Authors :
Presenting Author: Rita Garbelli, – IRCCS Foundation Neurological Institute Carlo Besta
Dalia De Santis, PhD – Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
Cinzia Cagnoli, PhD – Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
Laura Rossini, – Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
Michele Rizzi, MD – Instituto Neurologico Besta
Ester Cifaldi, PhD – Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna
Barbara Castellotti, PhD – Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta
Marco De Curtis, MD – Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Roberta Di Giacomo, MD – Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
Rationale:
Focal cortical dysplasia type II (FCDII) is one of the most common epileptogenic cortical malformations, particularly in frontal lobe. Microscopic FCDII hallmarks are a combination of architectural and cytoarchitectural abnormalities with dysmorphic neurons (subtype IIa) plus balloon cells (subtype IIb). Recently, brain mosaic variants have been detected suggesting a genetic cause in about 16 to 57% of FCDII cases with mutations in the mammalian target of rapamycin (mTOR) pathway and a predominant association with either GATOR1 or MTOR variants were found in FCDIIa or IIb subtype, respectively. Here, we describe a case of a 29-year-old woman with focal drug-resistant epilepsy and an unusual FCDIIa with lipofuscin accumulation in DN at histopathology (FCDIIa-L).
Methods:
Electroclinical analysis, MRI and FCD-PET evaluation, intraoperative EEG data, neuropathology and genetic data were performed. To study the spatial profile of peptides, Matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS) was simultaneously performed on paraffin sections of this case and, for comparative purpose, from an FCDIIa case without detectable lipofuscin accumulation in DN.
Results:
Clinical, neurophysiological and radiological findings were consistent with a right frontal FCDII and a cortectomy was performed. Intraoperative lesional electrocorticography using a stereoEEG electrode (3D-ECoG) was also suggestive for FCDII. Seven months after surgery the patient is still seizure free. Neuropathology showed the presence of DNs with a peculiar vacuolized feature: the cytoplasmic neurofilaments accumulation was marginalized to the periphery of the neurons for the presence of abnormal PAS-positive and p62-positive granular inclusions, suggestive for neuronal lipofuscin. Genetic testing on blood showed a novel germline heterozygous splicing variant, c.393+1G >A, in the NPRL3 gene. However, MALDI spectra clearly segregated this FCDIIa-L from “classic” FCDIIa suggesting a different peptide composition.
Conclusions:
The presence of dysmorphic neurons with abnormal lipofuscin accumulation in the context of surgically removed epileptic lesions was firstly described in 2016 and the authors proposed the term “focal neuronal lipofuscinosis” (FNL) to describe this pattern. Since then, three other studies reported similar neuropathological findings, with a total of 14 previously described cases submitted to epilepsy surgery in frontal and temporal lobe and the lesion was variably classified as FNL or FCDIIa at histology. The presence of germline variant in GATOR1-complex claim for consider this cases as FCDIIa but some discrepancy are present at clinical and histopatological/proteomic level. Extending the description of these rare cases will allow collection of more clinical history and perform genotype-phenotype correlations. Moreover, data on mass spectra profile if extended on larger series, could contributed to better deciphering this entity in term of similarities/discrepancies with “classic” FCDIIa without lipofuscin aggregates.
Funding:
European Union-Next Generation EU-NRRP M6C2-Investment 2.1 Enhancement and strengthening of biomedical research in the NHS, PNRR-MCNT2-2023-12377819 grant.