Reduced steroidogenesis in patients with PCDH19-female limited epilepsy.

Marina Trivisano,Alessandra Terracciano,Chiara Lucchi,Grazia Maria Ubertini,Jozef Gecz,Giuseppe Biagini,Cecilia Rustichelli,Enrico Silvio Bertini,Federico Vigevano,Raffaella Cusmai,Germana Giannone,Nicola Specchio

doi:10.1111/epi.13772

Abstract

Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays. Apart from estradiol and progesterone, all the considered hormones were evaluated in basal condition and after stimulation with adrenocorticotropic hormone (ACTH). A generalized decrease in blood levels of almost all measured neuroactive steroids was found. When considering sexual development, cortisol and pregnenolone sulfate basal levels were significantly reduced in postpubertal girls affected by PCDH19-FE. Of interest, ACTH administration did not recover pregnenolone sulfate serum levels but restored cortisol to control levels. In prepubertal girls with PCDH19-FE, by challenging adrenal function with ACTH we disclosed defects in the production of cortisol, pregnenolone sulfate, and 17OH-progesterone, which were not apparent in basal condition. These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity.

Highlights

These genes have multiple other activities in the synthesis of a broad range of steroids, and it is plausible that the protocadherin 19 (PCDH19)-FE patients are deficient for a range of neuroactive steroids. This observation led us to postulate that the remarkable deficit of production of AP and other neurosteroids could be responsible for an imbalance in the ratio of anticonvulsant and proconvulsant hormones, so to favor the occurrence of recurrent, difficult to treat seizures in PCDH19-FE patients. To address these important issues, we aimed to investigate the production of a variety of neuroactive steroids in the PCDH19-FE patients
No statistically significant differences were found for estradiol, progesterone was lower in PCDH19-FE girls (0.355 Æ 0.083 vs. 0.740 Æ 0.115 in controls; p < 0.05, Student’s t-test)
Cortisol levels were not influenced by puberty and a trend was found for 17OH-progesterone (p = 0.07) only, but for this latter hormone, the interaction between puberty and adrenocorticotropic hormone (ACTH) administration was significant (p < 0.05)