Gray matter heterotopy as a cause of seizure: purpose of a case diagnosed in adults

Context: Epilepsy affects more than 50 million people worldwide, which is an important cause of morbidity and functional limitations. Cortical development malformations represent about 8% of epilepsy cases, and are associated with cognitive deficits, that are frequently diagnosed in childhood. Case report: L.G.M, female, 35 years old, was attended in an emergency department with psychotic symptoms, aggressiveness and lowering of the sensorium. Computed Tomography (CT) scan of the brain evidenced hypodensity and loss of cortico-medullary differentation in the left temporo-parietal region. The neuroimaging findings motivated the referral to our service for investigation. Upon admission, has been shown a history of frequent focal motor and non-motor seizures associated with cognitive deficit since the age of 12. During hospitalization, a Magnetic Resonance Imaging (MRI) of the brain was performed, which showed subependymal heterotopy of gray matter (Figures 1 and 2). Since then, the monotherapy treatment with carbamazepine aiming at seizure control was chosen. Discussion and conclusion: Cortical development malformations can be classified into three groups of abnormalities, such as: 1) neuronal and glial proliferation and apoptosis; 2) neuronal migration; 3) cortical organization. A heterotopy of the gray matter is related to the migration disorder of the germinal matrix neurons on the wall of ventricle lateral to the cortex. It is the most frequent anomaly of cortical development. The perception of cognitive deficit associated with epileptic seizures should always awaken to the need for early investigation by image examination, in particular brain MRI, in order to diagnose possible malformations of cortical development.

A Case of Agyria-Pachygyria Presenting as Seizure Disorder in A Young Girl

“Lissencephaly”, a rare gene linked defective neuroblast migration disorder resulting in defective cortical lamination, abnormal gyral development and subcortical heterotropia. Advances in molecular genetics have led to the identification of lissencephaly gene on chromosome 17p13.3 and causing Type-1 Lissencephaly or miller Diecker syndrome where lissencephaly is severe in posterior brain region. Another X-linked gene Doublecortin (DCX) gene where the lissencephaly is more severe in anterior region of the brain. Usually this defect manifests in early infancy or childhood as seizure disorder. A case of lissencephaly with features of Miller Dieker syndrome in a young girl is reported and literature is reviewed. The important feature of the case was its late presentation in a 17 years old girl.

Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the PAFAH1B1 (mouse: Pafah1b1) gene and is characterized by brain malformation, developmental delays, and epilepsy. Here, we investigate the impact of Pafah1b1 mutation on the cellular migration, morphophysiology, microcircuitry, and transcriptomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes. We find that cell-autonomous mutations within interneurons disrupts morphophysiological development of PV+INTs and results in the emergence of a non-canonical ‘intermediate spiking (IS)’ subset of PV+INTs. We also find that now dominant IS/NFS cells are prone to entering depolarization block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.

Emergence of Non-Canonical Parvalbumin-Containing Interneurons in Hippocampus of a Murine Model of Type I Lissencephaly

ABSTRACTType I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the LIS1 gene and is characterized in humans by agyria, mislamination of brain structures, developmental delays, and epilepsy. Here, we investigate the impact of LIS1 mutation on the cellular migration, morphophysiology, microcircuitry and genomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes (basket, axo-axonic, bistratified, radiatum-targeting). We also discover that cell-autonomous mutations within interneurons disrupts morphological development of PV+INTs and results in the emergence of a non-canonical “intermediate spiking (IS)” subset of PV+INTs. In the GlobalLis mutant, IS/NFS cells become the dominant PV+INT subtypes (56%) and the percentage of FS cells shrinks to 44%. We also find that IS/NFS cells are prone to entering depolarizing block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.

The Clinical Picture of a Bilateral Perisylvian Syndrome as the Initial Symptom of Mega-Corpus-Callosum Syndrome due to a MAST1-Gene Mutation

Congenital bilateral perisylvian syndrome (CBPS) is a rare neurological disorder associated with typical clinical and imaging features such as bilateral symmetrical polymicrogyria, either exclusively or mainly affecting the perisylvian region of the brain. We present a girl with the typical clinical picture of a CBPS and a complex migration disorder, predominantly presenting as bilateral symmetrical polymicrogyria associated with corpus callosum hyperplasia, ventricular dilation, and pontine hypoplasia. At the age of 6 months, the girl showed a profound global developmental delay, seizures refractory to treatment, and severe oromotor dysfunction. Exome analysis revealed a de novo mutation in microtubule-associated serine/threonine kinase 1 (MAST1). Recently, mutations in this gene were described in six patients with a cortical migration disorder named mega-corpus-callosum syndrome with cerebellar hypoplasia. Although all patients present the clinical and imaging features of CBPS, a clear assignment between CBPS and MAST1 mutations has not been reported yet.

