Heterozygous truncating variant of TAOK1 in a boy with periventricular nodular heterotopia: a case report and literature review of TAOK1-related neurodevelopmental disorders.

BACKGROUND: Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility. CASE PRESENTATION: We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia. CONCLUSIONS: To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1-related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects.

Stereo-EEG-based ictal functional connectivity in patients with periventricular nodular heterotopia-related epilepsy.

Nodular heterotopia (NH)-related drug-resistant epilepsy is challenging due to the deep location of the NH and the complexity of the underlying epileptogenic network. Using ictal stereo-electroencephalography (SEEG) and functional connectivity (FC) analyses in 14 patients with NH-related drug-resistant epilepsy, we aimed to determine the leading structure during seizures. For this purpose, we compared node IN and OUT strength between bipolar channels inside the heterotopia and inside gray matter, at the group level and at the individual level. At seizure onset, the channels within NH belonging to the epileptogenic and/or propagation network showed higher node OUT-strength than the channels within the gray matter (p = .03), with higher node OUT-strength than node IN-strength (p = .03). These results are in favor of a "leading" role of NH during seizure onset when involved in the epileptogenic- or propagation-zone network (50% of patients). However, when looking at the individual level, no significant difference between NH and gray matter was found, except for one patient (in two of three seizures). This result confirms the heterogeneity and the complexity of the epileptogenic network organization in NH and the need for SEEG exploration to characterize more precisely patient-specific epileptogenic network organization.

Diffuse interstitial lung disease in a male fetus with periventricular nodular heterotopia and filamin A mosaic variant.

BACKGROUND: Most periventricular nodular heterotopias (PNHs) are associated with a mutation in the filamin A (FLNA) gene in Xq28. This condition is associated with cardiovascular malformations, connective tissue abnormalities, epilepsy, and intellectual deficiency of varying severity. MATERIALS AND METHODS: We report a new FLNA gene mutation in a male patient associated with PNH and diffuse interstitial lung disease. RESULTS: A 23-year-old woman was referred at 31 gestational weeks to evaluate a suspected mega cisterna magna and ventricular septal defect with atrioventricular valve alignment in a male fetus. The fetal magnetic resonance imaging showed PNH associated with corpus callosum dysgenesis and a mega cisterna magna. At 2 months of age, the infant was diagnosed with severe respiratory distress with hypoxemia. A chest CT scan demonstrated a diffuse interstitial lung pattern with emphysema, multiple atelectasis foci, and signs of pulmonary hypertension. Rapid worsening led to his death at 4 months. Targeted sequencing of the FLNA gene identified a de novo hemizygous variant in 75% mosaic in lymphocyte cells, resulting in incomplete FLNA function loss. DISCUSSION & CONCLUSION: On the diagnosis of antenatal PNH, the possibility of such lung involvement should be considered in the prognostic evaluation during prenatal counseling.

Periventricular nodular heterotopias is associated with mutation at the FLNA locus-a case history and a literature review.

BACKGROUND: Periventricular nodular heterotopia (PNH), associated with FLNA mutations, is a rare clinical condition potentially associated with multiple systemic conditions, including cardiac, pulmonary, skeletal, and cutaneous diseases. However, due to a paucity of information in the literature, accurate prognostic advice cannot be provided to patients with the disease. CASE PRESENTATION: We report a 2-year-old female whose PNH was associated with a nonsense mutation in the q28 region of the X chromosome, in exon 31 of FLNA (c.5159dupA). The patient is currently seizure-free and has no congenital heart disease, lung disease or skeletal or joint issues, and her development is normal. CONCLUSIONS: FLNA-associated PNH is a genetically-heterogeneous disease, and the FLNA mutation, c.5159dupA (p.Tyr1720*) is a newly identified pathogenic variant. FLNA characterization will help the clinical diagnosis and treatment of PNH and provide individualized genetic counseling for patients.

Is periventricular heterotopia a useful endpoint for developmental thyroid hormone system disruption in mouse toxicity studies?

