Myelin Pathology Beyond White Matter in Tuberous Sclerosis Complex (TSC) Cortical Tubers

Author:

Mühlebner Angelika1,van Scheppingen Jackelien1,de Neef Andrew1,Bongaarts Anika1ORCID,Zimmer Till S1,Mills James D1,Jansen Floor E2,Spliet Wim G M3,Krsek Pavel4,Zamecnik Josef5,Coras Roland6,Blumcke Ingmar6,Feucht Martha7,Scholl Theresa7,Gruber Victoria-Elisabeth7,Hainfellner Johannes A8,Söylemezoğlu Figen9,Kotulska Katarzyna10,Lagae Lieven11,Jansen Anna C12,Kwiatkowski David J13,Jozwiak Sergiusz1415,Curatolo Paolo16,Aronica Eleonora117

Affiliation:

1. Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

2. Department of Pediatric Neurology, Brain Center University Medical Center

3. Department of Pathology, University Medical Center Utrecht (WGMS) Utrecht, The Netherlands

4. Department of Paediatric Neurology

5. Department of Pathology and Molecular Medicine

6. Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic; Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany

7. Department of Pediatrics

8. Institute of Neurology

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

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

11. Department of Development and Regeneration-Section Pediatric Neurology, University Hospitals KU Leuven, Leuven

12. Pediatric Neurology Unit-UZ Brussel, Brussels Belgium

13. Brigham and Women's Hospital, Harvard Medical School, Boston, MA

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

15. Department of Child Neurology, Medical University of Warsaw Warsaw, Poland

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

17. Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands

Abstract

Abstract 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.

Funder

Austrian Science Fund

FWF

Czech Ministry of Health grant

Framework Programme

DESIRE

EPISTOP

Publisher

Oxford University Press (OUP)

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Neurology,General Medicine,Pathology and Forensic Medicine

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