Abstract
BackgroundTuberous sclerosis complex (TSC) is a multisystem disorder that results from mutations in the TSC1 or TSC2 genes, leading to constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway. Cortical tubers represent typical lesions of the central nervous system (CNS) in TSC. The pattern of cortical layering disruption observed in brain tissue of TSC patients is not yet fully understood, and little is known about the origin and phenotype of individual abnormal cell types recognized in tubers.MethodsIn the present study, we aimed to characterize dysmorphic neurons (DNs) and giant cells (GCs) of cortical tubers using neocortical layer-specific markers (NeuN, SMI32, Tbr1, Satb2, Cux2, ER81, and RORβ) and to compare the features with the histo-morphologically similar focal cortical dysplasia (FCD) type IIb. We studied a cohort of nine surgically resected cortical tubers, five FCD type IIb, and four control samples using immunohistochemistry and in situ hybridization.ResultsCortical tuber displayed a prominent cell loss in all cortical layers. Moreover, we observed altered proportions of layer-specific markers within the dysplastic region. DNs, in both tubers and FCD type IIb, were found positive for different cortical layer markers, regardless of their laminar location, and their immunophenotype resembles that of cortical projection neurons.ConclusionsThese findings demonstrate that, similar to FCD type IIb, cortical layering is markedly disturbed in cortical tubers of TSC patients. Distribution of these disturbances is comparable in all tubers and suggests a dysmaturation affecting early and late migratory patterns, with a more severe impairment of the late stage of maturation.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9142-0) contains supplementary material, which is available to authorized users.
Highlights
Tuberous sclerosis complex (TSC) is a multisystem disorder that results from mutations in the TSC1 or TSC2 genes, leading to constitutive activation of the mammalian target of rapamycin signaling pathway
We aimed to investigate the expression of a panel of layer-specific markers covering all cortical layers (Satb2, Cux2, RORβ, ER81, Tbr1, SMI32, and NeuN) in cortical tubers of patients with TSC compared to perilesional cortex of the same patients, as well as to focal cortical dysplasia (FCD) type IIb or aged- and location-matched controls
Our findings indicate a tendency towards a loss of Satb2+ neurons in layer 5 and an increase of Tbr1+ cells throughout all cortical layers SG supragranular, IG infragranular, FCD focal cortical dysplasia, PLx perilesional cortex
Summary
Tuberous sclerosis complex (TSC) is a multisystem disorder that results from mutations in the TSC1 or TSC2 genes, leading to constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway. Cortical tubers represent typical lesions of the central nervous system (CNS) in TSC. The pattern of cortical layering disruption observed in brain tissue of TSC patients is not yet fully understood, and little is known about the origin and phenotype of individual abnormal cell types recognized in tubers. Tuberous sclerosis complex (TSC) is a genetic disease caused by mutations in the TSC1 and TSC2 genes. Brain lesions can be found in about 90 % of patients with TSC and are often associated with intractable epilepsy [2,3,4]. In a selected subset of TSC patients, epilepsy surgery is considered as a therapeutic option after careful presurgical evaluation [5]
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