In rats, hypothyroidism during fetal and neonatal development can disrupt neuronal migration and induce the formation of periventricular heterotopia in the brain. However, it remains uncertain if heterotopia also manifest in mice after developmental hypothyroidism and whether they could be used as a toxicological endpoint to detect TH-mediated effects caused by TH system disrupting chemicals. Here, we performed a mouse study where we induced severe hypothyroidism by exposing pregnant mice (n = 3) to a very high dose of propylthiouracil (PTU) (1500 ppm) in the diet. This, to obtain best chances of detecting heterotopia. We found what appears to be very small heterotopia in 4 out of the 8 PTU-exposed pups. Although the incidence rate could suggest some utility for this endpoint, the small size of the ectopic neuronal clusters at maximum hypothyroidism excludes the utility of heterotopia in mouse toxicity studies aimed to detect TH system disrupting chemicals. On the other hand, parvalbumin expression was manifestly lower in the cortex of hypothyroid mouse offspring demonstrating that offspring TH-deficiency caused an effect on the developing brain. Based on overall results, we conclude that heterotopia formation in mice is not a useful toxicological endpoint for examining TH-mediated developmental neurotoxicity.

ARF1-related disorder: phenotypic and molecular spectrum.

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Periventricular nodular heterotopia associated with a "transmantle band sign" in patients with epilepsy.

OBJECTIVE: Previous studies using advanced magnetic resonance imaging (MRI) techniques have documented abnormal transmantle bands connecting ectopic nodules to overlying cortex in patients with periventricular nodular heterotopia (PNH). We describe a similar finding using conventional MRI techniques. METHODS: Patients were identified by means of a full-text search of radiological reports. All scanning was performed using conventional sequences at 3 Tesla (3T). Scans were reviewed by three neuroradiologists, and we characterized imaging features based on type of PNH and cortical irregularities associated with the transmantle band. RESULTS: A total 57 PNH patients were reviewed, of whom 41 demonstrated a "transmantle band" connecting the nodule to the overlying cortex. One or more periventricular heterotopic nodules was present in all 41 patients-this was bilateral in 29 of 41 (71%) and unilateral in the remaining 29%. In many cases there was more than one such band, and in some cases this band was nodular. In 19 of the cases, the cortex to which the band connected was abnormal, showing thinning in 4 cases, thickening in 5 cases, and polymicrogyria in another 10. SIGNIFICANCE: The transmantle band can be seen frequently in both unilateral and bilateral cases of PNH and can be visualized with conventional 3T MRI sequences. The band highlights the underlying neuronal migration issues at play in the pathogenesis of this disorder, but its underlying role in the complex, patient-specific epileptogenic networks in this cohort has yet to be determined and warrants further investigation.

The phenotypic spectrum of epilepsy associated with periventricular nodular heterotopia.

BACKGROUND: Periventricular nodular heterotopia (PVNH) is a congenital brain malformation often associated with seizures. We aimed to clarify the spectrum of epilepsy phenotypes in PVNH and the significance of specific brain malformation patterns. METHODS: In this retrospective cohort study, we recruited people with PVNH and a history of seizures, and collected data via medical record review and a standardized questionnaire. RESULTS: One hundred individuals were included, aged 1 month to 61 years. Mean seizure onset age was 7.9 years. Ten patients had a self-limited epilepsy course and 35 more were pharmacoresponsive. Fifty-five had ongoing seizures, of whom 23 met criteria for drug resistance. Patients were subdivided as follows: isolated PVNH ("PVNH-Only") single nodule (18) or multiple nodules (21) and PVNH with additional brain malformations ("PVNH-Plus") single nodule (8) or multiple nodules (53). Of PVNH-Only single nodule, none had drug-resistant seizures. Amongst PVNH-Plus, 55% with multiple unilateral nodules were pharmacoresponsive, compared to only 21% with bilateral nodules. PVNH-Plus with bilateral nodules demonstrated the highest proportion of drug resistance (39%). A review of genetic testing results revealed eight patients with pathogenic or likely pathogenic single-gene variants, two of which were FLNA. Five had copy number variants, two of which were pathogenic. CONCLUSIONS: The spectrum of epilepsy phenotypes in PVNH is broad, and seizure patterns are variable; however, epilepsy course may be predicted to an extent by the pattern of malformation. Overall, drug-resistant epilepsy occurs in approximately one quarter of affected individuals. When identified, genetic etiologies are very heterogeneous.

