Periventricular nodular heterotopia (PNH) is a neuronal migrational anomaly frequently associated with filamin-A (FLNA) gene variants. However, in the absence of a pathogenic FLNA gene or in the context of other genetic mutations, PNH may demonstrate a distinct pattern of distribution, often accompanied by a variety of brain abnormalities. PNH associated with cerebellar hypodysgenesis (CHD) and malformation of cortical development (MCD) involving the mesial temporal lobes, without detectable FLNA variants, is a known, but under-reported, association. PNH in this context demonstrates a phenotypically distinct distribution (i.e., along the infrasylvian lateral ventricles). In this review, we report the prenatal MRI finding of this unusual association and provide key insights into this abnormality.

The CELSR1 gene is a core component of the tissue/planar cell polarity signaling pathway. It encodes a developmentally regulated protein that belongs to the adhesion G protein-coupled receptors. Herein we describe seven subjects, from five unrelated families, featuring a neurodevelopmental disorder associated with biallelic CELSR1 variants. The main phenotypic features of this disorder are different types of brain malformations (including pachygyria, periventricular nodular heterotopia, abnormal corpus callosum, white matter abnormalities, hypoplasia of brainstem and cerebellum), variable degrees of neurodevelopmental delay and intellectual disability, behavioral disorders, and, in some subjects, epilepsy. Using whole exome sequencing, we identify five compound heterozygous variants and one homozygous variant of CELSR1 in these subjects. We infer the pathogenicity and functional effects of these variants through bioinformatic analysis, protein modelling and prediction tools. To further characterize the effects of mutant CELSR1, we generate Celsr1 knockout mice, which exhibit partial agenesis of the corpus callosum, periventricular heterotopia and irregular shape of the ventricular/subventricular zone, enlarged lateral ventricles with a fully penetrant phenotype, and increased susceptibility to seizures. These findings emphasize the importance of CELSR1 in several polarity-dependent processes during embryonic and postnatal development.

Brain network characteristics of favorable outcomes following radiofrequency thermocoagulation for drug-resistant epilepsy in periventricular nodular heterotopia patients.

X-linked cardiac valvular dysplasia (XCVD) has been associated with missense or in-frame deletion variants in FLNA. We report a Japanese family with cardiac valvular dysplasia. The proband was diagnosed with multiple valve dysplasia at a primary school health checkup. He also exhibited skin hyperextensibility and joint hypermobility. His younger monozygotic twin brothers were diagnosed with multiple valve dysplasia during their 1-month pediatric checkups. One of them exhibited severe valvular disease and required aortic and mitral valve replacement at age 16 due to progressive regurgitation. All three patients showed no developmental delay or evidence of periventricular nodular heterotopia on brain MRI. We identified a novel hemizygous FLNA variant, NM_001456.4(FLNA):c.2023-6_2026delinsACGCT, in all three patients. Splicing analysis revealed an in-frame deletion of two amino acids, p.Val675_Lys676del. No significant difference was observed in overall expression levels of FLNA transcript between the patient and a healthy individual. In silico structural modeling revealed that this deletion disrupts an α-helix positioned between β-strands of domains 4 and 5, which would impair the structural stability of FLNA. This variant was not found in public genomic databases. In conclusion, we identified a novel likely pathogenic variant in FLNA, p.Val675_Lys676del, the smallest in-frame deletion reported to date in XCVD. Patients with this variant showed variable severity, and some presented with extracardiac features. Our findings expand both the genetic and phenotypic spectrum of XCVD.

7T MRI has specific technical features that are advantageous for epilepsy. This study aims to evaluate whether new potentially epileptogenic abnormalities can be identified on 7T MRI in patients with epilepsy with negative 3T MRI findings. Clinical 7T epilepsy MRI examinations in patients with prior negative 3T imaging findings were retrospectively reviewed by 3 neuroradiologists. Their consensus 7T scan interpretations were reviewed by a neurologist for concordance with EEG findings. Descriptive characteristics of any 7T MRI abnormalities and their locations were recorded. The clinical and EEG findings in subjects with abnormal 7T scan findings were compared with those of subjects without a 7T abnormality. In patients with epilepsy with nonlesional 3T MRI, new abnormal findings were identified on 7T MRI in 36% (18/50) of cases. Of the 14 pediatric cases, there were 7T MRI abnormal findings in 6/14 (42.9%). Across all cases, a total of 21 discrete abnormal findings were identified, including meningoencephaloceles (5/21, 23.8%), cavernous malformations/possible vascular lesions (5/21, 23.8%), focal cortical dysplasia (3/21, 14.3%), gray matter heterotopia (3/21, 14.3%), mesial temporal sclerosis (3/21, 14.3%), 1 indeterminant hippocampal morphology finding (1/21), and 1 case of a diffuse migrational abnormality (1/21). Noninvasive EEG monitoring unit data were concordant with the location of 7T abnormalities in 60.0% (9/15) of cases with these clinical data available. Participants with generalized seizures (OR, 0.2; 95% CI, 0.041-0.75) and those with multiple seizure types (OR, 0.14; 95% CI, 0.027-0.52) were significantly less likely to have new potentially epileptogenic lesions detected at 7T. Two 7T cases with abnormal findings underwent surgical resection with good clinical outcomes (Engel Class IA). In clinical practice, 7T MRI revealed additional epileptogenic lesions in 36% of nonlesional 3T MRI cases.

This study aimed to compare the clinical characteristics of patients with periventricular nodular heterotopia (PNH) and various outcomes following stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) and to construct a nomogram for predicting surgical outcomes. A retrospective analysis was performed on data from 47 patients with drug-resistant epilepsy due to PNH who underwent SEEG-guided RFTC at four epilepsy centers in China. Clinical characteristics, including imaging, electrophysiology, and surgical features, were compared among patients with different postoperative outcomes and heterotopic nodule (HN) distributions (unilateral vs. bilateral). A Cox regression model was constructed using a training cohort from three centers, with variable selection via the least absolute shrinkage and selection operator (LASSO) method. Data from the remaining center were used for external validation. Of the 47 patients, 22 had unilateral HNs and 25 bilateral HNs. The mean follow-up was 49months. Seizure freedom was achieved in 61.7%, and the response rate was 72.3%. Patients with bilateral HNs developed more seizure types, frequent FBTCS, and had higher response rates, whereas those who were seizure-free had later onset ages, less extra-HN RFTC, and fewer post-RFTC discharges. Cox regression identified four key predictors of seizure freedom: Extra-HN cortex SOZ, Extra-HN cortex RFTC, post-RFTC discharges, and HNs onset pattern (C-index: 0.94). For response, three predictors were identified: Extra-HN RFTC, post-RFTC discharges, and unilateral interictal discharges (C-index: 0.94). A nomograms constructed from these features demonstrated a high predictive performance in both internal and external cohorts. These models demonstrate robust performance in predicting seizure outcomes following SEEG-guided RFTC in PNH, making them ideal tools for implementing personalized clinical decision-making.

With the ultimate goal of elucidating the brain mechanisms underlying intelligence, I have been tackling this question by investigating the mechanisms that underlie the formation of brain structures during development. Cell migration and completion of neurotransmission are crucial events that support the development. Because the cytoskeleton is essential for these processes, I have been studying these themes from a cytoskeletal perspective. Periventricular nodular heterotopia is a genetic disorder characterized by the presence of a second cortex (a cluster of neurons) around the ventricles, known as a double cortex. One of the characteristics of this disorder is intractable epilepsy. This disease is believed to be caused by mutations in the actin-binding protein filamin A, which is located on the X chromosome. It has been suggested that filamin A plays a crucial role in cell migration from the ventricular region during cortical development. We have identified and are currently studying a novel molecule, FILIP (filamin A-interacting protein), which promotes the degradation of filamin A. Recently, mutations in FILIP (FILIP1 in humans) have been reported to cause arthrogryposis multiplex congenita, intellectual disability, and encephalocele in humans (FILIP1 disease). At first, I will introduce our research on FILIP and its regulatory factors. Next, we will present our data on how other cytoskeletal molecules contribute to brain development and maturation. On the other hand, when we look at neural circuits, we notice that function and circuit formation are intricately intertwined to enable the brain to function. From this perspective, we have also taken an approach to unravel cells and their associated circuits that are specific to higher animals. We will cite examples of such research and introduce our current approach.

