Tuberous sclerosis complex (TSC) is a monogenetic disease that arises due to mutations in either the TSC1 or TSC2 gene and affects multiple organ systems. One of the hallmark manifestations of TSC are cortical malformations referred to as cortical tubers. These tubers are frequently associated with treatment-resistant epilepsy. Some of these patients are candidates for epilepsy surgery. White matter abnormalities, such as loss of myelin and oligodendroglia, have been described in a small subset of resected tubers but mechanisms underlying this phenomenon are unclear. Herein, we analyzed a variety of neuropathologic and immunohistochemical features in gray and white matter areas of resected cortical tubers from 46 TSC patients using semi-automated quantitative image analysis. We observed divergent amounts of myelin basic protein as well as numbers of oligodendroglia in both gray and white matter when compared with matched controls. Analyses of clinical data indicated that reduced numbers of oligodendroglia were associated with lower numbers on the intelligence quotient scale and that lower amounts of myelin-associated oligodendrocyte basic protein were associated with the presence of autism-spectrum disorder. In conclusion, myelin pathology in cortical tubers extends beyond the white matter and may be linked to cognitive dysfunction in TSC patients.

2nd Faculty of Medicine Charles University Motol University Hospital Prague Czech Republic; Department of Neuropathology University Hospital Erlangen Erlangen Germany

Brigham and Women's Hospital Harvard Medical School Boston MA

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Rome Italy

Department of Child Neurology Medical University of Warsaw Warsaw Poland

Department of Development and Regeneration Section Pediatric Neurology University Hospitals KU Leuven Leuven

Department of Neurology and Epileptology The Children's Memorial Health Institute

Department of Neurology and Epileptology The Children's Memorial Health Institute Warsaw Poland

Department of Paediatric Neurology

Department of Pathology Amsterdam Neuroscience Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

Department of Pathology and Molecular Medicine

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatric Neurology Brain Center University Medical Center

Department of Pediatrics

Institute of Neurology

Medical University of Vienna Vienna Austria; Department of Pathology Faculty of Medicine Hacettepe University Ankara Turkey

Pediatric Neurology Unit UZ Brussel Brussels Belgium

Stichting Epilepsie Instellingen Nederland Heemstede The Netherlands

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