Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile.
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ABSTRACT:
SUBMITTER: Solomon DA
PROVIDER: S-EPMC7787982 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile.
Solomon David A DA Korshunov Andrey A Sill Martin M Jones David T W DTW Kool Marcel M Pfister Stefan M SM Fan Xuemo X Bannykh Serguei S Hu Jethro J Danielpour Moise M Li Rong R Johnston James J Cham Elaine E Cooney Tabitha T Sun Peter P PP Oberheim Bush Nancy Ann NA McDermott Michael M Van Ziffle Jessica J Onodera Courtney C Grenert James P JP Bastian Boris C BC Villanueva-Meyer Javier E JE Pekmezci Melike M Bollen Andrew W AW Perry Arie A
Acta neuropathologica 20180713 2
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Project description:"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.
| S-EPMC7780370 | biostudies-literature
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| S-EPMC9425008 | biostudies-literature
Project description:Myxoid glioneuronal tumors (MGNT) are low-grade glioneuronal neoplasms composed of oligodendrocyte-like cells in a mucin-rich stroma. These tumors feature a unique dinucleotide change at codon 385 in the platelet-derived growth factor receptor α (encoded by the PDGFRA gene), resulting in the substitution of lysine 385 into leucine or isoleucine. The functional consequences of these mutations remain largely unexplored. Here, we demonstrated their oncogenic potential in fibroblast and Ba/F3 transformation assays. We showed that the K385I and K385L mutants activate STAT and AKT signaling in the absence of ligand. Co-immunoprecipitations and BRET experiments suggested that the mutations stabilized the active dimeric conformation of the receptor, pointing to a new mechanism of oncogenic PDGF receptor activation. Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Finally, K385 substitution into another hydrophobic amino acid also activated the receptor. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.
| S-EPMC10965988 | biostudies-literature
Project description: Not available
| S-BSST1235 | biostudies-other
Project description:This myxoid glioneuronal tumor, PDGFRA p.K385L-mutant, arose in the midbrain tectum rather than in the septum pellucidum, as in the previously-reported cases.
| S-EPMC8713525 | biostudies-literature
Project description:Previous studies report that cavum septum pellucidum (CSP) is frequent among athletes with a history of repeated traumatic brain injury (TBI), such as boxers. Few studies of CSP in athletes, however, have assessed detailed features of the septum pellucidum in a case-control fashion. This is important because prevalence of CSP in the general population varies widely (2% to 85%) between studies. Further, rates of CSP among American pro-football players have not been described previously. We sought to characterize MRI features of the septum pellucidum in a series of retired pro-football players with a history of repeated concussive/subconcussive head traumas compared with controls. We retrospectively assessed retired American pro-football players presenting to our memory clinic with cognitive/behavioral symptoms in whom structural MRI was available with slice thickness ≤2 mm (n=17). Each player was matched to a memory clinic control patient with no history of TBI. Scans were interpreted by raters blinded to clinical information and TBI/football history, who measured CSP grade (0-absent, 1-equivocal, 2-mild, 3-moderate, 4-severe) and length according to a standard protocol. Sixteen of 17 (94%) players had a CSP graded ≥2 compared with 3 of 17 (18%) controls. CSP was significantly higher grade (p<0.001) and longer in players than controls (mean length±standard deviation: 10.6 mm±5.4 vs. 1.1 mm±1.3, p<0.001). Among patients presenting to a memory clinic, long high-grade CSP was more frequent in retired pro-football players compared with patients without a history of TBI.
| S-EPMC4696427 | biostudies-literature
Project description:ObjectivesTo investigate the prevalence and changes of cavum septum pellucidum (CSP) in first-episode psychosis (FEP) patients.MethodsMedline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify eligible studies comparing FEP patients and healthy controls from inception to Feb 29, 2016.ResultsTen cross-sectional studies and three longitudinal studies reported in ten articles met our criteria. Our meta-analysis found no significant differences in the prevalence of either "any CSP" (OR = 1.41; 95% CI 0.90-2.20; p = 0.13; I2 = 52.7%) or "large CSP" (OR = 1.10; 95% CI 0.77-1.58; p = 0.59; I2 = 24.1%) between FEP patients and healthy controls. However, the heterogeneity analysis of the prevalence of "any CSP" suggested bias in outcome reporting.ConclusionsThe results based on current evidence suggest it is unclear whether "any CSP" is a risk factor for FEP due to the heterogeneity of the studies. There is insufficient evidence to support that "large CSP" is a possible risk factor for FEP.
