Asymmetrical aortic root aneurism in patient with Filamin A mutation.

We report the case of a 28 years old woman with periventricular nodular heterotopia, due to Filamin A mutation. She had an asymmetrical aneurysm of the aortic root, involving, above all, noncoronary Valsalva sinus. She was asymptomatic and she had moderate aortic regurgitation. Reimplantation of the aortic valve with replacement of the aortic root was successfully accomplished. Filamin A is a protein that is encoded by the FLNA gene, which shows X-linked dominant inheritance. This protein is involved in neuronal migration, angiogenesis, cytoskeleton regulation, and cell signaling. Therefore, mutations of FLNA gene might result in brain, blood vessels, heart, and connective tissue disorders. A miscellany of cardiovascular abnormalities could be present in this subset of patients; cardiac symptoms may precede neurological manifestations. Aorta seems to be frequently affected. Consequently, in presence of FLNA gene mutations, cardiovascular evaluation should include vascular magnetic resonance imaging or computed tomography scan.

Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia.

Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions2. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines1,3. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.

The spectrum of structural and functional network alterations in malformations of cortical development.

Neuroimaging studies of malformations of cortical development have mainly focused on the characterization of the primary lesional substrate, while whole-brain investigations remain scarce. Our purpose was to assess large-scale brain organization in prevalent cortical malformations. Based on experimental evidence suggesting that distributed effects of focal insults are modulated by stages of brain development, we postulated differential patterns of network anomalies across subtypes of malformations. We studied a cohort of patients with focal cortical dysplasia type II (n = 63), subcortical nodular heterotopia (n = 44), and polymicrogyria (n = 34), and compared them to 82 age- and sex-matched controls. Graph theoretical analysis of structural covariance networks indicated a consistent rearrangement towards a regularized architecture characterized by increased path length and clustering, as well as disrupted rich-club topology, overall suggestive of inefficient global and excessive local connectivity. Notably, we observed a gradual shift in network reconfigurations across subgroups, with only subtle changes in focal cortical dysplasia type II, moderate effects in heterotopia and maximal effects in polymicrogyria. Analysis of resting state functional connectivity also revealed gradual network changes, with most marked rearrangement in polymicrogyria; contrary to findings in the structural domain, however, functional architecture was characterized by decreases in both local and global parameters. Diverging results in the structural and functional domain were supported by formal structure-function coupling analysis. Our findings support the concept that time of insult during corticogenesis impacts the severity of topological network reconfiguration. Specifically, late-stage malformations, typified by polymicrogyria, may selectively disrupt the formation of large-scale cortico-cortical networks and thus lead to a more profound impact on whole-brain organization than early stage disturbances of predominantly radial migration patterns observed in cortical dysplasia type II, which likely affect a relatively confined cortical territory.

Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells.

Malformations of the cerebral cortex (MCCs) are devastating developmental disorders. We report here that mice with embryonic neural stem-cell-specific deletion of Llgl1 (Nestin-Cre/Llgl1fl/fl), a mammalian ortholog of the Drosophila cell polarity gene lgl, exhibit MCCs resembling severe periventricular heterotopia (PH). Immunohistochemical analyses and live cortical imaging of PH formation revealed that disruption of apical junctional complexes (AJCs) was responsible for PH in Nestin-Cre/Llgl1fl/fl brains. While it is well known that cell polarity proteins govern the formation of AJCs, the exact mechanisms remain unclear. We show that LLGL1 directly binds to and promotes internalization of N-cadherin, and N-cadherin/LLGL1 interaction is inhibited by atypical protein kinase C-mediated phosphorylation of LLGL1, restricting the accumulation of AJCs to the basolateral-apical boundary. Disruption of the N-cadherin-LLGL1 interaction during cortical development in vivo is sufficient for PH. These findings reveal a mechanism responsible for the physical and functional connection between cell polarity and cell-cell adhesion machineries in mammalian cells.

Clinical and neuroimaging findings in children with gray matter heterotopias: A single institution experience of 36 patients.

