title: Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. In the present study we discuss the neuropathological findings of a 32-year-old patient with a germ-line mutation in the TSC2 gene. Post mortem MRI combined with histology and immunocytochemical analysis was applied to demonstrate widespread anatomical abnormalities of gray and white matter structure. TSC brain lesions were analyzed for loss of heterozygosity (LOH) on chromosome 16p13. The neuropathological supratentorial abnormalities were represented by multiple subependymal nodules (SENs) and cortical tubers. In addition to cerebral cortical lesions, cerebellar lesions and hippocampal sclerosis were also observed. LOH was not found in the cortical tubers and SENs of this patient. Immunocytochemical analysis of the TSC brain lesions confirmed the cell-specific activation of the mTOR pathway in cortical tubers, SENs and cerebellum, as well as differential cellular localization of hamartin and tuberin, the TSC1 and TSC2 gene products. Examination of the pathological brain regions revealed activated microglial cells and disruption of blood-brain barrier permeability. Predominant intralesional cell-specific distribution was also detected for the multidrug transporter protein P-gp, possibly explaining the mechanisms underlying the pharmacoresistance to antiepileptic drugs. Autopsy findings confirm the complexity of the brain abnormalities encountered in TSC patients and proved useful in clarifying certain aspects of the pathogenesis, epileptogenesis and pharmacoresistance of TSC lesions.
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Boer
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Floor
authors.initials: F
authors.lastname: Jansen
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: Jeroen J G
authors.initials: JJ
authors.lastname: Geurts
authors.forename: Wim G M
authors.initials: WG
authors.lastname: Spliet
authors.forename: Peter
authors.initials: P
authors.lastname: Crino
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D001344:Autopsy; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000002:abnormalities / Q000473:pathology*; D001927:Brain Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006652:Histological Techniques; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins