Abstract
Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development.
Highlights
Introduction and Historical ContextMalformations of cortical development such as focal cortical dysplasia (FCD) are major causes of drug-resistant focal epilepsy, with surgical resection often being the only effective treatment
Data from the European Epilepsy Brain Bank estimated that malformations of cortical development contributed to 19.8% of specimens collected through epilepsy surgery, and 70.6% of these specimens corresponded to different FCD subtypes [1]
This review summarises how the field reached its current understanding of FCD, with a particular focus on FCDII and its relationship with the mammalian target of rapamycin (mTOR) signalling pathway
Summary
Malformations of cortical development such as focal cortical dysplasia (FCD) are major causes of drug-resistant focal epilepsy, with surgical resection often being the only effective treatment. The relationship between cortical lesions and epileptic seizures was established by the work of Sir John Hughlings Jackson in the 19th century [2], emphasising the pathological and anatomical basis of epilepsy. The authors noted the “most striking” feature in these specimens being the “localized disruption of the normal cortical lamination by an excess of larger aberrant neurones scattered randomly through all but the first layer” These “aberrant neurones” with “inappropriate size”, “bizarre structure”, and “pointed in all directions”, are what we know as “dysmorphic neurons”, an abnormal cell type found in some. In seven of the 10 individuals, they reported the presence of “malformed cells of uncertain origin with large, sometimes multiple, nuclei surrounded by an excess of opalescent, pseudopodic cytoplasm” This referred to the second abnormal cell type that can sometimes be found in FCD specimens–the “balloon cells”. We begin the story with the early recognition of mTOR pathway dysregulation in FCDII, describe the discovery of somatic mosaicism in focal brain lesion and the evidence of two-hit mechanism, and discuss challenges in the field and future directions
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