Thyroid hormones (THs) regulate development, growth, and metabolism. Integral to the regulation of their action are the deiodinases (Dios), metabolizing enzymes that activate (Dio1 and Dio2) and deactivate (Dio3) THs, exerting precise control over local TH action. We examined the effect of chemical interference with Dios on brain development in a rodent pregnancy model using iopanoic acid (IOP). Pregnant rat dams were exposed to 0, 5, or 10 mg/kg IOP daily by gavage from gestational day 6 to postnatal (PN) day 15. Pups were euthanized at PN0, 2, 6, and 14. Serum and brain TH and Dio activity in cortical microsomes were measured, and 2 neuroanatomical defects emblematic of TH insufficiency were examined in the brains of offspring. IOP increased serum total T4 and rT3 in dams and pups. IOP decreased Dio2 and Dio3 activity in the dam cortex and forebrain of PN0 and PN2 pups, with no effect seen on PN14. On PN2, brain T4 was increased, brain T3 was reduced, and TH-responsive genes were downregulated. A periventricular heterotopia was present in the brains of IOP-treated pups on PN14, whereas no change was seen in the numbers of parvalbumin-expressing neurons. The observation that IOP induced changes in serum THs that were not predictive of brain effects has profound implications for the interpretation of altered serum TH profiles in a chemical regulatory context as well as in a clinical setting.

MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation. Disease-causing variants (DCVs) in MAP1B have recently emerged as a cause of neurodevelopmental disorders characterized by intellectual disability, epilepsy, and cortical malformations, including periventricular nodular heterotopia (PVNH) and polymicrogyria (PMG). However, the phenotypic and neuroimaging spectrum associated with MAP1B-related disease remains incompletely defined. We describe seven affected individuals from three unrelated families with pathogenic MAP1B variants. Clinical, neuroimaging, and genetic data were analyzed in the context of emerging literature to delineate the pathogenic mechanisms and phenotypic variability associated with MAP1B dysfunction. All individuals carried loss of function MAP1B variants. Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy. Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available. These findings reinforce MAP1B's central role in cytoskeletal regulation, neuronal positioning, and synaptic connectivity. Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching. Our case series expands the clinical and radiological phenotype associated with MAP1B-related disorders and highlights its position as a key cytoskeletal regulator in human corticogenesis. Systematic genotype-phenotype correlation and functional studies are needed to inform diagnostic interpretation and explore therapeutic avenues in MAP1B-associated disease.

Background22q11.2 deletion syndrome is associated with schizophrenia, seizures, and often experience intolerance to antipsychotics. Periventricular nodular heterotopia (PNH) is a neuronal migration disorder that can also be observed in individuals with 22q11.2 deletion syndrome. However, to our knowledge, the use of clozapine in adolescent patients with treatment‐resistant schizophrenia and comorbid 22q11.2 deletion syndrome and PNH has not been previously reported.Case PresentationA 17‐year‐old female with treatment‐resistant schizophrenia was referred to our hospital. She presented with auditory hallucinations, disorganized behavior, and insomnia. Multiple antipsychotics, mood stabilizers, benzodiazepines, and modified electroconvulsive therapy were either ineffective or poorly tolerated due to extrapyramidal symptoms. Brain magnetic resonance imaging (MRI) performed under sedation revealed PNH. Genetic testing confirmed a diagnosis of 22q11.2 deletion syndrome. Clozapine was initiated with close monitoring, and her symptoms gradually improved following a slow titration. She was discharged after approximately 6 months and has remained clinically stable for 15 months.ConclusionBrain MRI and genetic testing—even when performed under sedation—may be valuable diagnostic tools in adolescents with treatment‐resistant schizophrenia. Furthermore, the presence of structural brain abnormalities does not preclude the efficacy of clozapine, which may remain a viable and effective treatment option in such cases.

Periventricular nodular heterotopia 9 (PVNH9) arises from defective neuronal migration, which leads to the accumulation of ectopic neurons near the lateral ventricle. PVNH9 is caused by a heterozygous mutation in the microtubule-associated protein 1B (MAP1B) gene. We report a PVNH9 family with a MAP1B variant. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the family. In vitro functional experiments, including messenger RNA (mRNA) splicing validation, quantitative polymerase chain reaction (qPCR) and western-blotting, were performed to determine the pathogenicity of the novel variant of MAP1B. WES showed that both the patient and her father carried a heterozygous MAP1B variant (c.7091 dup). Sanger sequencing confirmed that this variant occurred de novo in the father. In vitro functional experiments, mRNA splicing verification indicated normal splicing for both wild-type and mutant types. The qPCR and western blot analyses demonstrated significantly reduced mRNA and protein expression, respectively, in the mutant compared with that in the wild-type. Additionally, by comprehensive summary on genotype-phenotype associations of MAP1B in previously reported literatures, we found that loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness. We clarified the genetic diagnosis for the family. Additionally, this study reveals a novel LOF variant in MAP1B and provides a comprehensive overview of MAP1B genotype and phenotype, aiding in the diagnosis and genetic counseling.

Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration. Loss-of-function (LOF) variants give rise to a wide variety of symptoms with periventricular nodular heterotopia (PVNH) and epilepsy as the most common features. FLNA deficiency manifests as a multisystemic disorder with abnormalities of connective tissue and involvement of the cardiovascular, pulmonary, gastrointestinal and hematological system. Affected individuals need a multidisciplinary follow-up, but guidelines are lacking. Here, we present findings from a monocentric cross-sectional cohort study as a basis for improving clinical practices and surveillance for individuals with FLNA deficiency. 24 index patients with FLNA deficiency were identified. In the cohort, 23 patients exhibited clinical features of PVNH, while one individual presented with congenital pulmonary airway malformation (CPAM). The incidence of clinical features such as epilepsy (84%) and cardiovascular involvement (56%) align with previously published cohorts. Systematic multidisciplinary follow-up, particularly regular cardiological screening, was lacking in a significant number of individuals. Additionally, lesser-known symptoms such as constipation and thrombocytopenia were underreported, highlighting the need for comprehensive phenotypic assessment in FLNA deficiency. The incidence of clinical features in this tertiary cohort aligns with existing literature. The absence of uniform and multidisciplinary guidelines hampers effective surveillance and management. Implementation of regular cardiological screening and increased awareness of less overt symptoms could improve medical outcomes for individuals with pathogenic FLNA variants.

Small supernumerary marker chromosomes (sSMC) constitute a rare group of structural chromosomal abnormalities characterized by additional genetic material that cannot be identified by conventional banding cytogenetics. The incidence of sSMC is extremely rare, and most are expected to have no clinical phenotypic abnormalities. Advanced cytogenetic modalities are crucial for sSMCs identification, characterization, and analysis of chromosomal structure. An 8-day-old neonate born to a G2P2 mother with gestational diabetes and a history of infertility was admitted for respiratory distress. Clinical evaluations included chromosomal microarray, karyotyping, fluorescence insitu hybridization (FISH), brain magnetic resonance imaging (MRI), and cardiac computed tomography (CT). Initial echocardiography revealed atrial and ventricular septal defects, patent ductus arteriosus, and left pulmonary artery stenosis. Brain MRI showed trigonocephaly, ventriculomegaly, corpus callosum dysgenesis, and gray matter heterotopia. Chromosomal microarray identified proximal duplication of 15q and duplication of 2p. Despite intensive care and surgical interventions, the infant faced recurrent respiratory complications and failed extubation attempts. SMC involving chromosomes 15 and 2 presenting with multiple congenital anomalies delineate the genotype-phenotype correlation roadmap. Rapid and immense development in cytogenetics may expand further correlation strategies in the future.

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.

ABSTRACTBackground: The ADP‐ribosylation factor 1 (ARF1) gene encodes a protein which plays a critical role in intra‐Golgi transport. Clinical evidence suggests that individuals harbouring variants in the ARF1 gene display a consistent set of phenotypic features, including intellectual disability, microcephaly, epilepsy, and periventricular nodular heterotopia (PVNH). Methods: This study describes the case of a 6‐year and 5‐month‐old female presenting with focal seizures on a fixed side that were resistant to various anti‐seizure medications. The genetic aetiology was elucidated through exome sequencing of the pedigree. The pathogenicity of the identified variant was subsequently assessed using molecular dynamics structural analysis, western blotting, and co‐immunoprecipitation techniques. Results: A de novo variant, c.509T > C (p.Leu170Pro), was detected in the ARF1 gene, and functional analysis demonstrated that this modification is anticipated to hinder its association with the Golgi‐localising, γ‐adaptin ear homology domain and ARF‐binding protein, thereby playing a role in the pathogenesis of the disease. Conclusion: This study introduces the initial instance of ARF1‐related disease in China, wherein the patient is without the presence of PVNH. The findings add novel clinical phenotypes to the range of ARF1‐related diseases, and an investigation into the potential pathogenic mechanisms of this condition was conducted by confirming the deleterious impacts of the variant.

