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Biomedicines Jun 2022Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes-mainly regulating...
Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes-mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had received molecular diagnosis by high-depth targeted next-generation sequencing in our center. Clinical and imaging features were correlated with the sequence variants identified in lesional tissues. Six of nine patients with capillary malformation and overgrowth (CMO) carried the recurrent somatic mutation p.Arg183Gln, while two had mutations. Unexpectedly, 8 of 11 cases of diffuse CM with overgrowth (DCMO) carried known mutations, and the remaining 3 had pathogenic variants. Recurrent mutations were identified in the patients with megalencephaly-CM-polymicrogyria (MCAP), CLOVES, and Klippel-Trenaunay syndrome. Interestingly, somatic mutations were associated with hand/foot anomalies not only in MCAP and CLOVES, but also in CMO and DCMO. Two patients with blue rubber bleb nevus syndrome carried double somatic mutations, two of which were previously undescribed. In addition, a novel sporadic case of Parkes Weber syndrome (PWS) due to an mosaic pathogenic variant was described. Finally, a girl with a mild PWS and another diagnosed with CMO carried pathogenic somatic variants, showing the variability of phenotypic features associated with mutations. Overall, our findings expand the clinical and molecular spectrum of sporadic VMs, and show the relevance of genetic testing for accurate diagnosis and emerging targeted therapies.
PubMed: 35740480
DOI: 10.3390/biomedicines10061460 -
Child's Nervous System : ChNS :... Jan 2020Malformations of cortical development (MCD) are a heterogeneous group of disorders characterized by abnormal structure of the cerebral cortex. MCDs are an important... (Review)
Review
PURPOSE
Malformations of cortical development (MCD) are a heterogeneous group of disorders characterized by abnormal structure of the cerebral cortex. MCDs are an important cause of development delay and intractable epilepsy in children. In this review, we explore the embryological stages of development of neo-cortex, the imageology of various malformations which may occur during the journey of this development, the recent advances in imaging techniques used for diagnosing these malformations, and finally a simplified radiological approach to malformations of cortical development.
REVIEW
We discuss the classification of MCD according to the embryologic stage of cerebral cortex at which the abnormality occurred and the unique imaging features of various malformations, including microcephaly, hemimegalencephaly, lissencephaly, focal cortical dysplasia, heterotopias, polymicrogyria, schizencephaly, and neonatal CMV infection. Also, a rare variant of hemimegalencephaly, namely posterior quadrantic dysplasia, is illustrated; the diagnosis of which is crucial for neurosurgeons to decide management. The technological advancement in the imaging of MCD has taken a leap in the recent years. Imaging now also plays an enormous role in mapping of the abnormalities, delineation of proper surgical boundaries, and quantifying risks of visual, language, and sensorimotor dysfunction. With the introduction of various motor-sparing surgeries and disconnection procedures, proper identification and delineation of these malformations have gained utmost significance.
CONCLUSION
Knowledge of the wide imaging spectrum of MCD, familiarity with recent advances in imaging and an optimal radiological approach is essential for the general radiologist to accurately diagnose and prognosticate MCD as well as provide the best surgical approach to the operating surgeon.
Topics: Cerebral Cortex; Child; Epilepsy; Humans; Infant, Newborn; Lissencephaly; Magnetic Resonance Imaging; Malformations of Cortical Development; Polymicrogyria
PubMed: 31776716
DOI: 10.1007/s00381-019-04429-0 -
Seminars in Cell & Developmental Biology Apr 2018Cerebral cortical development involves a complex series of highly regulated steps to generate the laminated structure of the adult neocortex. Neuronal migration is a key... (Review)
Review
Cerebral cortical development involves a complex series of highly regulated steps to generate the laminated structure of the adult neocortex. Neuronal migration is a key part of this process. We provide here a detailed review of cortical malformations thought to be linked to abnormal neuronal migration. We have focused on providing updated views related to perturbed mechanisms based on the wealth of genetic information currently available, as well as the study of mutant genes in animal models. We discuss mainly type 1 lissencephaly, periventricular heterotopia, type II lissencephaly and polymicrogyria. We also discuss functional classifications such as the tubulinopathies, and emphasize how modern genetics is revealing genes mutated in atypical cases, as well as unexpected genes for classical cases. A role in neuronal migration is revealed for many mutant genes, although progenitor abnormalities also predominate, depending on the disorder. We finish by describing the advantages of human in vitro cell culture models, to examine human-specific cells and transcripts, and further mention non-genetic mechanisms leading to cortical malformations.
Topics: Humans; Malformations of Cortical Development, Group I
PubMed: 28951247
DOI: 10.1016/j.semcdb.2017.09.031 -
Developmental Medicine and Child... Feb 2024Malformations of cortical development (MCDs) represent a heterogeneous spectrum of disorders characterized by atypical development of the cerebral cortex. MCDs are most... (Review)
Review
Malformations of cortical development (MCDs) represent a heterogeneous spectrum of disorders characterized by atypical development of the cerebral cortex. MCDs are most often diagnosed on the basis of imaging, although subtle lesions, such as focal cortical dysplasia, may only be revealed on neuropathology. Different subtypes have been defined, including lissencephaly, heterotopia, cobblestone malformation, polymicrogyria, and dysgyria. Many MCDs are of genetic origin, although acquired factors, such as congenital cytomegalovirus infections and twinning sequence, can lead to similar phenotypes. In this narrative review, we provide an overview of the diagnostic approach to MCDs, which is illustrated with clinical vignettes, on diagnostic pitfalls such as somatic mosaicism and consanguinity, and recognizable phenotypes on imaging, such as tubulinopathies, the lissencephaly spectrum, tuberous sclerosis complex, and FLNA-related periventricular nodular heterotopia.
PubMed: 38394064
DOI: 10.1111/dmcn.15882 -
Journal of Neuroscience Methods Feb 2016Pharmaco-resistant epilepsies, and also some neuropsychiatric disorders, are often associated with malformations in hippocampal and neocortical structures. The... (Review)
Review
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.
Topics: Animals; Cerebral Cortex; Disease Models, Animal; Epilepsy; Freezing; Malformations of Cortical Development; Rodentia; Teratogens
PubMed: 25850077
DOI: 10.1016/j.jneumeth.2015.03.034 -
Pediatric Radiology Dec 2020Fetal MRI is the modality of choice to study supratentorial brain malformations. To accurately interpret the MRI, the radiologist needs to understand the normal sequence... (Review)
Review
Fetal MRI is the modality of choice to study supratentorial brain malformations. To accurately interpret the MRI, the radiologist needs to understand the normal sequence of events that occurs during prenatal brain development; this includes familiarity with the processes of hemispheric cleavage, formation of interhemispheric commissures, neuro-glial proliferation and migration, and cortical folding. Disruption of these processes results in malformations observed on fetal MRI including holoprosencephaly, callosal agenesis, heterotopic gray matter, lissencephaly and other malformations of cortical development (focal cortical dysplasia, polymicrogyria). The radiologist should also be familiar with findings that have high association with specific conditions affecting the central nervous system or other organ systems. This review summarizes and illustrates common patterns of supratentorial brain malformations and emphasizes aspects that are important to patient care.
Topics: Brain; Female; Fetus; Gray Matter; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malformations of Cortical Development; Nervous System Malformations; Pregnancy
PubMed: 33252760
DOI: 10.1007/s00247-020-04696-z -
Brain Communications 2023Polymicrogyria is estimated to be one of the most common brain malformations, accounting for ∼16% of malformations of cortical development. However, the prevalence and...
