Periventricular Heterotopia Research Articles

Unusual atypical language lateralization.

Determining the language-dominant hemisphere is essential for planning epilepsy surgery. A 60-year-old right-handed woman with epilepsy since age 16 failed a partial right anterior lobectomy at age 21. Later, a brain MRI found extensive right-sided cortical dysplasia and periventricular heterotopia. Subsequently, prolonged video-EEG monitoring localized her seizures to the right temporoparietal region. Functional MRI was inconclusive in lateralizing her language, prompting a Wada test, which strongly lateralized language to the right. This unique case of atypical language representation in a right-handed individual with an extensive right-hemispheric congenital malformation and seizure focus illustrates the important thorough presurgical language assessment.

Evaluation of Subependymal Gray Matter Heterotopias on Fetal MRI.

Subependymal grey matter heterotopias are seen in a high proportion of children with Chiari II malformation and are potentially clinically relevant. However, despite its growing use, there is little in the literature describing its detection on fetal MRI. Our aim was to evaluate the accuracy in diagnosing subependymal gray matter heterotopias in fetuses with spinal dysraphism on fetal MR imaging. This study is a retrospective analysis of 203 fetal MRIs performed at a single institution for spinal dysraphism during a 10-year period. Corresponding obstetric sonography, postnatal imaging, and clinical/operative reports were reviewed. Of the fetal MRIs reviewed, 95 fetuses were included in our analysis; 23.2% (22/95) were suspected of having subependymal gray matter heterotopias on fetal MR imaging prospectively. However, only 50% (11/22) of these cases were confirmed on postnatal brain MR imaging. On postnatal brain MR imaging, 28.4% (27/95) demonstrated imaging findings consistent with subependymal gray matter heterotopia. Only 40.7% (11/27) of these cases were prospectively diagnosed on fetal MR imaging. Fetal MR imaging is limited in its ability to identify subependymal gray matter heterotopias in fetuses with spinal dysraphism. It is believed that this limitation relates to a combination of factors, including artifacts from fetal motion, the very small size of fetal neuroanatomy, differences in imaging techniques, and, possibly, irregularity related to denudation of the ependyma/subependyma in the presence of spinal dysraphism and/or stretching of the germinal matrix in ventriculomegaly.

Mutation in the sixth immunoglobulin domain of L1CAM is associated with migrational brain anomalies.

Objective:To describe the phenotype of a patient with classical features of X-linked L1 syndrome associated with novel brain malformations.Methods:Diagnostic analysis included physical and dysmorphology examinations, MRI of the brain, and exome sequencing of the family trio.Results:We report a 2.5-year-old boy with developmental delay, dysmorphic facies, and adducted thumbs. MRI of the brain showed a truncated corpus callosum and periventricular heterotopias associated with polymicrogyria (PMG). Variant segregation analysis with exome sequencing discovered a novel maternally derived hemizygous variant in exon 14 of the L1CAM gene (c.1759 G>C; p.G587R).Conclusions:This novel L1CAM mutation was located in the protein's sixth immunoglobin domain and involved glycine-587, a key residue in the structure of L1CAM because of its interactions with lysine-606, which indicates that any mutation at this site would likely affect the secondary structure and function of the protein. The replacement of the small nonpolar glycine residue with a large basic arginine would have an even more dramatic result. The presentation of periventricular nodular heterotopias with overlying PMG is very uncommon, and its association with L1CAM may provide insight into other similar cases. Furthermore, this presentation indicates the important role that L1CAM plays in neuronal migration and brain development and extends the phenotype associated with L1CAM-associated disorders.

Periventricular white matter abnormalities and restricted repetitive behavior in autism spectrum disorder.