In a recent study conducted by Laura Stourm et al., the authors identified that patients with pulmonary hypertension (PH) harboring loss‐of‐function variants in the Filamin A (FLNA) gene exhibit a unique spectrum of phenotypes. These include pulmonary involvement with lung parenchymal abnormalities and emphysema, as well as a range of extrapulmonary manifestations such as dysmorphic facial features, epilepsy, congenital heart defects, valvular and aortic diseases, thrombocytopenia, and periventricular nodular heterotopia (PVNH). Based on these findings, the study advocates for FLNA genetic screening in patients with PH who present with these specific phenotypic features. Here, we describe a clinical case that aligns closely with the observations reported in their study.

Filamin A (FLNA) is a key protein that binds actin filaments to transmembrane integrins and plays an important role in maintaining cell shape and signaling. In the brain, FLNA is emerging as a critical regulator of neurodevelopment, neuronal migration, actin organization, and neuromodulation. Mutations and/or aberrant expression of the FLNA gene are associated with various brain diseases, such as periventricular heterotopia, Ehlers-Danlos syndrome, and other disorders with impaired cognitive function and brain maldevelopment. Here, we discuss the critical role of FLNA in brain function; its interactions with receptors, integrins, and signaling molecules, as well as the implications of its activity for brain health and disease.

Revision LITT for Epilepsy: How likely are patients to get a second treatment if the first fails?

Market authorization of a pesticide or biocide in Europe requires the hazard assessment of endocrine-disrupting properties, including the thyroid modality. Substances inducing thyroid histopathological and/or thyroid hormone effects in rodent studies need to be further investigated to rule out whether the substance can be considered as an endocrine disruptor for the thyroid pathway, including neurodevelopmental impact in pups and its relevance in humans. Histopathological assessment for identifying reliable biomarkers for assessing neurodevelopmental effects is an important aspect of this testing scheme in rats. Periventricular heterotopia in the corpus callosum and persistence of the external granular layer in the cerebellum have been proposed as potential histopathological biomarkers in the brain. The correlation in the cochlea for hearing impairment seen in rat pups derived from hypothyroid dams is another potential biomarker. Herein, we provide a brief overview of the histopathological endpoints. The technical challenges in correctly identifying these changes during brain development and their significance in detecting the impact of maternal hypothyroidism in rodents are discussed. This mini review is part of a scientific presentation by Dr Gangadharan during the developmental neurotoxicity (DNT) session at the 21st ESTP's Annual Congress (2024).

CHARGE is a syndrome that affects the brain, eyes, ears, heart, face, and genitourinary system. Prenatal diagnosis could optimize counseling, delivery planning, and therapeutic interventions; however, reports of associated fetal neuroimaging features are scarce. While some findings are nonspecific, olfactory, inner ear, and skull base anomalies are commonly present and may be observable at the time of fetal imaging. We sought to determine the scope of prenatal CNS MRI findings in CHARGE syndrome with emphasis on findings not included in the diagnostic criteria for CHARGE syndrome, such as coronal clival cleft. Retrospective review of fetal +/- postnatal neuroimaging from patients with genetic diagnosis of CHARGE syndrome was conducted. Brain, ear, eye, face, and skull base bone abnormalities were documented. Descriptive statistics were employed to characterize the findings. Eighteen fetal-maternal dyads were included. Median gestational age at time of prenatal MRI was 26.25 weeks. Thirteen (72%) subjects were born alive, of which 10 (55.6%) were males. One died on the first day of life (5.6%) and 4/18 (22.2%) underwent termination of pregnancy. Twelve (66.7%) had postnatal brain MRI and/or temporal bone CT. On prenatal MRI, coronal clival cleft was seen in 72% of the cases and confirmed in all patients with postnatal imaging. Inner ear dysplasia was universally seen in all prenatal MRI, except for 1 case, in which this was not evaluable, and confirmed in all cases postnatally. On prenatal imaging, olfactory apparatus hypoplasia/absence was detected in 83% of the cases, followed by globe dysmorphia and/or colobomas in 44% of the cases, atresia of choanae (39%), facial clefts (22%), and cerebellar malformation (16.7%). Of the 10 cases with postnatal brain MRI available, 4 (40%) demonstrated cerebellar gray matter heterotopia. The most common fetal neuroimaging findings supporting the diagnosis of CHARGE syndrome are olfactory deficiency and inner ear dysplasia. Coronal clival clefts are often present and are frequently visible on prenatal MR imaging. The presence of a clival coronal cleft should raise the possibility of CHARGE syndrome, particularly when associated with other known cardinal findings, such as cerebellar dysgenesis, olfactory apparatus deficiency, and inner ear dysplasia.