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Open Access 01-12-2023 | Magnetic Resonance Imaging | Research

Deep histopathology genotype–phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb

Authors: Jonas Honke, Lucas Hoffmann, Roland Coras, Katja Kobow, Costin Leu, Tom Pieper, Till Hartlieb, Christian G. Bien, Friedrich Woermann, Thomas Cloppenborg, Thilo Kalbhenn, Ahmed Gaballa, Hajo Hamer, Sebastian Brandner, Karl Rössler, Arnd Dörfler, Stefan Rampp, Johannes R. Lemke, Sara Baldassari, Stéphanie Baulac, Dennis Lal, Peter Nürnberg, Ingmar Blümcke

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype–phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin–eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype–phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration.

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Title: Deep histopathology genotype–phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb
Authors: Jonas Honke
Lucas Hoffmann
Roland Coras
Katja Kobow
Costin Leu
Tom Pieper
Till Hartlieb
Christian G. Bien
Friedrich Woermann
Thomas Cloppenborg
Thilo Kalbhenn
Ahmed Gaballa
Hajo Hamer
Sebastian Brandner
Karl Rössler
Arnd Dörfler
Stefan Rampp
Johannes R. Lemke
Sara Baldassari
Stéphanie Baulac
Dennis Lal
Peter Nürnberg
Ingmar Blümcke
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Magnetic Resonance Imaging
Magnetic Resonance Imaging
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01675-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Deep histopathology genotype–phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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