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Frontiers in Neuroscience 2015Neuronal migration disorders are human (or animal) diseases that result from a disruption in the normal movement of neurons from their original birth site to their final... (Review)
Review
Neuronal migration disorders are human (or animal) diseases that result from a disruption in the normal movement of neurons from their original birth site to their final destination during early development. As a consequence, the neurons remain somewhere along their migratory route, their location depending on the pathological mechanism and its severity. The neurons form characteristic abnormalities, which are morphologically classified into several types, such as lissencephaly, heterotopia, and cobblestone dysplasia. Polymicrogyria is classified as a group of malformations that appear secondary to post-migration development; however, recent findings of the underlying molecular mechanisms reveal overlapping processes in the neuronal migration and post-migration development stages. Mutations of many genes are involved in neuronal migration disorders, such as LIS1 and DCX in classical lissencephaly spectrum, TUBA1A in microlissencephaly with agenesis of the corpus callosum, and RELN and VLDLR in lissencephaly with cerebellar hypoplasia. ARX is of particular interest from basic and clinical perspectives because it is critically involved in tangential migration of GABAergic interneurons in the forebrain and its mutations cause a variety of phenotypes ranging from hydranencephaly or lissencephaly to early-onset epileptic encephalopathies, including Ohtahara syndrome and infantile spasms or intellectual disability with no brain malformations. The recent advances in gene and genome analysis technologies will enable the genetic basis of neuronal migration disorders to be unraveled, which, in turn, will facilitate genotype-phenotype correlations to be determined.
PubMed: 26052266
DOI: 10.3389/fnins.2015.00181 -
Neurobiology of Disease Nov 2022Malformations of cortical development (MCDs) are common causes of drug-resistant epilepsy. The mechanisms underlying the associated epileptogenesis and ictogenesis... (Review)
Review
OBJECTIVES
Malformations of cortical development (MCDs) are common causes of drug-resistant epilepsy. The mechanisms underlying the associated epileptogenesis and ictogenesis remain poorly elucidated. EEG can help in understanding these mechanisms. We systematically reviewed studies reporting scalp or intracranial EEG features of MCDs to characterise interictal and seizure-onset EEG patterns across different MCD types.
METHODS
We conducted a systematic review in accordance with PRISMA guidelines. MEDLINE, PubMed, and Cochrane databases were searched for studies describing interictal and seizure-onset EEG patterns in MCD patients. A classification framework was implemented to group EEG features into 20 predefined patterns, comprising nine interictal (five, scalp EEG; four, intracranial EEG) and 11 seizure-onset (five, scalp EEG; six, intracranial EEG) patterns. Logistic regression was used to estimate the odds ratios (OR) of each seizure-onset pattern being associated with specific MCD types.
RESULTS
Our search yielded 1682 studies, of which 27 comprising 936 MCD patients were included. Of the nine interictal EEG patterns, five (three, scalp EEG; two, intracranial EEG) were detected in ≥2 MCD types, while four (rhythmic epileptiform discharges type 1 and type 2 on scalp EEG; repetitive bursting spikes and sporadic spikes on intracranial EEG) were seen only in focal cortical dysplasia (FCD). Of the 11 seizure-onset patterns, eight (three, scalp EEG; five, intracranial EEG) were found in ≥2 MCD types, whereas three were observed only in FCD (suppression on scalp EEG; delta brush on intracranial EEG) or tuberous sclerosis complex (TSC; focal fast wave on scalp EEG). Among scalp EEG seizure-onset patterns, paroxysmal fast activity (OR = 0.13; 95% CI: 0.03-0.53; p = 0.024) and repetitive epileptiform discharges (OR = 0.18; 95% CI: 0.05-0.61; p = 0.036) were less likely to occur in TSC than FCD. Among intracranial EEG seizure-onset patterns, low-voltage fast activity was more likely to be detected in heterotopia (OR = 19.3; 95% CI: 6.22-60.1; p < 0.001), polymicrogyria (OR = 6.70; 95% CI: 2.25-20.0; p = 0.004) and TSC (OR = 4.27; 95% CI: 1.88-9.70; p = 0.005) than FCD.
SIGNIFICANCE
Different MCD types can share similar interictal or seizure-onset EEG patterns, reflecting common underlying biological mechanisms. However, selected EEG patterns appear to point to distinct MCD types, suggesting certain differences in their neuronal networks.
