The importance of neurosteroid hormones in the pathogenesis of Protocadherin 19 female limited epilepsy and intellectual disability (PCDH19-FE). J. Gecz1,2,3,4, C. Tan1, E. Ranieri2, D. Pham1,3, C. Shard4, K. Hynes1, E. Douglas2, L. S. Nguyen1, M. Corbett1, D. Leach5, G. Buchanan5, E. Haan6, L. G. Sadleir7, C. Depienne8, R. S. Moller9, R. Guerrini10, C. Marini10, S. F. Berkovic11, I. E. Scheffer11,12 1) Paediatrics, The University of Adelaide at Women's & Children's Hosp, Adelaide, South Australia, Australia; 2) SA Pathology, Adelaide Australia; 3) Robinson Institute, The University of Adelaide, Adelaide, SA, Australia; 4) School Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, Australia; 5) Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia; 6) South Australian Clinical Genetics Service, SA Pathology (at Womens and Childrens Hospital), North Adelaide, Australia; 7) Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; 8) INSERM UMR 975, Hôpital Pitié-Salpêtrière, Paris, France; 9) Danish Epilepsy Centre, Dianalund and Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark; 10) Pediatric Neurology Uni, Children's Hospital, Florence, Italy; 11) Epilepsy Research Centre, The University of Melbourne, Heidelberg, Australia; 12) Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.

   PCDH19-Female-Epilepsy (PCDH19-FE) is an unusual X-linked disorder that primarily affects females. PCDH19-FE encompasses a broad clinical spectrum from infantile epileptic encephalopathy resembling Dravet syndrome to epilepsy with or without intellectual disability and autism spectrum disorders. PCDH19-FE is highly, but not fully penetrant. We have used transcriptome profiling of primary skin fibroblasts of PCDH19-FE females (n=12 and n=3 age and passage matched normal controls) and unaffected transmitting males (n=3 and n=3 age and passage matched control males) to study PCDH19-FE pathology. We found 94 significantly de-regulated genes between PCDH19-FE and control females (One-way ANOVA, p < 0.05, fold change > 2), of which 73 were annotated. Among these 94 genes there were 43 genes, which showed sex-biased expression in our control male versus control female comparison (223 genome-wide sex-biased genes). The enrichment of sexually biased genes among our significantly de-regulated genes was highly significant, p = 2.51 x 10-47, Two-tail Fishers exact test. Followup studies using additional patient skin fibroblast cell lines (including the cell line from one affected somatic mosaic male) validated the majority of deregulated genes, among them the aldo-keto reductase family 1, members C1-3 (AKR1C1-3) genes. The AKR1C genes play a crucial role in neurosteroid hormone metabolism. Human skin is endowed to metabolise neurosteroids. Of relevance to this is, that germline mutations of AKR1C genes cause disorders of sexual development (ie. sex reversal). We subsequently showed that AKR1C protein levels are affected and as a result of this the PCDH19-FE girls are allopregnanolone deficient (based on peripheral blood allopregnanolone tests). Additional support for the role of steroid hormones in the pathology of PCDH19-FE came from the age of onset (mean ~10 months) and offset (mean ~12.5 years) of epilepsy (n=140 patients), both of which coincide with dramatically varying sex hormone levels (onset - after minipuberty at ~8-9 months and offset - with the advent of puberty at ~12 years). Our data together with the broadly discussed role of steroids in epilepsy led us to postulate that steroid hormones and specifically neurosteroids like allopregnanolone are involved in the pathology of PCDH19-FE. These findings open realistic opportunities for targeted therapeutic interventions.

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