Unusual context of CENPJ variants and primary microcephaly: compound heterozygosity and nonconsanguinity in an Argentinian patient

Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Patients with MCPH present head circumference values two or three standard deviations (SDs) significantly below the mean for age- and sex-matched populations. MCPH is associated with a nonprogressive mild to severe intellectual disability, with normal brain structure in most patients, or with a small brain and gyri without visceral malformations. We present the case of an adult patient born from Argentinian nonconsanguineous healthy parents. He had a head circumference >5 SD below the mean, cerebral neuroimaging showing hypoplasia of the corpus callosum, bilateral migration disorder with heterotopia of the sylvian fissure and colpocephaly. The patient was compound heterozygous for pathogenic variants in the CENPJ gene (c.289dupA inherited from his mother and c.1132 C > T inherited from his father). Our patient represents an uncommon situation for the usual known context of CENPJ and MCPH, including family origin (Argentinian), pedigree (nonconsanguineous), and genotype (a compound heterozygous case with two variants predicting a truncated protein). Next-generation sequencing studies applied in a broader spectrum of clinical presentations of MCPH syndromes may discover additional similar patients and families.

Lack of dcf1 leads to neuronal migration delay, axonal swollen and autism-related deficits

Perturbed neuronal migration and abnormal axonogenesis have been shown to be implicated in the pathogenesis of autism spectrum disorder (ASD). However, the molecular mechanism remains unknown. Here we demonstrate that dendritic cell factor 1(DCF1) is involved in neuronal migration and axonogenesis. The deletion of dcf1 in mice delays the localization of callosal projection neurons, while dcf1 overexpression restores normal migration. Delayed neurons appear as axon swelling and axonal boutons loss, resulting in a permanent deficit in the callosal projections. Western blot analysis indicates that absence of dcf1 leads to the abnormal activation of ERK signal. Differential protein expression assay shows that PEBP1, a negative regulator of the ERK signal, is significant downregulation in dcf1 KO mice. Direct interaction between DCF1 and PEBP1 is confirmed by Co-immunoprecipitation test, thus indicating that DCF1 regulates the ERK signal in a PEBP1-dependent pattern. As a result of the neurodevelopmental migration disorder, dcf1 deletion results in ASD-like behaviors in mice. This finding identifies a link between abnormal activated ERK signaling, delayed neuronal migration and autistic-like behaviors in humans.

Sevoflurane postconditioning ameliorates neuronal migration disorder through Reelin/Dab1 and improves long-term cognition in neonatal rats after hypoxic-ischemic injury

Sevoflurane postconditioning (SPC) had been reported to attenuate developing brain injury after hypoxia-ischemia encephalopathy (HIE)via inhibiting neural necrosis and autophagy process. Moreover, recent report elucidated sevoflurane may involve in neural cells migration after injury. Here we hypothesize neuronal migration and long-term cognition were ruined after HIE and SPC alleviated these injuries .Classical Rice–Vannucci model of Hypoxia-ischemia was conducted on P7 pups , which was followed by SPC at the 1 minimum alveolar concentration (MAC 2.4%) for 30 min. Piceatannol which can cleave Reelin into proteolytic fragments was used to detect whether Reelin/Dab1 is involved in neuroprotection exerted by SPC. Our findings suggest that hypoxia-ischemia disrupted cytoarchitecture of dentate gyrus (DG) by inhibiting the migration of dentate neurons of hippocampus, which may eventually lead to long-term cognition deficits. However, SPC could relieve the restricted hippocampal neurons from the subgranular zone of hippocampi combined with the repair of hippocampal-dependent memory function damaged by HIE through attenuating the overactivation of the Reelin/Dab1pathway. Taken together, these results demonstrate that SPC plays a pivotal role in ameliorating neuronal migration disorder and maintain normal cytoarchitecture and spatial learning ability of DG by regulating the Reelin/Dab1 downstream signaling pathway. This indicates the potential therapeutic use of SPC in treating HIE perinatally.