Topics: Humans; Electrocorticography; Electroencephalography; Magnetic Resonance Imaging; Malformations of Cortical Development; Seizures; Tuberous Sclerosis
PubMed: 36165814
DOI: 10.1016/j.nbd.2022.105863 -
Seizure Nov 2019To define Stereo-EEG (SEEG) ictal and interictal patterns associated with different pathologies in a cohort of patients with drug-resistant focal epilepsy.
PURPOSE
To define Stereo-EEG (SEEG) ictal and interictal patterns associated with different pathologies in a cohort of patients with drug-resistant focal epilepsy.
METHODS
We retrospectively analyzed findings from 102 patient with epilepsy due to Polymicrogyria (PMG), Periventricular Nodular Heterotopia (PNH), Focal Cortical Dysplasia (FCD) type I, IIa, IIb and Hippocampal Sclerosis (HS). Ictal and interictal SEEG recordings were reviewed to describe Seizure Onset Zone (SEEG-SOZ) patterns and to define the Lesional and Irritative Zones.
RESULTS
Five SEEG-SOZ patterns were identified: significant associations were found between low-voltage fast activity and PMG and between repetitive fast spikes bursts and FCD type IIa. A trend was found between fast activity and PNH, rhythmic sharp activity and FCD type I, repetitive fast spikes bursts and FCD type IIb, slow burst and HS. In 62 of the 102 patients, a complete surgical resection of the SEEG-SOZ was performed, and in 12 patients a partial resection was carried out to preserve eloquent areas. In 18 patients (15 with PNH) the SEEG-SOZ was thermo-coagulated. Seizure freedom was achieved in 58% of surgically treated patients and in 72% of those treated with thermocoagulation (mean ± SD follow-up 5.9 ± 2.3 years). Seizure freedom after surgery was achieved in 84% of the patients with PMG, FCD I, IIa and IIb presenting with characteristic SEEG-SOZ patterns. With the exception of FCD type II, interictal activity was not sufficient to identify SEEG-SOZ boundaries.
CONCLUSION
The study demonstrates that specific histopathologies correlate with particular neurophysiological patterns, reflecting lesion-specific seizure patterns in focal epilepsies.
Topics: Adolescent; Adult; Child; Electroencephalography; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Retrospective Studies; Stereotaxic Techniques; Young Adult
PubMed: 31606703
DOI: 10.1016/j.seizure.2019.10.001 -
Genetics in Medicine : Official Journal... Jul 2023Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase...
PURPOSE
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.
METHODS
Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences.
RESULTS
We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model.
CONCLUSION
The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.
Topics: Humans; Infant; Fibroblasts; Genetic Diseases, Inborn; HEK293 Cells; Mechanistic Target of Rapamycin Complex 1; Monomeric GTP-Binding Proteins; Multiprotein Complexes; Mutation, Missense; TOR Serine-Threonine Kinases
PubMed: 37057673
DOI: 10.1016/j.gim.2023.100838 -
Molecular Neurobiology Feb 2013GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, is integral to the development of the cortex, as mutations in GPR56 cause bilateral... (Review)
Review
GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, is integral to the development of the cortex, as mutations in GPR56 cause bilateral frontoparietal polymicrogyria (BFPP). BFPP is a cobblestone-like cortical malformation, characterized by overmigrating neurons and the formation of neuronal ectopias on the surface of the brain. Since its original cloning a decade ago, GPR56 has emerged from an orphaned and uncharacterized protein to an increasingly well-understood receptor, both in terms of its signaling and function. Collagen III is the ligand of GPR56 in the developing brain. Upon binding to collagen III, GPR56 activates RhoA via coupling to Gα(12/13). This pathway appears to be particularly critical in the preplate neurons, which are the earliest born neurons in the cortex, as the expression pattern of GPR56 in these neurons mimics the anterior to posterior gradient of malformation associated with loss of GPR56 in both humans and mice. Further characterizing the role of GPR56 in the preplate will shed light on the mechanism of cortical development and patterning.
Topics: Animals; Cell Movement; Cerebral Cortex; Extracellular Matrix; Humans; Neurons; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 23001883
DOI: 10.1007/s12035-012-8343-0 -
Epilepsia Open Mar 2023Bilateral frontoparietal polymicrogyria (BFPP) is a rare genetic-related migration disorder. It has been attributed to loss-of-function of the ADGRG1 gene, which encodes... (Review)
Review
Identification and clinical characteristics of a novel missense ADGRG1 variant in bilateral Frontoparietal Polymicrogyria: The electroclinical change from infancy to adulthood after Callosotomy in three siblings.