OBJECTIVE: To describe the clinical spectrum and neuroimaging features of childhood gray matter heterotopias in a single tertiary hospital in Taiwan. METHODS: We retrospectively reviewed the medical records and magnetic resonance images (MRI) of 36 patients with gray matter heterotopias, 19 females and 17 males, between July 1999 and June 2014. The MRI morphologic findings of gray matter heterotopias were recorded along with the presence of associated cerebral malformations. The clinical, electrophysiological and associated systemic malformation data were also recorded. RESULTS: A total of 36 patients were included in the study. Their ages ranged from 1 month to 18 years with a mean age of 3 years 6 months. According to the location of gray matter heterotopias, patients were classified into two groups: periventricular (26) and band (10). The phenotypic spectrum in our population differed from that described previously. In the periventricular group, additional cerebral malformations were found in 18/26 (69%) and systemic malformations in 14/26 (54%). In the band group, additional cerebral malformations were found in 5/10 (50%) and systemic malformations in 2/10 (20%). The majority of patients had developmental delay and intellectual deficit. Twenty-two patients suffered from epileptic seizures with 12 developing refractory epilepsy. CONCLUSIONS: In periventricular heterotopias, the most common associated cerebral malformation was ventriculomegaly, followed by agenesis of corpus callosum. Congenital heart disease was the most common additional systemic malformation. However, the most common associated cerebral malformation was pachygyria in band form. The majority of patients had developmental delay, intellectual deficit, especially in band heterotopias.

Nodule excitability in an animal model of periventricular nodular heterotopia: c-fos activation in organotypic hippocampal slices.

OBJECTIVE: Aberrations in brain development may lead to dysplastic structures such as periventricular nodules. Although these abnormal collections of neurons are often associated with difficult-to-control seizure activity, there is little consensus regarding the epileptogenicity of the nodules themselves. Because one common treatment option is surgical resection of suspected epileptic nodules, it is important to determine whether these structures in fact give rise, or essentially contribute, to epileptic activities. METHODS: To study the excitability of aberrant nodules, we have examined c-fos activation in organotypic hippocampal slice cultures generated from an animal model of periventricular nodular heterotopia created by treating pregnant rats with methylazoxymethanol acetate. Using this preparation, we have also attempted to assess tissue excitability when the nodule is surgically removed from the culture. We then compared c-fos activation in this in vitro preparation to c-fos activation generated in an intact rat treated with kainic acid. RESULTS: Quantitative analysis of c-fos activation failed to show enhanced nodule excitability compared to neocortex or CA1 hippocampus. However, when we compared cultures with and without a nodule, presence of a nodule did affect the excitability of CA1 and cortex, at least as reflected in c-fos labeling. Surgical removal of the nodule did not result in a consistent decrease in excitability as reflected in the c-fos biomarker. SIGNIFICANCE: Our results from the organotypic culture were generally consistent with our observations on excitability in the intact rat-as seen not only with c-fos but also in previous electrophysiologic studies. At least in this model, the nodule does not appear to be responsible for enhanced excitability (or, presumably, seizure initiation). Excitability is different in tissue that contains a nodule, suggesting altered network function, perhaps reflecting the abnormal developmental pattern that gave rise to the nodule.

Morphometric changes in subcortical structures of the central auditory pathway in mice with bilateral nodular heterotopia.

Malformations of cortical development (MCD) have been observed in human reading and language impaired populations. Injury-induced MCD in rodent models of reading disability show morphological changes in the auditory thalamic nucleus (medial geniculate nucleus; MGN) and auditory processing impairments, thus suggesting a link between MCD, MGN, and auditory processing behavior. Previous neuroanatomical examination of a BXD29 recombinant inbred strain (BXD29-Tlr4(lps-2J)/J) revealed MCD consisting of bilateral subcortical nodular heterotopia with partial callosal agenesis. Subsequent behavioral characterization showed a severe impairment in auditory processing-a deficient behavioral phenotype seen across both male and female BXD29-Tlr4(lps-2J)/J mice. In the present study we expanded upon the neuroanatomical findings in the BXD29-Tlr4(lps-2J)/J mutant mouse by investigating whether subcortical changes in cellular morphology are present in neural structures critical to central auditory processing (MGN, and the ventral and dorsal subdivisions of the cochlear nucleus; VCN and DCN, respectively). Stereological assessment of brain tissue of male and female BXD29-Tlr4(lps-2J)/J mice previously tested on an auditory processing battery revealed overall smaller neurons in the MGN of BXD29-Tlr4(lps-2J)/J mutant mice in comparison to BXD29/Ty coisogenic controls, regardless of sex. Interestingly, examination of the VCN and DCN revealed sexually dimorphic changes in neuronal size, with a distribution shift toward larger neurons in female BXD29-Tlr4(lps-2J)/J brains. These effects were not seen in males. Together, the combined data set supports and further expands the observed co-occurrence of MCD, auditory processing impairments, and changes in subcortical anatomy of the central auditory pathway. The current stereological findings also highlight sex differences in neuroanatomical presentation in the presence of a common auditory behavioral phenotype.