Malformations of cortical development are found at higher rates in autism spectrum disorder (ASD) than in healthy controls on postmortem neuropathological evaluation but are more variably observed on visual review of in-vivo MRI brain scans. This may be due to the visually elusive nature of many malformations on MRI. Here, we utilize a quantitative approach to determine whether a volumetric measure of heterotopic gray matter in the white matter is elevated in people with ASD, relative to typically developing controls (TDC). Data from a primary sample of 48 children/young adults with ASD and 48 age-, and gender-matched TDCs, selected from the Autism Brain Imaging Data Exchange (ABIDE) open-access database, were analyzed to compare groups on (1) blinded review of high-resolution T1-weighted research sequences; and (2) quantitative measurement of white matter hypointensity (WMH) volume calculated from the same T1-weighted scans. Groupwise WMH volume comparisons were repeated in an independent, multi-site sample (80 ASD/80 TDC), also selected from ABIDE. Visual review resulted in equivalent proportions of imaging abnormalities in the ASD and TDC group. However, quantitative analysis revealed elevated periventricular and deep subcortical WMH volumes in ASD. This finding was replicated in the independent, multi-site sample. Periventricular WMH volume was not associated with age but was associated with greater restricted repetitive behaviors on both parent-reported and clinician-rated assessment inventories. Thus, findings demonstrate that periventricular WMH volume is elevated in ASD and associated with a higher degree of repetitive behaviors and restricted interests. Although the etiology of focal WMH clusters is unknown, the absence of age effects suggests that they may reflect a static anomaly.

47 patients with FLNA associated periventricular nodular heterotopia.

BackgroundHeterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established.MethodsSanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients.ResultsThirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age.ConclusionsWe report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.

Epilepsy is a possible feature in Williams‐Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region

Seizures are rarely reported in Williams-Beuren syndrome (WBS)--a contiguous-gene-deletion disorder caused by a 7q11.23 heterozygous deletion of 1.5-1.8 Mb--and no previous study evaluated electro-clinical features of epilepsy in this syndrome. Furthermore, it has been hypothesized that atypical deletion (e.g., larger than 1.8 Mb) may be responsible for a more pronounced neurological phenotypes, especially including seizures. Our objectives are to describe the electro-clinical features in WBS and to correlate the epileptic phenotype with deletion of the 7q11.23 critical region. We evaluate the electro-clinical features in one case of distal 7q11.23 deletion syndrome and in eight epileptic WBS (eWBS) patients. Additionally, we compare the deletion size-and deleted genes-of four epileptic WBS (eWBS) with that of four non-epileptic WBS (neWBS) patients. Infantile spasms, focal (e.g., motor and dyscognitive with autonomic features) and generalized (e.g., tonic-clonic, tonic, clonic, myoclonic) seizures were encountered. Drug-resistance was observed in one patient. Neuroimaging discovered one case of focal cortical dysplasia, one case of fronto-temporal cortical atrophy and one case of periventricular nodular heterotopia. Comparison of deletion size between eWBS and neWBS patients did not reveal candidate genes potentially underlying epilepsy. This is the largest series describing electro-clinical features of epilepsy in WBS. In WBS, epilepsy should be considered both in case of typical and atypical deletions, which do not involve HIP1, YWHAG or MAGI2.

NEURONAL MIGRATION DISORDER – A CLINICAL CASE

The authors present the case of a newborn transferred to the Neonatology Section of IOMC Polizu, 43 hours after birth suffering from syndrome of neonatal respiratory distress and suspicion of maternal – fetal infection, extensively investigated during hospitalization for persistency of muscle tone disorder which could not be explained by asphyxia at birth, diagnosed after MRI with right periventricular heterotopia associated with left temporal porencephalic cyst and schizencephaly on the same side.

Phenotypic and imaging features of FLNA-negative patients with bilateral periventricular nodular heterotopia and epilepsy.

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development due to impaired neuronal migration resulting in the formation of nodular masses of neurons and glial cells in close proximity to the ventricular walls. We report the clinical characteristics of the largest case series of FLNA-negative patients with seizures and bilateral periventricular heterotopia. Participants were recruited through the Epilepsy Phenome/Genome Project (EPGP), a multicenter collaborative effort to collect detailed phenotypic data and DNA on a large number of individuals with epilepsy, including a cohort with symptomatic epilepsy related to PVNH. Included subjects had epilepsy, and MRI confirmed bilateral PVNH. Magnetic resonance imaging studies were visually and quantitatively reviewed to investigate the topographic extent of PVNH, symmetry, and laterality. We analyzed data on 71 patients with bilateral PVNH. The incidence of febrile seizures was 16.6%. There was at least one other family member with epilepsy in 36.9% of this population. Developmental delay was present in 21.8%. Focal onset seizures were the most common type of seizure presentation (79.3%). High heterotopia burden was strongly associated with female gender and trigonal nodular localization. There was no evidence for differences in brain volume between PVNH subjects and controls. No relationship was observed between heterotopic volume and gender, developmental delay, location of PVNH, ventricular or cerebellar abnormalities, laterality of seizure onset, age at seizure onset, and duration of epilepsy. A direct correlation was observed between high heterotopia burden, female gender, and trigonal location in this large cohort of FLNA-negative bilateral PVNH patients with epilepsy. Quantitative MRI measurements indicated that this correlation is based on the diffuse nature of the heterotopic nodules rather than on the total volume of abnormal heterotopic tissue.

Cell Junction Pathology of Neural Stem Cells Is Associated With Ventricular Zone Disruption, Hydrocephalus, and Abnormal Neurogenesis.

Fetal-onset hydrocephalus affects 1 to 3 per 1,000 live births. It is not only a disorder of cerebrospinal fluid dynamics but also a brain disorder that corrective surgery does not ameliorate. We hypothesized that cell junction abnormalities of neural stem cells (NSCs) lead to the inseparable phenomena of fetal-onset hydrocephalus and abnormal neurogenesis. We used bromodeoxyuridine labeling, immunocytochemistry, electron microscopy, and cell culture to study the telencephalon of hydrocephalic HTx rats and correlated our findings with those in human hydrocephalic and nonhydrocephalic human fetal brains (n = 12 each). Our results suggest that abnormal expression of the intercellular junction proteins N-cadherin and connexin-43 in NSC leads to 1) disruption of the ventricular and subventricular zones, loss of NSCs and neural progenitor cells; and 2) abnormalities in neurogenesis such as periventricular heterotopias and abnormal neuroblast migration. In HTx rats, the disrupted NSC and progenitor cells are shed into the cerebrospinal fluid and can be grown into neurospheres that display intercellular junction abnormalities similar to those of NSC of the disrupted ventricular zone; nevertheless, they maintain their potential for differentiating into neurons and glia. These NSCs can be used to investigate cellular and molecular mechanisms underlying this condition, thereby opening the avenue for stem cell therapy.

Graves' hyperthyroidism‐induced psychosis in a patient with periventricular nodular heterotopia

Cases of gray matter heterotopia with schizophrenia,1 bipolar disorder,2 and depression3 have been reported; however, the relation between malformations of cortical development and psychotic symptoms is unknown. Here, we describe a woman with a malformation of cortical development who was diagnosed with Graves' hyperthyroidism-induced psychosis. The patient has provided written consent authorizing publication of this report. The patient was an unemployed 40-year-old woman who lived with her parents. About a year before her admission, she started to embarrass her parents occasionally by exhibiting transient paranoid and hallucinatory behavior. This culminated in an acute exacerbation of disorganized behavior, including self-injury and confining herself in a closet a week before her admission. While under the influence of an imperative hallucination, she jumped out of an upstairs window, and was brought to the emergency unit due to fractures of her thoracic and lumbar vertebrae and right calcaneus and damage of her lumbar spine. After admission, she responded sluggishly with a monotonous expression while sometimes crying out suddenly. She was under the strong influence of auditory hallucinations and exhibited delusions of persecution and disorganized thought and behavior. An examination revealed slight exophthalmos, tachycardia, elevated levels of free thyroxine (4.6 ng/dL [normal range: 0.8–1.8]) and free triiodothyronine (FT4; 7.2 pg/mL [2–4.5]), decreased level of thyroid-stimulating hormone (TSH; 0.005 μIU/mL [0.34–4.5]), and the presence of TSH-binding inhibitory immunoglobulin (TBII), which fulfilled the diagnostic criteria of Graves' disease. Brain magnetic resonance imaging revealed unilateral periventricular nodular heterotopia with polymicrogyria in the trigone of right lateral ventricle, accompanied by the dysplasia of right hippocampus and amygdala (Fig. S1). An electroencephalogram showed normal occipital alpha waves (range: 9–10 Hz) with no paroxysmal discharge. Testing with the Wechsler Adult Intelligence Scale-Third Edition showed an almost borderline IQ (verbal: 89; performance: 84; and full-scale: 85) with low processing speed (72). After her admission, we started treating her with olanzapine (up to 10 mg) and thiamazole (15 mg) once a day. As her FT4 levels normalized, so did her behavior. After tapering thiamazole to 5 mg and olanzapine to 1.25 mg once a day, we discharged her and continued treating her as an outpatient. During the 2 years after her discharge, very short recurrences of disorganized behavior were reported twice, while the hyperthyroidism remission and normal social functioning were maintained. To the best of our knowledge, this is the first reported case of heterotopia with Graves' hyperthyroidism-induced psychosis. This case may help clarify the relation between malformations of cortical development and psychotic symptoms. Figure S1. Brain magnetic resonance imaging of the present case. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Can emotional stress trigger the onset of epilepsy?