OBJECTIVE
Bilateral frontoparietal polymicrogyria (BFPP) is a rare genetic-related migration disorder. It has been attributed to loss-of-function of the ADGRG1 gene, which encodes an adhesion G protein-coupled receptor, ADGRG1/GPR56. We report the EEG findings of BFPP in three Asian patients, and confirmed that change in protein function was caused by the novel missense variant (p.Leu290Pro).
METHODS
We reviewed the medical records of three siblings with BFPP including one elder girl and two identical twin boys from birth to adulthood. The clinical symptoms, electroencephalography (EEG), brain MRI, whole-exome sequencing, treatment including medications, neuromodulation, and epilepsy surgery, and clinical outcomes were reviewed. The protein structure of a novel missense variant (p.Leu290Pro) was predicted by in silico studies, and molecular analysis was performed via typical flow cytometry and Western blotting.
RESULTS
The elder girl (Patient 1) was 22 years old and the twin boys (Patients 2 and 3) were 20 years old at the time of publication. All of them presented with typical clinical symptoms/signs and MRI findings of BFPP. Whole-exome sequencing followed by Sanger confirmation showed that all three patients had compound heterozygous variants in the ADGRG1 gene. The missense variant (p.Leu290Pro) was confirmed to be related to a reduction in cell surface GPR56 expression. High-amplitude rhythmic activity was noted in sleep EEG during infancy, which may have been due to excessive sleep spindle, and the rhythm disappeared when they were of pre-school age. Partial callosotomy provided short-term benefits in seizure control in Patients 1 and 2, and combined vagus nerve stimulation and partial callosotomy provided longer benefits in Patient 3.
SIGNIFICANCE
Sleep EEG findings of high-amplitude rhythmic activity in our BFPP cases were only noted during infancy and childhood. We also confirmed that the missense variant (p.Leu290Pro) led to loss of function due to a reduction in cell surface GPR56 expression.
Topics: Male; Female; Humans; Infant; Child, Preschool; Child; Young Adult; Adult; Polymicrogyria; Siblings; Receptors, G-Protein-Coupled; Mutation, Missense
PubMed: 36524291
DOI: 10.1002/epi4.12685 -
Epileptic Disorders : International... Sep 2003Malformations of cortical development are classified on the basis of imaging features and stages of cortical development. They are grouped by causes of the malformation:... (Review)
Review
Malformations of cortical development are classified on the basis of imaging features and stages of cortical development. They are grouped by causes of the malformation: abnormal glial and neuronal proliferation, abnormal neuronal migration and abnormal cortical organisation. Focal or multifocal and generalised forms are recognised in each of these groups. In the first group, generalised forms include microlissencephalies. Among focal-multifocal abnormalities, neoplastic forms include ganglioglioma and dysembryoplastic neuroepithelial tumours. Non-neoplastic forms include focal cortical dysplasia and tuberous sclerosis. Malformations due to abnormal migration include lissencephalies; cortical heterotopias are recognised in both focal and generalised forms. Abnormal cortical organisation includes polymicrogyria, in generalised or focal forms, and schizencephalies among the focal forms.
Topics: Brain Diseases; Brain Neoplasms; Cell Movement; Cerebral Cortex; Humans; Magnetic Resonance Imaging
PubMed: 14617422
DOI: No ID Found -
AJNR. American Journal of Neuroradiology Aug 2018Asymmetry of the corticospinal tract in congenital lesions is a good prognostic marker for preserved motor function after hemispherectomy. This study aimed to assess...
BACKGROUND AND PURPOSE
Asymmetry of the corticospinal tract in congenital lesions is a good prognostic marker for preserved motor function after hemispherectomy. This study aimed to assess this marker and provide a clinically feasible approach in selected cases of unilateral polymicrogyria.
MATERIALS AND METHODS
Corticospinal tract asymmetry of 9 patients with unilateral polymicrogyria substantially affecting the central region was retrospectively assessed on axial T1WI and DTI. Volumes of the brain stem and thalamus and DTI parameters of the internal capsule were measured. Two neuroradiologists independently rated the right-left asymmetry at 4 levels along the corticospinal tract. DTI tractography was used to determine the motor cortex within polymicrogyria, with task-based functional MR imaging available in 3/9 cases.
RESULTS
Visual assessment of the brain stem asymmetry showed excellent correlation with quantitative measures on both T1WI and color-coded DTI maps ( = .007 and = .023). Interrater reliability regarding structural and DTI-based corticospinal tract asymmetry was best at the midbrain (Cohen κ = 0.77, = .018). Three patients underwent functional hemispherectomy with postsurgical stable motor function, all showing marked corticospinal tract asymmetry preoperatively. Following the DTI-based corticospinal tract trajectories allowed identifying the presumed primary motor region within the dysplastic cortex in 9/9 patients, confirmed by functional MR imaging in 3/3 cases.
