. Trp53 ablation in a Cep135-deficient background prevents cell death but not MCPH, and it leads to subcortical heterotopias, a malformation seen in MCPH8 patients. These results suggest that MCPH in some MCPH patients can arise from the lack of adaptation to centriole defects in NPs and may lead to architectural defects if chromosomally unstable cells are not eliminated during brain development.

A novel missense variant in the EML1 gene associated with bilateral ribbon-like subcortical heterotopia leads to ciliary defects

Heterotopia is a brain malformation caused by a failed migration of cortical neurons during development. Clinical symptoms of heterotopia vary in severity of intellectual disability and may be associated with epileptic disorders. Abnormal neuronal migration is known to be associated with mutations in the doublecortin gene (DCX), the platelet-activating factor acetylhydrolase gene (PAFAH1B1), or tubulin alpha-1A gene (TUBA1A). Recently, a new gene encoding echinoderm microtubule-associated protein-like 1 (EML1) was reported to cause a particular form of subcortical heterotopia, the ribbon-like subcortical heterotopia (RSH). EML1 mutations are inherited in an autosomal recessive manner. Only six unrelated EML1-associated heterotopia-affected families were reported so far. The EML1 protein is a member of the microtubule-associated proteins family, playing an important role in microtubule assembly and stabilization as well as in mitotic spindle formation in interphase. Herein, we present a novel homozygous missense variant in EML1 (NM_004434.2: c.692G>A, NP_004425.2: p.Gly231Asp) identified in a male RSH-affected patient. Our clinical and molecular findings confirm the genotype-phenotype associations of EML1 mutations and RSH. Analyses of patient-derived fibroblasts showed the significantly reduced length of primary cilia. In addition, our results presented, that the mutated EML1 protein did not change binding capacities with tubulin. The data described herein will expand the mutation spectrum of the EML1 gene and provide further insight into molecular and cellular bases of the pathogenic mechanisms underlying RSH.

Epileptic children with hemispheres’ asymmetry. Quantitative brain magnetic resonance-based analysis of apparently unaffected hemisphere. Case-control study

ObjectiveWe performed a quantitative hemispheres analysis in epileptic children with hemispheres’ asymmetry -due to unilateral dysplastic malformation- in order to recognize subtle volumetric changes of the contralateral and apparently unaffected hemisphere. Methods13 children with Hemimegalencephaly (HME) and 20 with Hemimicrencephaly (Hme) were clustered in subgroups according to underlying hemispheric cortical dysplastic malformation and epilepsy pattern. 3D FSPGR T1weighted images were used to assess white and grey matter volumes for both hemispheres. Each volumetric parameter was compared with the average of an age-matched healthy control group. ResultsHME subgroups: HME with pachygyria and focal (HME-PG-F; n 6) or multifocal epilepsy (HME-PG-MF; n.7). In both subgroups affected hemisphere (AH) volume was increased and contralateral hemisphere (CH) showed white matter volume reduction; in HME-PG-MF grey matter volume of CH was more reduced than HME-PG-F.Hme subgroups: Hme with polimicrogyria and focal epilepsy (Hme-PMG-F; n.8), Hme with giant subcortical nodular heterotopia and focal (Hme-SCH-F; n.6) or multifocal epilepsy (Hme-SCH-MF; n.6). In all subgroups AH volume was reduced; the volume of CH was significantly increased in Hme-PMG-F and Hme-SCH-MF while it was not significantly increased in Hme-SCH-F compared to affected hemisphere. ConclusionsIn patients with hemispheres’ asymmetry, quantitative high-resolution MRI offers a more objective assessment of brain structures volume. The type of hemispheric dysplastic malformation together with the age of epilepsy onset and epileptic pattern may contribute to changes in contralateral and apparently unaffected hemisphere. Future studies are warranted to evaluate whether the early identification of these changes might help in planning future antiepileptic treatments.

Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimics the Pathophysiology of Human Cortical Dysplasia.

Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasing studies have implicated innate immunity in CD with epilepsy. However, it is unclear whether innate immune factors induce epileptogenic CD. Here, we injected recombinant human high mobility group box 1 (rHMGB1) into embryonic rat ventricles to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD. Compared with controls and 0.1 μg rHMGB1-treated rats, the cortical organization was severely disrupted in the 0.2 μg rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented and deformed neurons were observed in the cortical lesions and heterotopias. Subcortical heterotopia appeared in the white matter and the gray–white junction of the 0.2 μg rHMGB1-treated rats. Moreover, there was decreased number of neurons in layer V–VI and an increased number of astrocytes in layer I and V of the cortical lesions. And the HMGB1 antagonist dexmedetomidine alleviated the changes induced by rHMGB1. Further, we found that TLR4 and NF-κB were increased after rHMGB1 administration. In addition, the excitatory receptors, N-methyl-D-aspartate receptor 1 (NR1), 2A (NR2A), and 2B (NR2B) immunoreactivity were increased, and immunoreactivity of excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2) were reduced in 0.2 μg rHMGB1-treated rats compared with controls. While there were no differences in the glutamic acid decarboxylase 65/67 (GAD65/67) immunoreactivity between the two groups. These results indicate that the excitation of cortical lesions was significantly increased. Furthermore, electroencephalogram (EEG) showed a shorter latency of seizure onset and a higher incidence of status epilepticus in the 0.2 μg rHMGB1-treated rats; the frequency and amplitude of EEG were higher in the treated rats than controls. Intriguingly, spontaneous electrographic seizure discharges were detected in the 0.2 μg rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronous propagated waves throughout the general brain cortex. Taken together, these findings indicate that rHMGB1 exposure during pregnancy could contribute to the development of epileptogenic CD, which mimicked some pathophysiological characteristics of human CD.

Epilepsy with eyelid myoclonias and Sotos syndrome features in a patient with compound heterozygous missense variants in APC2 gene

Epilepsy with eyelid myoclonias and Sotos syndrome features in a patient with compound heterozygous missense variants in APC2 gene

Chudley-McCullough Syndrome: A Recognizable Clinical Entity Characterized by Deafness and Typical Brain Malformations

Chudley-McCullough syndrome, a rare autosomal recessive disorder due to pathogenic variants in the GPSM2 (G-protein signaling modulator 2) gene, is characterized by early-onset sensorineural deafness and a typical combination of brain malformations, including ventriculomegaly, (partial) agenesis of the corpus callosum, cerebellar dysplasia, arachnoid cysts, frontal subcortical heterotopia, and midline polymicrogyria. When hearing loss is managed early, most patients have minor or no impairment of motor and cognitive development, despite the presence of brain malformations. We report 2 cases of Chudley-McCullough syndrome, one presenting with congenital deafness and normal development except for speech delay and one presenting prenatally with ventriculomegaly and an atypical postnatal course characterized by epileptic spasms, deafness, and moderate intellectual disability. These highlight the challenges faced by clinicians when predicting prognosis based on pre- or postnatal imaging of brain malformations. We have also reviewed the phenotype and genotype of previous published cases to better understand Chudley-McCullough syndrome.

Tensor-valued diffusion MRI differentiates cortex and white matter in malformations of cortical development associated with epilepsy.

Objective:Delineation of malformations of cortical development (MCD) is central in presurgical evaluation of drug-resistant epilepsy. Delineation using magnetic resonance imaging (MRI) can be ambiguous, however, because the conventional T1- and T2-weighted contrasts depend strongly on myelin for differentiation of cortical tissue and white matter. Variations in myelin content within both cortex and white matter may cause MCD findings on MRI to change size, become undetectable, or disagree with histopathology. The novel tensor-valued diffusion MRI (dMRI) technique maps microscopic diffusion anisotropy, which is sensitive to axons rather than myelin. This work investigated whether tensor-valued dMRI may improve differentiation of cortex and white matter in the delineation of MCD.Methods:Tensor-valued dMRI was performed on a 7 T MRI scanner in 13 MCD patients (age = 32 ± 13 years) featuring periventricular heterotopia, subcortical heterotopia, focal cortical dysplasia, and polymicrogyria. Data analysis yielded maps of microscopic anisotropy that were compared with T1-weighted and T2-fluid-attenuated inversion recovery images and with the fractional anisotropy from diffusion tensor imaging.Results:Maps of microscopic anisotropy revealed large white matter-like regions within MCD that were uniformly cortex-like in the conventional MRI contrasts. These regions were seen particularly in the deep white matter parts of subcortical heterotopias and near the gray-white boundaries of focal cortical dysplasias and polymicrogyrias.Significance:By being sensitive to axons rather than myelin, mapping of microscopic anisotropy may yield a more robust differentiation of cortex and white matter and improve MCD delineation in presurgical evaluation of epilepsy.