The aim of this study was to investigate the potential role of an acute adverse stress as "trigger" for the onset of epilepsy. Among 4618 consecutive patients, twenty-two reported a major life event within three months before the onset of epilepsy. All patients had focal epilepsy except one with idiopathic generalized epilepsy. The temporal lobe was involved in 90% of patients with focal epilepsy. More precisely, 13 patients (62% of patients with focal epilepsy) had medial temporal lobe epilepsy (MTLE), two had lateral temporal lobe epilepsy, four had temporoparietooccipital junction epilepsy, and two patients had central lobe epilepsy. The mean age and the median age at onset of epilepsy for patients with MTLE were both 38 years (range: 9.5-65 years). Ten patients had right and three had left MTLE. Among patients with focal epilepsy, MRI was abnormal in 7 (33%) with hippocampal sclerosis in four, periventricular nodular heterotopia in two, and complex cortical dysgenesis in one. The mean age at onset of epilepsy for patients with brain lesions was 26 years (range: 9.5-49). Twelve patients (54%) reported a death as a triggering factor for the onset of their epilepsy. Seven patients (32%) reported that a relationship of trust had been broken. Three patients (14%) had been subjects of violence. No patient reported sexual abuse as a triggering factor. This study provides evidence that some patients (5/1000 patients) began their seizures in the wake of significant life events. The average age at onset of epilepsy is quite late, around age 30, even in the presence of brain lesions. These patients are emotionally and affectively more prone to have consequences of a stressful life event. The recognition and management of such situations may bring significant relief with improvement of the control of epilepsy.

P157 – 2542: Movement disorder, periventricular nodular heterotopia and putaminal hyperintensity due to an ARFGEF2 gene mutation

Objective Periventricular heterotopia, one of the most common malformations of cortical development, is caused by extrinsic factors such as infections and prenatal injuries or genetic mutations. The most common genetic cause of periventricular heterotopia is mutations in the gene encoding filamin-A (FLNA) inherited in an X-linked dominant manner. Mutations in the ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) gene constitute another group of factors that cause association of autosomal recessive periventricular heterotopia with microcephaly. Methods A ten year-old girl was referred with severe developmental and growth delay, feeding problems and involuntary movements. The parents had first degree consanguinity. The birth history was unremarkable. Growth retardation and microcephaly were noticed around 4 months of age. Neurological examination revealed generalized hypotonia with poor head control and severe dystonic-choreoathetoid movements. The extended metabolic work-up of the case was unremarkable. The cranial MR imaging revealed bilateral periventricular nodular heterotopia, bilateral hyperintensity of the putamen and caudate nucleus with frontotemporal and hippocampal atrophy. The EEG of the patient who had no previous seizure history was found normal. Her echocardiography showed left ventricular non-compaction cardiomyopathy. Results The genetic analysis of ARFGEF2 gene revealed a homozygote c.5126G>A, p.Trp1709* mutation. Conclusion Mutations in the ARFGEF2 gene must be considered in the presence of bilateral periventricular nodular heterotopia and putaminal hyperintensity in children presented with movement disorders, severe developmental delay and microcephaly.

PP05.6 – 2896: Genotype-phenotype correlations and counseling in carriers of Filamin A gene mutations

Objective Mutations in the X-linked gene Filamin A (FLNA) are known to be linked to a broad clinical phenotype ranging from otopalatodigital syndromes (OPD1, OPD2) to frontometaphyseal dysplasia, Melnick-Needles syndrome and periventricular nodular heterotopia (PVNH). In the present study we investigate the phenotype-genotype correlation in carriers of FLNA mutations in order to improve the counseling of these patients and their relatives. Methods Clinical and neuroloradiological data from 16 FLNA mutation carriers were collected through retrospective analysis of their hospital files and a standardized questionnaire sent to the referring physician. These data were reviewed by a neurologist, molecular geneticists and a clinical geneticist. Results Fifteen of the carriers were female, as expected in dominant X-linked disorders. Half of the carriers belonged to a mother-child pair, with the mother being diagnosed secondary to the diagnosis in the child. Four carriers had the clinical diagnosis of OPD and their mutations were clustered in exons 3 and 4, whereas the mutations associated with PVNH were scattered throughout the gene. Besides the PVNH other findings on brain MRI included mega cisterna magna, corpus callosum and white matter anomalies. Cardiac investigations revealed aortic valve insufficiency and dilatation of the aorta, even at young age. In the majority of the patients, the clinical work-up focused on the primary indications for FLNA mutation analysis whereby other organs were not systematically investigated. Conclusion Although a lot is already known on the manifestations caused by FLNA mutations, and phenotype-genotype correlations can be made to a certain extent, many patients could benefit from a more extensive work-up and follow-up. This will not only lead to further improvement of our knowledge and understanding of the FLNA-related disorders, but will also allow us to anticipate on certain complications.

PP01.8 – 2708: Lissencephaly with gray matter heterotopias and spinal dysraphism – A new syndrome

Objective Lissencephaly is a rare migrational disorder. There are several subtypes differing in the genetic etiology. Among the entities are classic lissencephaly (LIS1 = PAFAH1B), isolated lissencephaly sequence (PAFAH1B), subcortical band heterotopia (DCX), tubulinopathy (TUBA1A), cobblestone cortical malformation () and microlissencephaly (NDE1). Recently, a new type of severe lissencephaly was described [Abumansour et al., 2014] whose characteristics were lissencephaly with brainstem and cerebellar hypoplasia and congenital cataracts. Methods We describe a patient with severe lissencephaly, extreme microcephaly, dysmorphic features reminiscent of Miller-Dieker Syndrome, grey matter heterotopias and evidence of spinal dysraphism. Results A female patient with severe lissencephaly (grade 1), dysmorphic features, head circumference Conclusion We believe this phenotype should be added to the previously reported entities of severe lissencephaly.

Models of cortical malformation—Chemical and physical

Pharmaco-resistant epilepsies, and also some neuropsychiatric disorders, are often associated with malformations in hippocampal and neocortical structures. The mechanisms leading to these cortical malformations causing an imbalance between the excitatory and inhibitory system are largely unknown. Animal models using chemical or physical manipulations reproduce different human pathologies by interfering with cell generation and neuronal migration. The model of in utero injection of methylazoxymethanol (MAM) acetate mimics periventricular nodular heterotopia. The freeze lesion model reproduces (poly)microgyria, focal heterotopia and schizencephaly. The in utero irradiation model causes microgyria and heterotopia. Intraperitoneal injections of carmustine 1-3-bis-chloroethyl-nitrosurea (BCNU) to pregnant rats produces laminar disorganization, heterotopias and cytomegalic neurons. The ibotenic acid model induces focal cortical malformations, which resemble human microgyria and ulegyria. Cortical dysplasia can be also observed following prenatal exposure to ethanol, cocaine or antiepileptic drugs.All these models of cortical malformations are characterized by a pronounced hyperexcitability, few of them also produce spontaneous epileptic seizures. This dysfunction results from an impairment in GABAergic inhibition and/or an increase in glutamatergic synaptic transmission. The cortical region initiating or contributing to this hyperexcitability may not necessarily correspond to the site of the focal malformation. In some models wide-spread molecular and functional changes can be observed in remote regions of the brain, where they cause pathophysiological activities.This paper gives an overview on different animal models of cortical malformations, which are mostly used in rodents and which mimic the pathology and to some extent the pathophysiology of neuronal migration disorders associated with epilepsy in humans.