Genetic analysis of periventricular nodular heterotopia 7 caused by a novel NEDD4L missense mutation: Case and literature summary.

BACKGROUND: Neurodevelopmental disorders associated with periventricular nodular heterotopia (PVNH) are characterized by phenotypic and genetic heterogeneity. NEDD4L mutation can lead to PVNH7. However, at present, only eight NEDD4L pathogenic variants have been identified across 15 cases of PVNH7 worldwide. Given this dearth of evidence, the precise correlations between genetic pathogenesis and phenotypes remain to be determined. METHODS: This report discusses the case of a 19-month-old male child with cleft palate, seizures, psychomotor retardation, and hypotonia, for whom we verified the genetic etiology using Trio-whole-exome and Sanger sequencing to analyze the potential pathogenicity of the mutant protein structure. Mutant plasmids were constructed for in vitro analyses. After transfection into human 293 T cells, the mutant transcription process was analyzed using real-time PCR (RT-PCR), and levels of mutant protein expression were examined using western blotting (WB) and immunofluorescence (IF) experiments. RESULTS: Genetic analyses revealed a novel missense mutation Gln900Arg, located in the homologous to E6-APC terminal (HECT) domain of NEDD4L and that the parents were wild-type, suggestive of a de novo mutation. The variant was predicted to be pathogenic by bioinformatics software, which also suggested alterations in the structural stability of the mutant protein. RT-PCR results indicated that the mutation did not affect mRNA expression, whereas WB and IF results indicated that the level of mutant protein was significantly reduced by 41.07%. CONCLUSION: Functional experiments demonstrated that Gln900Arg probably did not lead to transcriptional abnormalities in this patient, instead leading to increased ubiquitination activity owing to the constitutive activation of the HECT domain, thereby promoting protein degradation. Extensive clinical reports should be generated for patients presenting with PVNH and/or polymicrogyria, developmental delay, syndactyly, and hypotonia to increase the pool of evidence related to NEDD4L.

Localized activity alternations in periventricular nodular heterotopia-related epilepsy.

OBJECTIVE: Periventricular nodular heterotopia (PNH) is a common type of heterotopia usually characterized by epilepsy. Previous studies have identified alterations in structural and functional connectivity related to this disorder, but its local functional neural basis has received less attention. The purpose of this study was to combine univariate analysis and a Gaussian process classifier (GPC) to assess local activity and further explore neuropathological mechanisms in PNH-related epilepsy. METHODS: We used a 3.0-T scanner to acquire resting-state data and measure local regional homogeneity (ReHo) alterations in 38 patients with PNH-related epilepsy and 38 healthy controls (HCs). We first assessed ReHo alterations by comparing the PNH group to the HC group using traditional univariate analysis. Next, we applied a GPC to explore whether ReHo could be used to differentiate PNH patients from healthy patients at an individual level. RESULTS: Compared to HCs, PNH-related epilepsy patients exhibited lower ReHo in the left insula extending to the putamen as well as in the subgenual anterior cingulate cortex (sgACC) extending to the orbitofrontal cortex (OFC) [p < 0.05, family-wise error corrected]. Both of these regions were also correlated with epilepsy duration. Furthermore, the ReHo GPC classification yielded a 76.32% accuracy (sensitivity = 71.05% and specificity = 81.58%) with p < 0.001 after permutation testing. INTERPRETATION: Using the resting-state approach, we identified localized activity alterations in the left insula extending to the putamen and the sgACC extending to the OFC, providing pathophysiological evidence of PNH. These local connectivity patterns may provide a means to differentiate PNH patients from HCs.

Periventricular heterotopia in a male child with USP9X missense variant.

The ubiquitin-specific protease USP9X has been found to play a role in multiple aspects of neural development including processes of neuronal migrations. In males, hemizygous partial loss of function variants in USP9X lead to a clinical phenotype primarily characterized by intellectual disability, hypotonia, speech and language impairment, behavioral disturbances accompanied by additional clinical features with variable expressivity. Structural brain abnormalities are reported in all cases where neuro-imaging was performed. The most common radiological features described include hypoplasia/agenesis of the corpus callosum, widened ventricles, white matter disturbances, and cerebellar hypoplasia. Here we report a child harboring a missense variant in USP9X presenting with the classical neurodevelopmental phenotype and a previously unreported radiological picture of periventricular heterotopia. This case expands the phenotypic landscape of this emergent condition and supports the critical role of USP9X in neuronal migration processes.

A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome.

KCNB1 encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1-S6), comprising the voltage-sensing domain (S1-S4) and the pore domain (S5-P-S6). Heterozygous KCNB1 pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novo KCNB1 variant c.574G>A, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of -50 to -30 mV. Our case could expand the phenotypic spectrum of patients with KCNB1 variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.

Periventricular nodular heterotopia is coupled with the neocortex during resting and task states.

Periventricular nodular heterotopia (PVNH) is a well-defined developmental disorder characterized by failed neuronal migration, which forms ectopic neuronal nodules along the ventricular walls. Previous studies mainly focus on clinical symptoms caused by the PVNH tissue, such as seizures. However, little is known about whether and how neurons in the PVNH tissue functionally communicate with neurons in the neocortex. To probe this, we applied magnetoencephalography (MEG) and stereo-electroencephalography (sEEG) recordings to patients with PVNH during resting and task states. By estimating frequency-resolved phase coupling strength of the source-reconstructed neural activities, we found that the PVNH tissue was spontaneously coupled with the neocortex in the α-ß frequency range, which was consistent with the synchronization pattern within the neocortical network. Furthermore, the coupling strength between PVNH and sensory areas effectively modulated the local neural activity in sensory areas. In both MEG and sEEG visual experiments, the PVNH tissue exhibited visual-evoked responses, with a similar pattern and latency as the ipsilateral visual cortex. These findings demonstrate that PVNH is functionally integrated into cognition-related cortical circuits, suggesting a co-development perspective of ectopic neurons after their migration failure.

[Modified posterior quadrant disconnection in surgical treatment of drug-resistant epilepsy in a patient with left temporal and occipital lobe malformation]. / Modifitsirovannaya zadnekvadrantnaya diskonnektsiya v khirurgicheskom lechenii farmakorezistentnoi epilepsii u patsienta s porokom razvitiya levykh visochnoi i zatylochnoi dolei.

Adults with large multilobar lesions of temporal, parietal and occipital lobes of the dominant hemisphere suffering from drug-resistant epilepsy were considered inoperable for a long time. OBJECTIVE: To demonstrate favorable postoperative outcome in a patient with massive periventricular heterotopia of the left temporal and occipital lobes complicated by drug-resistant epilepsy. MATERIAL AND METHODS: We analyzed localization of the brain malformation (massive periventricular heterotopia) and its relationship with surrounding structures in a 38-year-old patient considering preoperative MRI, functional MRI and MR tractography data. Quality of modified posterior quadrant disconnection was assessed within a day and 6 months after surgery in accordance with MRI data. Transcranial stimulation, direct cortical and subcortical monopolar stimulation were used for intraoperative monitoring of corticospinal tract. We also assessed neurological status and linguistic testing data before surgery, 4 days and 6 months after surgery. RESULTS: Modified posterior disconnection of temporal, parietal and occipital lobes was performed. Intraoperative neurophysiological cortical mapping (asleep-awake-sedation protocol) verified localization of Wernicke's area. There was an expected right-sided homonymous hemianopsia in postoperative period without speech disorders. Postoperative outcome Engel grade 1A under anticonvulsant therapy was obtained. CONCLUSION: The authors report successful surgical treatment of massive malformation of the left temporal, parietal and occipital lobes and literature review devoted to this issue.

Distinctive Brain Malformations in Zhu-Tokita-Takenouchi-Kim Syndrome.

BACKGROUND AND PURPOSE: Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia. MATERIALS AND METHODS: Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities. RESULTS: Pathogenic variants in SON, causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria. CONCLUSIONS: The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation.

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

OBJECTIVES: 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). MATERIALS & METHODS: 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. RESULTS: 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. CONCLUSION: 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.