title: Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis omplex (TSC): evidence from layer-specific marker expression.
abstract: BACKGROUND
  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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  Cortical 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Center, Amsterdam, The Netherlands ; Department of Pediatrics, Medical University Vienna, Vienna, Austria.
authors.forename: Angelika
authors.initials: A
authors.lastname: Mühlebner
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anand M
authors.initials: AM
authors.lastname: Iyer
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jackelien
authors.initials: J
authors.lastname: van Scheppingen
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Anink
authors.affiliation: Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Floor E
authors.initials: FE
authors.lastname: Jansen
authors.affiliation: Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Veersema
authors.affiliation: Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kees P
authors.initials: KP
authors.lastname: Braun
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wim G M
authors.initials: WG
authors.lastname: Spliet
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van Hecke
authors.affiliation: Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Figen
authors.initials: F
authors.lastname: Söylemezoğlu
authors.affiliation: Department of Pediatrics, Medical University Vienna, Vienna, Austria.
authors.forename: Martha
authors.initials: M
authors.lastname: Feucht
authors.affiliation: Department of Neurology, Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Krsek
authors.affiliation: Department of Pathology and Molecular Medicine, Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Zamecnik
authors.affiliation: Epilepsy Centre Bethel, Krankenhaus Mara, Bielefeld, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Bien
authors.affiliation: Epilepsy Centre Bethel, Krankenhaus Mara, Bielefeld, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Polster
authors.affiliation: Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Coras
authors.affiliation: Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
authors.affiliation: Department of (Neuro) Pathology, Academic Medical Center, Amsterdam, The Netherlands ; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands ; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
keywords: Cortical layer markers; Epilepsy; Neuropathology; Neurosurgery; Tuberous sclerosis complex