T2-sequence with contrast inversion: diagnostic value in the investigation of gray matter heterotopias.

To compare the diagnostic value of T1-inversion recovery sequence (T1 IR) to that of a T2-sequence with contrast inversion (T2 CI) in the investigation of heterotopias. In this study, we processed a contrast-inverted copy of our coronal T2-sequence of 21 patients with subependymal and subcortical heterotopias on an online picture archiving and communication system workstation. The diagnostic performance of these images was compared with the T1 IR of the same patients by quantitative and qualitative assessments regarding signal-to-noise ratio (SNR), lesion-to-white matter contrast-to-noise ratio (CNR), lesion conspicuity, level of artifacts, overall image quality as well as diagnostic content. SNR values of the T2 CI were significantly higher than those of the T1 IR. CNR values of both sequences were similar. No relevant difference was found for lesion conspicuity and level of artifacts. Overall image quality of the T2 CI was rated slightly better by one reader. Both readers voted the images to have the same diagnostic content. Beside the exact depiction of the hippocampus in the high resoluted T2-sequence, its contrast-inverted copy (T2 CI) is also useful in the detection of heterotopias. In conjunction with the MPRAGE or MP2RAGE as a three-dimensional sequence, it could offer an equivalent and time-saving alternative to the T1 IR in the investigation of this type of malformation of cortical development.

Disruption in murine Eml1 perturbs retinal lamination during early development

During mammalian development, establishing functional neural networks in stratified tissues of the mammalian central nervous system depends upon the proper migration and positioning of neurons, a process known as lamination. In particular, the pseudostratified neuroepithelia of the retina and cerebrocortical ventricular zones provide a platform for progenitor cell proliferation and migration. Lamination defects in these tissues lead to mispositioned neurons, disrupted neuronal connections, and abnormal function. The molecular mechanisms necessary for proper lamination in these tissues are incompletely understood. Here, we identified a nonsense mutation in the Eml1 gene in a novel murine model, tvrm360, displaying subcortical heterotopia, hydrocephalus and disorganization of retinal architecture. In the retina, Eml1 disruption caused abnormal positioning of photoreceptor cell nuclei early in development. Upon maturation, these ectopic photoreceptors possessed cilia and formed synapses but failed to produce robust outer segments, implying a late defect in photoreceptor differentiation secondary to mislocalization. In addition, abnormal positioning of Müller cell bodies and bipolar cells was evident throughout the inner neuroblastic layer. Basal displacement of mitotic nuclei in the retinal neuroepithelium was observed in tvrm360 mice at postnatal day 0. The abnormal positioning of retinal progenitor cells at birth and ectopic presence of photoreceptors and secondary neurons upon maturation suggest that EML1 functions early in eye development and is crucial for proper retinal lamination during cellular proliferation and development.

A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat

Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy. Understanding the genetic and neurobiological mechanisms underlying MCD is a necessary step in elucidating novel therapeutic targets. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD with spontaneous seizures, but the underlying genetic mutation(s) have remained unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated first exon markedly diminished Eml1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat revealed early-onset of spontaneous spike-wave discharge (SWD) bursts beginning at postnatal day (P) 17. A dihybrid cross demonstrated that the mutant Eml1 allele segregates with the observed dysplastic cortex and the early-onset SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a deletion in Eml1.

EML1-associated brain overgrowth syndrome with ribbon-like heterotopia.

EML1 encodes the protein Echinoderm microtubule‐associated protein‐like 1 or EMAP‐1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug‐resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon‐like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria‐like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease‐causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.