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American Journal of Medical Genetics.... Dec 2019EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex... (Review)
Review
EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.
Topics: Brain; Humans; Malformations of Cortical Development, Group II; Microtubule-Associated Proteins; Mutation, Missense; Sequence Deletion
PubMed: 31710781
DOI: 10.1002/ajmg.c.31751 -
Developmental Cell Dec 2023The cerebral cortex-the brain's covering and largest region-has increased in size and complexity in humans and supports higher cognitive functions such as language and... (Review)
Review
The cerebral cortex-the brain's covering and largest region-has increased in size and complexity in humans and supports higher cognitive functions such as language and abstract thinking. There is a growing understanding of the human cerebral cortex, including the diversity and number of cell types that it contains, as well as of the developmental mechanisms that shape cortical structure and organization. In this review, we discuss recent progress in our understanding of molecular and cellular processes, as well as mechanical forces, that regulate the folding of the cerebral cortex. Advances in human genetics, coupled with experimental modeling in gyrencephalic species, have provided insights into the central role of cortical progenitors in the gyrification and evolutionary expansion of the cerebral cortex. These studies are essential for understanding the emergence of structural and functional organization during cortical development and the pathogenesis of neurodevelopmental disorders associated with cortical malformations.
Topics: Humans; Cerebral Cortex; Brain; Biological Evolution; Neurogenesis
PubMed: 38113850
DOI: 10.1016/j.devcel.2023.11.004 -
Journal of Neuropathology and... Apr 2020MIRAGE syndrome is a multisystem disorder characterized by myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy....
MIRAGE syndrome is a multisystem disorder characterized by myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Mutations in the sterile alpha motif domain containing 9 (SAMD9) gene which encodes a protein involved in growth factor signal transduction are thought to cause MIRAGE syndrome. SAMD9 mutations lead to an antiproliferative effect resulting in a multisystem growth restriction disorder. Though rare, a few patients with SAMD9 mutations were reported to have hydrocephalus and/or cerebellar hypoplasia on imaging. The neuropathologic features of MIRAGE syndrome have not been previously described. Here, we describe the postmortem neuropathologic examinations of 2 patients with a clinical diagnosis of MIRAGE syndrome and confirmed SAMD9 mutations. Common features included microcephaly, hydrocephalus, white matter abnormalities, and perivascular calcifications. One of the 2 cases showed marked cerebellar hypoplasia with loss of Purkinje and granule neurons as well as multifocal polymicrogyria and severe white matter volume loss; similar findings were not observed in the second patient. These cases demonstrate the variation in neuropathologic findings in patients with MIRAGE syndrome. Interestingly, the findings are similar to those reported in ataxia-pancytopenia syndrome caused by mutations in SAMD9L, a paralogue of SAMD9.
Topics: Adrenal Insufficiency; Brain; Central Nervous System Diseases; Female; Humans; Infant; Intracellular Signaling Peptides and Proteins; Lung Diseases; Myelodysplastic Syndromes; Neuropathology; Premature Birth
PubMed: 32106287
DOI: 10.1093/jnen/nlaa009 -
Epilepsia Apr 2021We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.
OBJECTIVE
We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.
METHODS
We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA.
RESULTS
Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.
SIGNIFICANCE
This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
Topics: Child; Child, Preschool; Cohort Studies; Epilepsy; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Phosphatidylinositol 3-Kinases; Polymicrogyria
PubMed: 33818783
DOI: 10.1111/epi.16854 -
Annals of Indian Academy of Neurology 2022Polymicrogyria (PMG) is a relatively common complex malformation with cortical development, characterized by an exorbitant number of abnormally tiny gyri separated by...
Polymicrogyria (PMG) is a relatively common complex malformation with cortical development, characterized by an exorbitant number of abnormally tiny gyri separated by shallow sulci. It is a neuronal migration disorder. Familial cases of PMG and the manifestation of PMG in patients with chromosomal aberrations and mutations indicate their important role of genetics in this disorder. The highly stereotyped and well-conserved nature of the cortical folding pattern in humans is suggestive of the genetic regulation of the process. The chromosomal abnormalities observed in PMG include deletions, duplications, chromosomal rearrangements, and aneuploidies. Two of the most common deletions in PMG are 22q11.2 deletion and 1p36 deletion. Further, mutations in several genes such as , and are known to be associated with PMG. Intriguingly, these genes are responsible only for a small number of cases of PMG. The protein products of these genes are implicated in diverse molecular and cellular functions. Taken together, PMG could be the result of the disruption of several biological pathways. Different modes of Mendelian inheritance and non-Mendelian inheritance are seen in PMG. We have suggested a gene panel that can be used for the detection of malformations of cortical development.
PubMed: 36211152
DOI: 10.4103/aian.aian_97_22 -
International Journal of Developmental... Nov 2023Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by... (Review)
Review
Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by anatomical cortical defects leading to varying degrees of neurocognitive impairment, developmental delay and seizures. Refractory epilepsy affects 15 million people worldwide, and it is thought that cortical developmental disorders are responsible for 25% of childhood cases. However, little is known about the epidemiology of these disorders, nor are their aetiologies fully understood, though many are associated with sporadic genetic mutations. In this review, we aim to highlight X-linked NMDs including lissencephaly, periventricular nodular heterotopia and polymicrogyria because of their mostly familial inheritance pattern. We focus on the most prominent genes responsible: including DCX, ARX, FLNA, FMR1, L1CAM, SRPX2, DDX3X, NSHDL, CUL4B and OFD1, outlining what is known about their prevalence among NMDs, and the underlying pathophysiology. X-linked disorders are important to recognise clinically, as females often have milder phenotypes. Consequently, there is a greater chance they survive to reproductive age and risk passing the mutations down. Effective genetic screening is important to prevent and treat these conditions, and for this, we need to know gene mutations and have a clear understanding of the function of the genes involved. This review summarises the knowledge base and provides clear direction for future work by both scientists and clinicians alike.
Topics: Female; Humans; Epilepsy; Sex Factors; Genetic Testing; Mutation; Malformations of Cortical Development, Group II; Fragile X Mental Retardation Protein; Cullin Proteins
PubMed: 37574439
DOI: 10.1002/jdn.10290 -
Soft Matter Feb 2021The characteristically folded surface of the human brain is critical for brain function and allows for higher cognitive abilities. Recent mostly computational research...
The characteristically folded surface of the human brain is critical for brain function and allows for higher cognitive abilities. Recent mostly computational research advances have shown that mechanical instabilities play a crucial role during early brain development and cortical folding. However, it is difficult to investigate such mechanisms in vivo. To experimentally gain deeper insights into the physical mechanisms that underlie the development of brain shape, we use a setup of swelling polymers. We investigate the influence of cortical thickness and the stiffness ratio between cortex and subcortex on the resulting surface pattern by taking the initially smooth fetal brain geometry at week 22 into consideration. The gel specimens possess a two-layered structure accounting for gray and white matter tissue and yield complex surface morphologies that well resemble patterns in the human brain. The results are in good agreement with analytical predictions. Through the variation of cortical thickness and stiffness, it is possible to reproduce cortical malformations such as polymicrogyria and lissencephaly. The results suggest that wrinkling with subsequent transition into folding is the driving instability mechanism during brain development. In addition, the experiments provide valuable insights towards the distinction between wrinkling and creasing instabilities. Taken together, the presented swelling experiments impressively demonstrate the purely physical aspects of brain shape and constitute a valuable tool to advance our understanding of human brain development.
Topics: Brain; Humans; Magnetic Resonance Imaging; Polymers
PubMed: 33480902
DOI: 10.1039/d0sm02209h -
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 -
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