Polymicrogyria is estimated to be one of the most common brain malformations, accounting for ∼16% of malformations of cortical development. However, the prevalence and incidence of polymicrogyria is unknown. Our aim was to estimate the prevalence, incidence rate, neuroimaging diversity, aetiology, and clinical phenotype of polymicrogyria in a population-based paediatric cohort. We performed a systematic search of MRI scans at neuroradiology department databases in Stockholm using the keyword polymicrogyria. The study population included all children living in the Stockholm region born from January 2004 to June 2021 with polymicrogyria. Information on the number of children living in the region during 2004-21 was collected from records from Statistics Sweden, whereas the number of births for each year during the study period was collected from the Swedish Medical Birth Register. All MRI scans were re-evaluated, and malformations were classified by a senior paediatric neuroradiologist. The prevalence and yearly incidence were estimated. Clinical data were collected from medical records. A total of 109 patients with polymicrogyria were included in the study. The overall polymicrogyria prevalence in Stockholm was 2.3 per 10 000 children, and the overall estimated yearly incidence between 2004 and 2020 was 1.9 per 10 000 person-years. The most common polymicrogyria distribution was in the frontal lobe (71%), followed by the parietal lobe (37%). Polymicrogyria in the peri-sylvian region was observed in 53%. Genetic testing was performed in 90 patients revealing pathogenic variants in 32%. Additionally, 12% had variants of uncertain significance. Five patients had a confirmed congenital infection, and in six individuals, the cause of polymicrogyria was assumed to be vascular. Epilepsy was diagnosed in 54%. Seizure onset during the first year of life was observed in 44%. The most common seizure types were focal seizures with impaired awareness, followed by epileptic spasms. Thirty-three of 59 patients with epilepsy (56%) were treated with more than two anti-seizure medications, indicating that pharmacoresistant epilepsy is common in polymicrogyria patients. Neurodevelopmental symptoms were observed in 94% of the individuals. This is the first population-based study on polymicrogyria prevalence and incidence. Confirmed genetic aetiology was present in one-third of individuals with polymicrogyria. Epilepsy was common in this patient group, and the majority had pharmacoresistant epilepsy. These findings increase our knowledge about polymicrogyria and will help in counselling patients and their families.
PubMed: 37614989
DOI: 10.1093/braincomms/fcad213 -
Annual Review of Pathology Jan 2019Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse... (Review)
Review
Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.
Topics: Cerebral Cortex; Hemimegalencephaly; Humans; Intellectual Disability; Lissencephaly; Malformations of Cortical Development; Microcephaly; Mutation; Neurodevelopmental Disorders; Neuroimaging; Polymicrogyria
PubMed: 30677308
DOI: 10.1146/annurev-pathmechdis-012418-012927 -
Neurology Apr 2021To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with...
OBJECTIVE
To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with polymicrogyria using a battery of standardized tests and correlated findings with topography and severity of polymicrogyria.
METHODS
Patients were identified via clinical research databases and invited to participate, irrespective of cognitive and verbal language abilities. We conducted standardized assessments of speech, oromotor structure and function, language, and nonverbal IQ. Data were analyzed according to normative assessment data and descriptive statistics. We conducted a correlation analysis between topographic pattern and speech and language findings.
RESULTS
Fifty-two patients (33 male, 63%) were studied at an average age of 12.7 years (range 2.5-36 years). All patients had dysarthria, which ranged from mild impairment to anarthria. Developmental speech errors (articulation and phonology), oral motor structure and function deficits, and language disorder were frequent. A total of 23/29 (79%) had cognitive abilities in the low average to extremely low range. In the perisylvian polymicrogyria group (36/52), speech, everyday language, and oral motor impairments were more severe, compared to generalized (1 patient), frontal (3), polymicrogyria with periventricular nodular heterotopia (3), parasagittal parieto-occipital (1), mesial occipital (1), and other (7) patterns.
CONCLUSIONS
Dysarthria is a core feature of polymicrogyria, often accompanied by receptive and expressive language impairments. These features are associated with all polymicrogyria distribution patterns and more severe in individuals with bilateral polymicrogyria, particularly in the perisylvian region.
Topics: Adolescent; Adult; Child; Child, Preschool; Dysarthria; Female; Humans; Language Development Disorders; Magnetic Resonance Imaging; Male; Polymicrogyria; Young Adult
PubMed: 33589534
DOI: 10.1212/WNL.0000000000011698