| S-EPMC5435239 | biostudies-literature
Project description:Cavum septum pellucidum (CSP) is commonly observed upon neuroimaging examination in individuals exposed to repetitive head impacts (RHI) and post-mortem in cases with chronic traumatic encephalopathy. Consequently, CSP has been proposed as a potential biomarker for RHI-related neurodegeneration, yet prevalence estimates of CSP across other neurodegenerative diseases and its clinical implications are largely unknown. We assessed CSP prevalence and clinical correlates in individuals with RHI exposure, a history of traumatic brain injury (TBI), a neurodegenerative disease (i.e. Alzheimer's disease or frontotemporal dementia) and normal cognition. The primary group of interest, i.e. individuals exposed to RHI in contact sports or military service (n = 65; mean exposure 21.58 years), was compared against age- and sex-matched participants with TBI (n = 57; number of TBI range: 1-5) and non-exposed participants of the Amsterdam Dementia Cohort (Alzheimer's disease, n = 30; frontotemporal dementia, n = 24; normal cognition, n = 27). Structural 3D brain MRI scans were visually rated for CSP grade (ranging 0-4) by two raters blinded to the clinical information. A CSP of at least Grade 2 was considered enlarged/abnormal. Inter-rater reliability was assessed with Cohens' weighted Kappa (κ). We investigated whether prevalence of enlarged CSP differed between groups and assessed associations with neuropsychological outcomes (verbal memory, processing speed, mental flexibility and semantic fluency), neuropsychiatric symptoms (neuropsychiatric inventory), ventricular enlargement as measured with Evan's index and MRI volumes of composite regions (limbic, temporal-meta regions and the whole brain). Inter-rater reliability was substantial [κ = 0.734 (95% confidence interval 0.67-0.80)]. An enlarged CSP was more often observed in the RHI group (44.6%) compared with individuals with Alzheimer's disease [13.3%, odds ratio (OR) = 5.24 (1.79-19.26)], frontotemporal dementia [16.7%, OR = 4.03 (1.35-15.02)] and normal cognition [18.5%, OR = 3.54 (1.27-11.62)], all P FDR < 0.05, but not compared with the TBI group [29.8%, OR = 1.90 (0.90-4.06), P FDR = 0.094]. In those with RHI, enlarged CSP was associated with lower outcomes on verbal memory learning (η² = 0.09, P FDR = 0.023) and recall (η² = 0.08, P FDR = 0.030). For TBI, enlarged CSP was associated with lower performance on verbal memory learning; however, this lost significance after multiple comparison correction (η² = 0.014, P FDR = 0.09). Enlarged CSP was not associated with the composite MRI volumes, ventricular enlargement or neuropsychiatric symptoms. In summary, enlarged CSP was more prevalent in RHI-exposed individuals compared with individuals with a neurodegenerative disease or normal cognition, but not compared with TBI, and was associated with lower verbal memory performance in the RHI group. Our study highlights enlarged CSP as a potential consequence of long-term head impact exposure and, to a lesser extent, TBI, rather than a general consequence of neurodegeneration.
| S-EPMC11879415 | biostudies-literature
Project description:ObjectiveAdolescent-onset exposure to highly addictive substances such as opiates may induce far-reaching deleterious effects on later mental and physical health. However, little is known about the neurodevelopmental basis for adolescent-onset opiate dependence. Here we examined whether having an abnormally large cavum septum pellucidum (CSP), a putative marker of limbic structural maldevelopment, is associated with opiate dependence particularly beginning in adolescence.MethodThe overall length of the CSP and the prevalence of abnormal enlargement of the CSP were assessed and compared in 65 opiate-dependent subjects (41 adolescent-onset opiate users and 24 adult-onset opiate users) and 67 healthy subjects.ResultsOpiate-dependent subjects showed a greater prevalence of abnormal CSP enlargement relative to healthy subjects (odds ratio [OR]=3.64, p=0.034). The overall CSP length of adolescent-onset opiate-dependent subjects was greater, as compared not only with healthy subjects (F?,???=11.03, p=0.001) but also with those who began opiate use during adulthood (F?,??=4.43, p=0.039).ConclusionsThe current findings provide the first evidence that abnormal CSP enlargement, which reflects limbic system dysgenesis of neurodevelopmental origin, may be linked to later development of opiate dependence. In addition, a greater CSP length, which indicates more severe limbic abnormalities, appears to confer higher risk for earlier onset of opiate use.
| S-EPMC3813473 | biostudies-literature
Project description:When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lacking Nkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.
| S-EPMC10592641 | biostudies-literature