Cytoskeletal proteins in cortical development and disease: actin associated proteins in periventricular heterotopia

The actin cytoskeleton regulates many important cellular processes in the brain, including cell division and proliferation, migration, and cytokinesis and differentiation. These developmental processes can be regulated through actin dependent vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with cellular membranes and proteins. Disruption in the actin cytoskeleton in the brain gives rise to periventricular heterotopia (PH), a malformation of cortical development, characterized by abnormal neurons clustered deep in the brain along the lateral ventricles. This disorder can give rise to seizures, dyslexia and psychiatric disturbances. Anatomically, PH is characterized by a smaller brain (impaired proliferation), heterotopia (impaired initial migration) and disruption along the neuroependymal lining (impaired cell-cell adhesion). Genes causal for PH have also been implicated in actin-dependent processes. The current review provides mechanistic insight into actin cytoskeletal regulation of cortical development in the context of this malformation of cortical development.

Familial periventricular nodular heterotopia, epilepsy and Melnick–Needles Syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects

BackgroundLoss-of-function mutations of the FLNA gene cause a neuronal migration disorder defined as X-linked periventricular nodular heterotopia (PNH); gain-of-function mutations are associated with a group of X-linked skeletal dysplasias designed...

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

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. 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. 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. 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.

Diverse phenotypic consequences of mutations affecting the C-terminus of FLNA.

Filamin A, the filamentous protein encoded by the X-linked gene FLNA, cross-links cytoskeletal actin into three-dimensional networks, facilitating its role as a signalling scaffold and a mechanosensor of extrinsic shear forces. Central to these functions is the ability of FLNA to form V-shaped homodimers through its C-terminal located filamin repeat 24. Additionally, many proteins that interact with FLNA have a binding site that includes the C-terminus of the protein. Here, a cohort of patients with mutations affecting this region of the protein is studied, with particular emphasis on the phenotype of male hemizygotes. Seven unrelated families are reported, with five exhibiting a typical female presentation of periventricular heterotopia (PH), a neuronal migration disorder typically caused by loss-of-function mutations in FLNA. One male presents with widespread PH consistent with previous male phenotypes attributable to hypomorphic mutations in FLNA. In stark contrast, two brothers are described with a mild PH presentation, due to a missense mutation (p.Gly2593Glu) inserting a large negatively charged amino acid into the hydrophobic dimerisation interface of FLNA. Co-immunoprecipitation, in vitro cross-linking studies and gel filtration chromatography all demonstrated that homodimerisation of isolated FLNA repeat 24 is abolished by this p.Gly2593Glu substitution but that extended FLNA(Gly2593Glu) repeat 16-24 constructs exhibit dimerisation. These observations imply that other interactions apart from those mediated by the canonical repeat 24 dimerisation interface contribute to FLNA homodimerisation and that mutations affecting this region of the protein can have broad phenotypic effects. • Mutations in the X-linked gene FLNA cause a spectrum of syndromes. • Genotype-phenotype correlations are emerging but still remain unclear. • C-term mutations can confer male lethality, survival or connective tissue defects. • Mutations leading to the latter affect filamin dimerisation. • This deficit is compensated for by remotely acting domains elsewhere in FLNA.

Physiological consequences of abnormal connectivity in a developmental epilepsy.

Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities. We employed transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recording in 8 patients with epilepsy from periventricular nodular heterotopia and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions. Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in 1 subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone. Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions.