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AJNR. American Journal of Neuroradiology Nov 2022The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a...
BACKGROUND AND PURPOSE
The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a sample of adults with hereditary hemorrhagic telangiectasia for the presence of malformations of cortical development, spatial coincidence of malformations of cortical development and AVMs, and the coincidence of brain and pulmonary AVMs.
MATERIALS AND METHODS
A total of 141 patients 18 years of age or older who were referred to the Augusta University hereditary hemorrhagic telangiectasia clinic and underwent brain MR imaging between January 19, 2018, and December 3, 2020, were identified. MR imaging examinations were reviewed retrospectively by 2 experienced neuroradiologists, and the presence of malformations of cortical development and AVMs was confirmed by consensus. Demographic and clinical information was collected for each case, including age, sex, hereditary hemorrhagic telangiectasia status by the Curacao Criteria, mutation type, presence of malformations of cortical development, presence of brain AVMs, presence of pulmonary AVMs, and a history of seizures or learning disabilities.
RESULTS
Five of 141 (3.5%) patients with hereditary hemorrhagic telangiectasia had malformations of cortical development. Two of the 5 patients with polymicrogyria also had closed-lip schizencephaly. One of the patients had a porencephalic cavity partially lined with heterotopic GM. The incidence of spatially coincident polymicrogyria and brain AVMs was 40% (2/5 cases). Of the patients with hereditary hemorrhagic telangiectasia and malformations of cortical development, 4/5 (80%) had pulmonary AVMs and 2/5 (40%) had brain AVMs.
CONCLUSIONS
To our knowledge, we are the first group to report the presence of schizencephaly in patients with hereditary hemorrhagic telangiectasia. The presence of schizencephaly and porencephaly lends support to the hypothesis of regional in utero cerebral hypoxic events as the etiology of malformations of cortical development in hereditary hemorrhagic telangiectasia.
Topics: Adult; Humans; Adolescent; Telangiectasia, Hereditary Hemorrhagic; Schizencephaly; Polymicrogyria; Retrospective Studies; Arteriovenous Malformations
PubMed: 36265891
DOI: 10.3174/ajnr.A7677 -
American Journal of Medical Genetics.... Dec 2018Oculocerebrocutaneous syndrome (OCCS) is a rare disorder characterized primarily by congenital skin, eye, and brain anomalies. The most distinctive findings are... (Review)
Review
Oculocerebrocutaneous syndrome (OCCS) is a rare disorder characterized primarily by congenital skin, eye, and brain anomalies. The most distinctive findings are hypoplastic or aplastic skin defects; pedunculated, typically hamartomatous, or nodular skin appendages; cystic microphthalmia; and a combination of forebrain anomalies and a specific mid-hindbrain malformation. Based on a review of 40 patients with OCCS, existing clinical criteria have been revised. Because of the asymmetric and patchy distribution of features, lack of recurrence in families, male preponderance and completely skewed X-inactivation in one female, OCCS is hypothesized to result from postzygotic mosaic variants in an X-linked gene. Whole exome and genome sequencing on blood DNA in two patients failed to identify pathogenic variants so far. In view of the overlapping features, in particular of the brain, of OCCS and Aicardi syndrome, both may be pathogenetically related or even result from different variants in the same gene. For the elucidation of the cause of OCCS, exome or genome sequencing on multiple lesional tissues is the primary goal.
Topics: Abnormalities, Multiple; Central Nervous System Cysts; Eye Abnormalities; Fingers; Humans; Phenotype; Skin Abnormalities
PubMed: 30580480
DOI: 10.1002/ajmg.c.31667 -
Science Advances Mar 2021Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria...
Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo variants in eight patients. Mutated causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with abnormalities.
PubMed: 33762331
DOI: 10.1126/sciadv.abd2368 -
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 -
Pediatric Neurology Briefs Nov 2015Investigators from Sainte Justine Hospital (Montreal), Montreal Neurological Hospital and Institute, King's College Hospital (London), and John Radcliffe Hospital...
Investigators from Sainte Justine Hospital (Montreal), Montreal Neurological Hospital and Institute, King's College Hospital (London), and John Radcliffe Hospital (Oxford) retrospectively reviewed medical records, autopsy reports, and genetic studies containing "Polymicrogyria."
PubMed: 26933543
DOI: 10.15844/pedneurbriefs-29-11-5 -
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 -
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 -
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 -
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 -
NeuroImage Jan 2019Spatial distribution and specific geometric and topological patterning of early sulcal folds have been hypothesized to be under stronger genetic control and are more... (Review)
Review
Spatial distribution and specific geometric and topological patterning of early sulcal folds have been hypothesized to be under stronger genetic control and are more associated with optimal organization of cortical functional areas and their white matter connections, compared to later developing sulci. Several previous studies of sulcal pit (putative first sulcal fold) distribution and sulcal pattern analyses using graph structures have provided evidence of the importance of sulcal pits and patterns as remarkable anatomical features closely related to human brain function, suggesting additional insights concerning the anatomical and functional development of the human brain. Recently, early sulcal folding patterns have been observed in healthy fetuses and fetuses with brain abnormalities such as polymicrogyria and agenesis of corpus callosum. Graph-based quantitative sulcal pattern analysis has shown high sensitivity in detecting emerging subtle abnormalities in cerebral cortical growth in early fetal stages that are difficult to detect via qualitative visual assessment or using traditional cortical measures such as gyrification index and curvature. It has proven effective for characterizing genetically influenced early cortical folding development. Future studies will be aimed at better understanding a comprehensive map of spatio-temporal dynamics of fetal cortical folding in a large longitudinal cohort in order to examine individual clinical fetal MRIs and predict postnatal neurodevelopmental outcomes from early fetal life.
Topics: Brain; Fetus; Humans
PubMed: 29601953
DOI: 10.1016/j.neuroimage.2018.03.057