Genesis of heterotopia in BCNU model of cortical dysplasia, detected by means of in utero electroporation.

Derangements of cortical development can cause a wide spectrum of malformations, generally termed 'cortical dysplasia' (CD), which are frequently associated with drug-resistant epilepsy and other neurological and mental disorders. 1,3-Bis-chloroethyl-nitrosurea (BCNU)-treated rats represent a model of CD due to the presence of histological alterations similar to those observed in human CD. BCNU is an alkylating agent that, administered at embryonic day 15 (E15), causes the loss of many cells destined to cortical layers; this results in cortical thinning but also in histological alterations imputable to migration defects, such as laminar disorganization and cortical and periventricular heterotopia. In the present study we investigated the genesis of heterotopia in BCNU-treated rats by labeling cortical ventricular zone (VZ) cells with a green fluorescent protein (GFP) expression vector by means of in utero electroporation. Here, we compared the migratory pattern and subsequent distribution of the GFP-labeled cells in the developing somatosensory cortex of control and BCNU-treated animals. To this aim, we investigated the expression of a panel of developmental marker genes which identified radial glia cells (Pax6), intermediate precursors cells (Tbr2), and postmitotic neurons destined to infragranular (Tbr1) or supragranular layers (Satb2). The VZ of BCNU-treated rats appeared disorganized since E18 and at E21 the embryos showed an altered migratory pattern: migration of superficial layers appeared delayed, with a number of migrating cells in the intermediate zone and some neurons destined to superficial layers arrested in the VZ, thus forming periventricular heterotopia. Moreover, neurons that reached their correct position did not extend their axons through the corpus callosum in the contralateral hemisphere as in the control, but toward the ipsilateral cingulated cortex. Our analysis sheds light on how a malformed cortex develops after a temporally discrete environmental insult.

Bilateral posterior periventricular nodular heterotopia: a recognizable cortical malformation with a spectrum of associated brain abnormalities.

BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.

Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion.

Neurological symptoms in tuberous sclerosis complex (TSC) and associated brain lesions are thought to arise from abnormal embryonic neurogenesis due to inherited mutations in Tsc1 or Tsc2. Neurogenesis persists postnatally in the human subventricular zone (SVZ) where slow-growing tumors containing Tsc-mutant cells are generated in TSC patients. However, whether Tsc-mutant neurons from the postnatal SVZ contribute to brain lesions and abnormal circuit remodeling in forebrain structures remain unexplored. Here, we report the formation of olfactory lesions following conditional genetic Tsc1 deletion in the postnatal SVZ using transgenic mice or targeted single-cell electroporation. These lesions include migratory heterotopias and olfactory micronodules containing neurons with a hypertrophic dendritic tree. Most significantly, our data identify migrating glial and neuronal precursors that are re-routed and infiltrate forebrain structures (e.g. cortex) and become glia and neurons. These data show that Tsc1-mutant cells from the neonatal and juvenile SVZ generate brain lesions and structural abnormalities, which would not be visible using conventional non-invasive imaging. These findings also raise the hypothesis that micronodules and the persistent infiltration of cells to forebrain structures may contribute to network malfunction leading to progressive neuropsychiatric symptoms in TSC.

Lung disease associated with periventricular nodular heterotopia and an FLNA mutation.

