{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T07:26:33Z","timestamp":1773645993440,"version":"3.50.1"},"reference-count":87,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1155224"],"award-info":[{"award-number":["APP1155224"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1091593"],"award-info":[{"award-number":["APP1091593"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Steroids yield great influence on neurological development through nuclear hormone receptor (NHR)-mediated gene regulation. We recently reported that cell adhesion molecule protocadherin 19 (encoded by the PCDH19 gene) is involved in the coregulation of steroid receptor activity on gene expression. PCDH19 variants cause early-onset developmental epileptic encephalopathy clustering epilepsy (CE), with altered steroidogenesis and NHR-related gene expression being identified in these individuals. The implication of hormonal pathways in CE pathogenesis has led to the investigation of various steroid-based antiepileptic drugs in the treatment of this disorder, with mixed results so far. Therefore, there are many unmet challenges in assessing the antiseizure targets and efficiency of steroid-based therapeutics for CE. We review and assess the evidence for and against the implication of neurosteroids in the pathogenesis of CE and in view of their possible clinical benefit.<\/jats:p>","DOI":"10.3390\/ijms22189769","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T12:20:37Z","timestamp":1631190037000},"page":"9769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Protocadherin 19 Clustering Epilepsy and Neurosteroids: Opportunities for Intervention"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9475-1160","authenticated-orcid":false,"given":"Rebekah","family":"de Nys","sequence":"first","affiliation":[{"name":"Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia"},{"name":"Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raman","family":"Kumar","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia"},{"name":"Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7884-6861","authenticated-orcid":false,"given":"Jozef","family":"Gecz","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia"},{"name":"Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia"},{"name":"School of Biological Sciences, The University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/s41380-018-0066-9","article-title":"A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity","volume":"24","author":"Kolc","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s41398-020-0803-0","article-title":"A standardized patient-centered characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy","volume":"10","author":"Kolc","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/ng.149","article-title":"X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment","volume":"40","author":"Dibbens","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1000381","DOI":"10.1371\/journal.pgen.1000381","article-title":"Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females","volume":"5","author":"Depienne","year":"2009","journal-title":"PLoS Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1111\/epi.13295","article-title":"PCDH19-related epilepsy in two mosaic male patients","volume":"57","author":"Terracciano","year":"2016","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1007\/s12035-020-02242-4","article-title":"Disrupted Excitatory Synaptic Contacts and Altered Neuronal Network Activity Underpins the Neurological Phenotype in PCDH19-Clustering Epilepsy (PCDH19-CE)","volume":"58","author":"Homan","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neuron.2017.12.005","article-title":"Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy","volume":"97","author":"Pederick","year":"2018","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.1126\/science.aaz3893","article-title":"Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder","volume":"372","author":"Hoshina","year":"2021","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1111\/epi.16675","article-title":"Characterization of seizure susceptibility in Pcdh19 mice","volume":"61","author":"Rakotomamonjy","year":"2020","journal-title":"Epilepsia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/B978-0-12-394311-8.00008-X","article-title":"Delta-protocadherins in health and disease","volume":"116","author":"Kahr","year":"2013","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3946","DOI":"10.1038\/s41467-019-11854-x","article-title":"TBR2 coordinates neurogenesis expansion and precise microcircuit organization via Protocadherin 19 in the mammalian cortex","volume":"10","author":"Lv","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26765","DOI":"10.1038\/srep26765","article-title":"Pcdh19 Loss-of-Function Increases Neuronal Migration In Vitro but is Dispensable for Brain Development in Mice","volume":"6","author":"Pederick","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.gene.2019.02.071","article-title":"miR-99b-3p promotes hepatocellular carcinoma metastasis and proliferation by targeting protocadherin 19","volume":"698","author":"Yao","year":"2019","journal-title":"Gene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1083\/jcb.201108115","article-title":"A complex of Protocadherin-19 and N-cadherin mediates a novel mechanism of cell adhesion","volume":"195","author":"Emond","year":"2011","journal-title":"J. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.brainres.2010.04.065","article-title":"Adhesion properties and retinofugal expression of chicken protocadherin-19","volume":"1344","author":"Tai","year":"2010","journal-title":"Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e18529","DOI":"10.7554\/eLife.18529","article-title":"Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy","volume":"5","author":"Cooper","year":"2016","journal-title":"eLife"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1093\/hmg\/ddy019","article-title":"The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological maturation of hippocampal neurons","volume":"27","author":"Bassani","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5336","DOI":"10.1007\/s12035-020-02099-7","article-title":"The Epilepsy-Related Protein PCDH19 Regulates Tonic Inhibition, GABAAR Kinetics, and the Intrinsic Excitability of Hippocampal Neurons","volume":"57","author":"Serratto","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.rdc.2015.08.002","article-title":"Corticosteroids: Mechanisms of Action in Health and Disease","volume":"42","author":"Ramamoorthy","year":"2016","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/B978-0-444-53630-3.00008-7","article-title":"Neurosteroids: Endogenous role in the human brain and therapeutic potentials","volume":"186","author":"Reddy","year":"2010","journal-title":"Prog Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/WCO.0b013e32833735cf","article-title":"Neurosteroids and epilepsy","volume":"23","author":"Biagini","year":"2010","journal-title":"Curr. Opin. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.seizure.2015.02.012","article-title":"Interactions between hormones and epilepsy","volume":"28","author":"Tauboll","year":"2015","journal-title":"Seizure"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.neubiorev.2019.05.023","article-title":"Cortisol levels and seizures in adults with epilepsy: A systematic review","volume":"103","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"535","DOI":"10.2147\/IJWH.S28872","article-title":"Diagnosis and management of catamenial seizures: A review","volume":"4","author":"Verrotti","year":"2012","journal-title":"Int. J. Womens Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.1093\/hmg\/ddv245","article-title":"Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency","volume":"24","author":"Tan","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e91","DOI":"10.1111\/epi.13772","article-title":"Reduced steroidogenesis in patients with PCDH19-female limited epilepsy","volume":"58","author":"Trivisano","year":"2017","journal-title":"Epilepsia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1210\/endo-70-2-196","article-title":"The Gonad-Brain Relationship: Effects of Female Sex Hormones on Electroshock Convulsions in the Rat","volume":"70","author":"Woolley","year":"1962","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2007.04.003","article-title":"Recent developments in the significance and therapeutic relevance of neuroactive steroids--Introduction to the special issue","volume":"116","author":"Morrow","year":"2007","journal-title":"Pharm. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/nrg2415","article-title":"Sex-specific genetic architecture of human disease","volume":"9","author":"Ober","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1469-8749.1989.tb03976.x","article-title":"Effects of puberty on seizure frequency","volume":"31","author":"Niijima","year":"1989","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S1474-4422(18)30495-2","article-title":"Management of epilepsy in women","volume":"18","author":"Stephen","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s10048-017-0517-5","article-title":"Male patients affected by mosaic PCDH19 mutations: Five new cases","volume":"18","author":"Rump","year":"2017","journal-title":"Neurogenetics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1586\/17512433.2016.1160777","article-title":"The effect of epilepsy and antiepileptic drugs on sexual, reproductive and gonadal health of adults with epilepsy","volume":"9","author":"Hamed","year":"2016","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1152\/physrev.2001.81.3.1269","article-title":"Nuclear Hormone Receptors and Gene Expression","volume":"81","author":"Aranda","year":"2001","journal-title":"Physiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nrm.2016.122","article-title":"Nuclear receptors outside the nucleus: Extranuclear signalling by steroid receptors","volume":"17","author":"Levin","year":"2016","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20150114","DOI":"10.1098\/rstb.2015.0114","article-title":"Epigenetic mechanisms in sexual differentiation of the brain and behaviour","volume":"371","author":"Forger","year":"2016","journal-title":"Philos. Trans. R Soc. Lond. B Biol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.ajhg.2011.06.009","article-title":"Why boys will be boys: Two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation","volume":"89","author":"Fluck","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1080\/17425255.2017.1376648","article-title":"Pharmacogenetics of aldo-keto reductase 1C (AKR1C) enzymes","volume":"13","author":"Alshogran","year":"2017","journal-title":"Drug. Metab. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.bcp.2007.09.008","article-title":"An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies","volume":"75","author":"Byrns","year":"2008","journal-title":"Biochem. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.mce.2018.07.002","article-title":"AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase\/prostaglandin F synthase): Roles in malignancy and endocrine disorders","volume":"489","author":"Penning","year":"2019","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5613","DOI":"10.1158\/1078-0432.CCR-13-1151","article-title":"Steroidogenic Enzyme AKR1C3 Is a Novel Androgen Receptor-Selective Coactivator that Promotes Prostate Cancer Growth","volume":"19","author":"Yepuru","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/mp.2014.77","article-title":"The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis","volume":"20","author":"LoParo","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1093\/hmg\/ddx094","article-title":"Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERalpha)","volume":"26","author":"Pham","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.biopsych.2010.12.022","article-title":"Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: A neurobehavioral model of autism","volume":"69","author":"Sala","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.celrep.2016.03.013","article-title":"The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2","volume":"15","author":"Leonzino","year":"2016","journal-title":"Cell. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.schres.2016.04.019","article-title":"Reduced oxytocin receptor gene expression and binding sites in different brain regions in schizophrenia: A post-mortem study","volume":"177","author":"Uhrig","year":"2016","journal-title":"Schizophr. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/epi.14678","article-title":"Schizophrenia is a later-onset feature of PCDH19 Girls Clustering Epilepsy","volume":"60","author":"Vlaskamp","year":"2019","journal-title":"Epilepsia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8119","DOI":"10.1073\/pnas.1705521114","article-title":"Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism","volume":"114","author":"Parker","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"555","DOI":"10.2217\/clp.10.37","article-title":"Apolipoproteins in the brain: Implications for neurological and psychiatric disorders","volume":"51","author":"Elliott","year":"2010","journal-title":"Clin. Lipidol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/0167-4781(93)90292-L","article-title":"Structure of the human apolipoprotein D genepromoter region","volume":"1172","author":"Lambert","year":"1993","journal-title":"Biochim. et Biophys. Acta\u2014Gene Struct. Exp."},{"key":"ref_51","first-page":"1115","article-title":"Additive Stimulatory Action of Glucocorticoids and Androgens on Basal and Estrogen-Repressed Apolipoprotein-D Messenger Ribonucleic Acid and Secretion in Human Breast Cancer Cells","volume":"130","author":"Simard","year":"1992","journal-title":"Endocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1016\/j.neurobiolaging.2014.01.148","article-title":"Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain","volume":"35","author":"Dassati","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1474-9726.2008.00395.x","article-title":"Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress","volume":"7","author":"Ganfornina","year":"2008","journal-title":"Aging Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.cub.2006.03.024","article-title":"Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila","volume":"16","author":"Sanchez","year":"2006","journal-title":"Curr. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.1007\/s12035-016-9920-4","article-title":"Apolipoprotein D Overexpression Protects Against Kainate-Induced Neurotoxicity in Mice","volume":"54","author":"Najyb","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"26804","DOI":"10.18632\/oncotarget.5757","article-title":"Characterizing PCDH19 in human induced pluripotent stem cells (iPSCs) and iPSC-derived developing neurons: Emerging role of a protein involved in controlling polarity during neurogenesis","volume":"6","author":"Compagnucci","year":"2015","journal-title":"Oncotarget"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Borghi, R., Magliocca, V., Petrini, S., Conti, L.A., Moreno, S., Bertini, E., Tartaglia, M., and Compagnucci, C. (2021). Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis. J. Clin. Med., 10.","DOI":"10.3390\/jcm10132754"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1111\/epi.14600","article-title":"Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study","volume":"59","author":"Trivisano","year":"2018","journal-title":"Epilepsia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.seizure.2016.01.006","article-title":"Effectiveness of antiepileptic therapy in patients with PCDH19 mutations","volume":"35","author":"Lotte","year":"2016","journal-title":"Seizure"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/S0006-8993(99)01619-4","article-title":"Steroid hormones affect limbic afterdischarge thresholds and kindling rates inadult female rats","volume":"838","author":"Edwards","year":"1999","journal-title":"Brain Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.seizure.2015.02.024","article-title":"Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial","volume":"28","author":"Herzog","year":"2015","journal-title":"Seizure"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"128","DOI":"10.2174\/157488908784534577","article-title":"New avenue of research: Antiepileptic drug and estradiol neuroprotection in epilepsy","volume":"3","year":"2008","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.eplepsyres.2013.04.005","article-title":"PCDH19-related female-limited epilepsy: Further details regarding early clinical features and therapeutic efficacy","volume":"106","author":"Higurashi","year":"2013","journal-title":"Epilepsy Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.seizure.2015.02.006","article-title":"Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy","volume":"27","author":"Higurashi","year":"2015","journal-title":"Seizure"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.seizure.2015.09.002","article-title":"Steroids efficacy in the acute management of seizure clusters in one case of PCDH19 female epilepsy","volume":"32","author":"Bertani","year":"2015","journal-title":"Seizure"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1212\/WNL.88.16_supplement.P5.236","article-title":"A multicenter, open-label trial of ganaxolone in children with PCDH19 epilepsy (P5.236)","volume":"88","author":"Lappalainen","year":"2017","journal-title":"Neurology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1080\/13543784.2018.1543398","article-title":"Investigational small