CONCLUSIONS
Visual assessment of corticospinal tract asymmetry in unilateral polymicrogyria involving the motor cortex is most reliable with T1WI and color-coded DTI maps at the level of the midbrain. Pronounced asymmetry predicts preserved motor function after hemispherectomy. DTI-based tractography can be used as a guidance tool to the motor cortex within polymicrogyria.
Topics: Adult; Aged; Diffusion Tensor Imaging; Female; Humans; Male; Polymicrogyria; Pyramidal Tracts; Retrospective Studies
PubMed: 29954815
DOI: 10.3174/ajnr.A5715 -
Brain Communications 2024Bilateral perisylvian polymicrogyria is the most common form of regional polymicrogyria within malformations of cortical development, constituting 20% of all... (Review)
Review
Bilateral perisylvian polymicrogyria is the most common form of regional polymicrogyria within malformations of cortical development, constituting 20% of all malformations of cortical development. Bilateral perisylvian polymicrogyria is characterized by an excessive folding of the cerebral cortex and abnormal cortical layering. Notable clinical features include upper motoneuron dysfunction, dysarthria and asymmetric quadriparesis. Cognitive impairment and epilepsy are frequently observed. To identify genetic variants underlying bilateral perisylvian polymicrogyria in Finland, we examined 21 families using standard exome sequencing, complemented by optical genome mapping and/or deep exome sequencing. Pathogenic or likely pathogenic variants were identified in 5/21 (24%) of families, of which all were confirmed as These variants were identified in five genes, i.e. , , , and , with and being associated with bilateral perisylvian polymicrogyria for the first time. In conclusion, our results confirm the previously reported genetic heterogeneity of bilateral perisylvian polymicrogyria and underscore the necessity of more advanced methods to elucidate the genetic background of bilateral perisylvian polymicrogyria.
PubMed: 38712318
DOI: 10.1093/braincomms/fcae142 -
Turkish Archives of Pediatrics Jul 2021The purpose of this study is to classify the malformations of cortical development in children according to the embryological formation, localization, and...
AIM
The purpose of this study is to classify the malformations of cortical development in children according to the embryological formation, localization, and neurodevelopmental findings. Seizure/epilepsy and electrophysiological findings have also been compared.
MATERIAL AND METHODS
Seventy-five children (age: 1 month-16.5 years; 56% male) followed with the diagnosis of malformation of cortical development, in Marmara University Pendik Research and Educational Hospital Department of Pediatric Neurology, were included in the study. Their epilepsy characteristics, electroencephalogram (EEG) findings, and prognosis were reported. Neurodevelopmental characteristics were evaluated by the Bayley Scales of Infant and Toddler Development (Bayley-III) for the ages of 0-42 months ( = 30); the Denver Developmental Screening Test-II (DDST-II) for ages 42 months-6 years ( = 11); and the Wechsler Intelligence Scales for Children (WISC-R), used for children 6 years and older ( = 34).
RESULTS
The patients were classified as 44% premigrational (14.6% microcephaly, 24% tuberous sclerosis, 2.7% focal cortical dysplasia, 1.3% hemimegalencephaly, and 1.3% diffuse cortical dysgenesis); 17.3% migrational (14.6% lissencephaly, 2.7% heterotopia); and 38.6% postmigrational (14.6% schizencephaly, 24% polymicrogyria) developmentally. According to involved area, the classification was 34.7% hemispheric/multilobar, 33.3% diffuse, and 32% focal. Seventy-five percent of the patients had a history of epilepsy, and 92% were resistant to treatment. The seizures started before the age of 12 months in diffuse malformations, and epileptic encephalopathy was more common in microcephaly with a rate of 80% and lissencephaly with a rate of 54.5% in the first EEGs. Ninety-five percent of patients had at least one level of neurodevelopmental delay detected by DDST/Bayley-III; this was more common in patients with accompanying epilepsy ( < .05). As seen more commonly in patients with diffuse pathologies and intractable frequent seizures, mental retardation was detected by WISC-R in 64.5% of patients ( < .05).
CONCLUSION
In cases with cortical developmental malformation, epilepsy/EEG features and neurodevelopmental prognosis can be predicted depending on the developmental process and type and extent of involvement. Patients should be followed up closely with EEG.
PubMed: 35005731
DOI: 10.5152/TurkArchPediatr.2021.20148