X-linked periventricular nodular heterotopia (PH) is a neuronal migration disorder caused by mutations in the gene encoding filamin A (FLNA). High phenotypic diversity, ranging from PH to otopalatodigital syndrome and frontometaphyseal dysplasia has been described in association with FLNA mutations. Extra-neurological features including cardiovascular abnormalities, coagulopathy, skeletal dysplasia and joint hypermobility have sometimes been described in patients with PH. Respiratory manifestations have not been associated with FLNA disorders with the exception of tracheal stenosis and pulmonary hypoplasia associated with frontometaphyseal dysplasia and Melnick-Needles syndrome. Here, we report on a male patient aged 6 years presenting with a mosaic nonsense mutation c.994delG within the FLNA gene, PH and severe congenital lung disease comprising bilateral atelectasis, lung cysts, tracheobronchomalacia, pulmonary arterial hypertension and long-term oxygen dependence; histology of resected lung showed panpulmonary emphysema with marked reduction of bronchial cartilage. Rare male patients with PH and FLNA mutations have already been reported, usually with early lethality. These observations suggest the possibility of a link between FLNA mutations and congenital lung disease. A prospective study of patients with PH and FLNA mutations would be helpful in order to test this hypothesis.

Functional MRI interactions between dysplastic nodules and overlying cortex in periventricular nodular heterotopia.

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development associated with epilepsy. It is unclear whether the epileptogenic focus is the nodule, overlying cortex, or both. We performed electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) in a patient with bilateral PVNH, capturing 45 "left temporal" epileptiform discharges. The relative time at which fMRI-involved regions became active was assessed. Additionally, nodule-cortex interactions were explored using fMRI functional connectivity. There was EEG-fMRI activity in specific periventricular nodules and overlying cortex in the left temporoparietal region. In both nodules and cortex, the peak BOLD response to epileptiform events occurred earlier than expected from standard fMRI hemodynamic modeling. Functional connectivity showed nodule-cortex interactions to be strong in this region, even when the influence of fMRI activity fluctuations due to spiking was removed. Nonepileptogenic, contralateral nodules did not show connectivity with overlying cortex. EEG-fMRI and functional connectivity can help identify which of the multiple abnormal regions are epileptogenic in PVNH.

Deletion of YWHAE in a patient with periventricular heterotopias and pronounced corpus callosum hypoplasia.

BACKGROUND: Malformations of cortical development are not rare and cause a wide spectrum of neurological diseases based on the affected region in the cerebral cortex. A significant proportion of these malformations could have a genetic basis. However, genetic studies are limited because most cases are sporadic and mendelian forms are rare. METHODS: In order to identify new genetic causes in patients presenting defects of cortical organisation, array based comparative genomic hybridisation was performed in a cohort of 100 sporadic cases with various types of cortical malformations in search for inframicroscopic chromosomal rearrangements. RESULTS: In one patient presenting with periventricular nodular heterotopias and pronounced corpus callosum hypoplasia, a small (400 kb) 17p13.3 deletion involving the YWHAE gene was identified. It is shown that YWHAE is the only brain expressed gene in the deleted region and that the other genes in the interval are unlikely to contribute to the brain malformation phenotype of this patient. CONCLUSION: Most 17p13.3 deletions reported to date are large, such as the deletions causing Miller-Dieker syndrome, and involve several genes implicated in various steps of brain development. Haploinsufficiency of the mouse orthologue of YWHAE causes a defect of neuronal migration. However, the human counterpart of this phenotype was not known. The case described here represents the smallest reported deletion involving the YWHAE gene and could represent the human counterpart of the abnormal cortical organisation phenotype presented by the Ywhae heterozygous knockout mouse.

Layer-specific genes reveal a rudimentary laminar pattern in human nodular heterotopia.