molecules in phase II clinical trials for the treatment of epilepsy","volume":"27","author":"Greco","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_68","first-page":"909","article-title":"Enhanced anticonvulsant activity of ganaxolone after neurosteroids withdrawal in a rat model of catamenial epilepsy","volume":"294","author":"Reddy","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_69","first-page":"1284","article-title":"Characterization of the Anticonvulsant Properties of Ganaxolone (CCD 1042; 3\u03b1-Hydroxy-3\u03b2-methyl-5\u03b1-pregnan-20-one), a Selective, High-Affinity, Steroid Modulator of the \u03b3-Aminobutyric AcidA Receptor","volume":"280","author":"Carter","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.nurt.2006.11.003","article-title":"Ganaxolone","volume":"4","author":"Nohria","year":"2007","journal-title":"Neurotherapeutics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1111\/epi.13705","article-title":"Randomized, double-blind, placebo-controlled phase 2 study of ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures","volume":"58","author":"Sperling","year":"2017","journal-title":"Epilepsia"},{"key":"ref_72","unstructured":"Caperelli, L.M. (2021, May 24). Marinus Pharmaceuticals Initiates Phase 3 Study in Children with PCDH19-Related Epilepsy. Available online: https:\/\/www.globenewswire.com\/news-release\/2019\/03\/06\/1748723\/0\/en\/Marinus-Pharmaceuticals-Initiates-Phase-3-Study-in-Children-with-PCDH19-Related-Epilepsy.html."},{"key":"ref_73","unstructured":"Ellis, S.D. (2021, September 06). Marinus Pharmaceuticals Provides Business Update and Reports Fourth Quarter 2020 Financial Results. Available online: https:\/\/www.businesswire.com\/news\/home\/20210309005403\/en\/Marinus-Pharmaceuticals-Provides-Business-Update-and-Reports-Fourth-Quarter-2020-Financial-Results."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.eplepsyres.2011.10.014","article-title":"PCDH19 mutation in Japanese females with epilepsy","volume":"99","author":"Higurashi","year":"2012","journal-title":"Epilepsy Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1111\/j.1528-1167.2012.03649.x","article-title":"Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy","volume":"53","author":"Marini","year":"2012","journal-title":"Epilepsia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ejpn.2019.12.020","article-title":"Levetiracetam efficacy in PCDH19 Girls Clustering Epilepsy","volume":"24","author":"Sadleir","year":"2020","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1007\/s00439-013-1331-2","article-title":"Where genotype is not predictive of phenotype: Towards an understanding of the molecular basis of reduced penetrance in human inherited disease","volume":"132","author":"Cooper","year":"2013","journal-title":"Hum. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/cge.12846","article-title":"The clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population","volume":"91","author":"Liu","year":"2017","journal-title":"Clin. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.seizure.2011.01.003","article-title":"Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs","volume":"20","author":"Loscher","year":"2011","journal-title":"Seizure"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5801","DOI":"10.1038\/s41598-017-06374-x","article-title":"Loss of X-linked Protocadherin-19 differentially affects the behavior of heterozygous female and hemizygous male mice","volume":"7","author":"Hayashi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13041-019-0519-3","article-title":"Autism-like behaviors in male mice with a Pcdh19 deletion","volume":"12","author":"Lim","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6987","DOI":"10.1073\/pnas.0800387105","article-title":"Null mutations in human and mouse orthologs frequently result in different phenotypes","volume":"105","author":"Liao","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1210\/en.2018-00220","article-title":"Comparing Postnatal Development of Gonadal Hormones and Associated Social Behaviors in Rats, Mice, and Humans","volume":"159","author":"Bell","year":"2018","journal-title":"Endocrinology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.clinms.2018.12.003","article-title":"Simultaneous measurement of 18 steroids in human and mouse serum by Liq. chromatography\u2013mass spectrometry without derivatization to profile the classical and alternate pathways of androgen synthesis and metabolism","volume":"11","author":"Desai","year":"2019","journal-title":"Clin. Mass Spectrom."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/1476-4598-8-121","article-title":"Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: Implications for modelling human cancers","volume":"8","author":"Velica","year":"2009","journal-title":"Mol. Cancer"},{"key":"ref_86","first-page":"8","article-title":"Effect of Ganaxolone on Seizure Frequency Across Subpopulations of Patients With CDKL5 Deficiency Disorder: Subgroup Analyses of the Marigold Study","volume":"13","author":"Aimetti","year":"2020","journal-title":"Am. Epilepsy Soc. Mar. Pharm."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"107897","DOI":"10.1016\/j.neuropharm.2019.107897","article-title":"Pregnenolone and pregnenolone-methyl-ether rescue neuronal defects caused by dysfunctional CLIP170 in a neuronal model of CDKL5 Deficiency Disorder","volume":"164","author":"Barbiero","year":"2020","journal-title":"Neuropharmacology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9769\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:59:42Z","timestamp":1760165982000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9769"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":87,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22189769"],"URL":"https:\/\/doi.org\/10.3390\/ijms22189769","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]}}}