A familiar study on Self-limited Childhood Epilepsy patients using hIPSC-derived neurons shows a bias towards immaturity at the morphological, electrophysiological and gene expression levels

CASALIA, M; CASABONA, JC; GARCIA, C; CAVALIERE CANDEDO, V; H.R QUINTÁ; FARÍAS, M; GONZALEZ, J; GONZALEZ MORÓN, D; CORDOBA, M; CONSALVO, D; MOSTOSLAVSKY, G; URBANO, F; PASQUINI JM; MURER, MG; RELA, L; KAUFFMAN, M; PITOSSI, F

Stem Cell Research & Therapy

BMC

Año: 2021

1757-6512

Self-limited Childhood Epilepsies (SLCE) are common, age-restricted focal epilepsy syndromes that affect 20/100.000 new children every year (1) . Two occipital variants of SLCE are eponymously known as Gastaut and Panayiotopoulos types. However, the electro-clinical overlap shown by patients affected by occipital SLCE precludes the use of rigid 37 classifications schemes (2) . Therefore, the more general term SLCE is favored for patients suffering from focal epilepsy during the first two decades of life that frequently remit during 39 adulthood (3) . 40 The existence of genetic determinants in the etiology of SLCE has long been proposed. 41 Familial aggregation has repeatedly been described for SLCE and occasional reports of 42 disease-causing mutations in occipital SLCE patients have been published. However, it is still 43 unclear if monogenic forms of occipital SLCE exist at all or, if their genetic architecture is 44 better explained by a complex inheritance model. Polygenic models of neurodevelopmental 45 disorders such as SLCE recognize core genes belonging to pathways that play a central role 46 in the disease, and peripheral genes spread across the genome that may have key effects 47 on heritability through trans-regulatory effects on the core genes (4). Emerging phenotypes, 48 especially in the case of neurodevelopmental disorders such as some forms of epilepsy, 49 depend not only on genetic variability but also on the stochastic execution of 50 developmental programs (5) . Moreover, recently, atypical maturation of white matter 51 microstructure has been found in benign epilepsy with centrotemporal spikes contributing 52 to epileptogenesis and suggesting a maturation defect underlying this disease (6). Despite its high impact in the study of neurological disorders, induced pluripotent stem cells 55 (iPSC)-derived neurons have been scarcely used to investigate epilepsies (7, 8) . In 56 particular, no in vitro model is available to study SLCE. 57 Here, we have studied a family of 7 siblings, among whom 4 suffer from occipital SLCE and 58 show high intra-familial phenotypic variability. Since this pattern of disease suggests an 59 underlying genetic component, using exome sequencing, a homozygous variant in the FYVE, 60 RhoGEF and PH Domain Containing 6 gene (FGD6) was identified as a putative genetic factor 61 that could contribute, under a possible oligogenic model, to the development of this familial 62 disorder. We have generated hiPSC-derived neurons from two affected siblings compared 63 to two familial controls that showed morphological and functional abnormalities that could 64 clarify some of the mechanisms leading to SLCE. In addition, these lines could serve as 65 cellular platforms for drug discovery in SLCE