OBJECTIVE: To define distinctive features of nodular heterotopia in specimens derived from drug-resistant patients with epilepsy by evaluating mRNA expression of three different layer-specific markers: Rorbeta, Er81, and Nurr1. METHODS: We analyzed the expression profile of these genes, recognized as markers mainly expressed in layer IV for Rorbeta, in layer V for Er81, and in layer VI for Nurr1, in surgical samples from 14 epileptic patients, using in situ hybridization. Six patients had subcortical nodular heterotopia and 8 patients were controls. The intrinsic organization of nodular formations and of the overlaying neocortex was assessed. RESULTS: In all patients, the 3 selected genes showed high cortical laminar specificity. In subcortical nodular heterotopia, the different gene expression profiles revealed a rudimentary laminar organization of the nodules. In the overlaying cortex, fewer cells expressed the 3 genes in the appropriate specific layer as compared to controls. CONCLUSIONS: These data provide new insights into possible ontogenetic mechanisms of nodular heterotopia formation and show the potential role of layer-specific markers to elucidate the neuropathology of malformations of cortical development.

De Morsier syndrome associated with periventricular nodular heterotopia: case report.

INTRODUCTION: Septo-optic dysplasia (De Morsier syndrome) is defined as the association between optic nerve hypoplasia, midline central nervous system malformations and pituitary dysfunction. CASE REPORT: Third child born to nonconsanguineous parents, female, adequate pre-natal medical care, cesarean term delivery due to breech presentation, Apgar score 3 at the first minute and 8 at 5 minutes, symptomatic hypoglycemia at 18 hours. Neurological follow-up identified a delay in acquisition of motor and language developmental milestones. Epileptic generalized seizures began at 12 months and were controlled with phenobarbital. EEG was normal. MRI revealed agenesis of the pituitary stalk, hypoplasia of the optic chiasm and periventricular nodular heterotopia. Ophthalmologic evaluation showed bilateral optic disk hypoplasia. Endocrine function laboratory tests revealed primary hypothyroidism and hyperprolactinemia. CONCLUSION: The relevance of this case report relies on its uniqueness, since periventricular heterotopia had not been described in association with septo-optic dysplasia until 2006.

De Morsier syndrome associated with periventricular nodular heterotopia: case reporte

INTRODUCTION: Septo-optic dysplasia (De Morsier syndrome) is defined as the association between optic nerve hypoplasia, midline central nervous system malformations and pituitary dysfunction. CASE REPORT: Third child born to nonconsanguineous parents, female, adequate pre-natal medical care, cesarean term delivery due to breech presentation, Apgar score 3 at the first minute and 8 at 5 minutes, symptomatic hypoglycemia at 18 hours. Neurological follow-up identified a delay in acquisition of motor and language developmental milestones. Epileptic generalized seizures began at 12 months and were controlled with phenobarbital. EEG was normal. MRI revealed agenesis of the pituitary stalk, hypoplasia of the optic chiasm and periventricular nodular heterotopia. Ophthalmologic evaluation showed bilateral optic disk hypoplasia. Endocrine function laboratory tests revealed primary hypothyroidism and hyperprolactinemia. CONCLUSION: The relevance of this case report relies on its uniqueness, since periventricular heterotopia had not been described in association with septo-optic dysplasia until 2006.

INTRODUÇÃO: Displasia septo-óptica (síndrome de De Morsier) é definida como a associação entre hipoplasia do nervo óptico, malformações de linha média do sistema nervoso central e disfunção pituitária. RELATO DE CASO: Terceiro filho, pais não consangüíneos, sexo feminino, pré-natal adequado, parto cesário a termo por apresentação pélvica, Apgar 3 no primeiro minuto e 8 no quinto minuto, hipoglicemia sintomática com 18 horas de vida. Durante o acompanhamento neurológico identificou-se atraso na aquisição dos marcos de desenvolvimento motor e linguagem. Crises epilépticas generalizadas iniciaram com 12 meses de vida sendo controladas com fenobarbital. EEG era normal. Ressonância magnética revelou agenesia de haste pituitária, hipoplasia de quiasma óptico e heterotopia nodular periventricular. Avaliação oftalmológica demonstrou hipoplasia bilateral de disco óptico. Investigação da função endócrina revelou hipotireoidismo primário e hiperprolactinemia. CONCLUSÃO: A relevância deste relato reside em seu ineditismo, já que heterotopia periventricular não havia sido descrita em associação com displasia septo-óptica até 2006.