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.

Department of Heemstede The Netherlands

Department of Neurology Charles University 2nd Faculty of Medicine Motol University Hospital Prague Czech Republic

Department of Neuropathology University Hospital Erlangen Erlangen Germany

Department of Pathology Academic Medical Center Amsterdam The Netherlands

Department of Pathology Academic Medical Center Amsterdam The Netherlands ; Department of Pediatrics Medical University Vienna Vienna Austria

Department of Pathology and Molecular Medicine Charles University 2nd Faculty of Medicine Motol University Hospital Prague Czech Republic

Department of Pathology Faculty of Medicine Hacettepe University Ankara Turkey

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatric Neurology Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatrics Medical University Vienna Vienna Austria

Epilepsy Centre Bethel Krankenhaus Mara Bielefeld Germany

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Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics