Aim: The inherit base of PCDH19-related epilepsy suggests a hormonal involvement due to de-regulation of AKR1C1-3 genes, which encode for crucial steroid hormone-metabolizing enzymes. Both mRNA and protein levels of AKR1C3 have been reported to be decreased in a small number of PCDH19 mutated patients. Aim of this study is to verify allopregnanolone and other neuroactive steroids serum levels in PCDH19 mutated patients. Methods: We performed a prospective case-control study. We enrolled 12 patients affected by PCDH19-related epilepsy and 15 controls, age-and sex-matched. Controls were recruited among subjects evaluated for praecox puberty or hyperandrogenism. In both groups blood samples were taken at basal (T0) and 60 min after (ACTH) administration (T1). Laboratory methods: Quantitative analysis of neuroactive steroids in serum was performed by liquid chromatography-electrospray tandem mass spectrometry. Study population: median age of PCDH19-mutated patients was 8.3+5.7 years (range 2.5-18.9). Other than epilepsy, 6 patients had mental retardation. Controls were all females, age 9.2+4.0 years (range 6.1-17.9). All controls had a normal cognitive profile. Nine patients had a diagnosis of praecox puberty and 6 hyperandrogenism. Results: All neuroactive steroids resulted down produced in patients with PCDH19-related epilepsy rather than controls. At basal assessment (T0), allopregnanolone was 0.9+0.5 vs 0.18+0.9 ng/ml (p<0.05); pregnanolone was 0.0+0.5 vs 0.3+0.5 ng/ml (p>0.05), but pregnanolone solphate sulfate was 7.39+5.53 vs 75.41+52.69 ng/ml (p<0.05). Also cortisol, progesterone and 17-OH progesterone resulted to be lowered in PCDH19-mutated patients compared with controls. After ACTH injection (T1), both neuroactive steroids and the other peripheral steroids, were confirmed to be lower compared with controls. ACTH test demonstrated a normal functioning of peripheral glands. Conclusion: We documented a down regulation of all steroidogenesis in PCDH19-related epilepsy. Particularly we found allopregnanolone and pregnaenolone solphate sulfate deficiency. Allopregnanolone is a GABA-A receptor modulators influencing the neuronal excitability, thus representing a realistic therapeutic target for PCDH19-related epilepsy.
Allopregnanolone is reduced in patients with PCDH19-related epilepsy / Trivisano, M; Lucchi, C; Terracciano, A; Rustichelli, C.; Cusmai, R; Ubertini, Gm; Giannone, G; Bertini, E; Vigevano, F; Gecz, J; Biagini, G; Specchio, N. - In: EPILEPSIA. - ISSN 1528-1167. - 57:2(2016), pp. 56-56. (Intervento presentato al convegno 12th European Congress on Epileptology tenutosi a Praga, Repubblica Ceca nel 11-15 Settembre 2016).
Allopregnanolone is reduced in patients with PCDH19-related epilepsy
C Lucchi;C. Rustichelli;G Biagini;
2016
Abstract
Aim: The inherit base of PCDH19-related epilepsy suggests a hormonal involvement due to de-regulation of AKR1C1-3 genes, which encode for crucial steroid hormone-metabolizing enzymes. Both mRNA and protein levels of AKR1C3 have been reported to be decreased in a small number of PCDH19 mutated patients. Aim of this study is to verify allopregnanolone and other neuroactive steroids serum levels in PCDH19 mutated patients. Methods: We performed a prospective case-control study. We enrolled 12 patients affected by PCDH19-related epilepsy and 15 controls, age-and sex-matched. Controls were recruited among subjects evaluated for praecox puberty or hyperandrogenism. In both groups blood samples were taken at basal (T0) and 60 min after (ACTH) administration (T1). Laboratory methods: Quantitative analysis of neuroactive steroids in serum was performed by liquid chromatography-electrospray tandem mass spectrometry. Study population: median age of PCDH19-mutated patients was 8.3+5.7 years (range 2.5-18.9). Other than epilepsy, 6 patients had mental retardation. Controls were all females, age 9.2+4.0 years (range 6.1-17.9). All controls had a normal cognitive profile. Nine patients had a diagnosis of praecox puberty and 6 hyperandrogenism. Results: All neuroactive steroids resulted down produced in patients with PCDH19-related epilepsy rather than controls. At basal assessment (T0), allopregnanolone was 0.9+0.5 vs 0.18+0.9 ng/ml (p<0.05); pregnanolone was 0.0+0.5 vs 0.3+0.5 ng/ml (p>0.05), but pregnanolone solphate sulfate was 7.39+5.53 vs 75.41+52.69 ng/ml (p<0.05). Also cortisol, progesterone and 17-OH progesterone resulted to be lowered in PCDH19-mutated patients compared with controls. After ACTH injection (T1), both neuroactive steroids and the other peripheral steroids, were confirmed to be lower compared with controls. ACTH test demonstrated a normal functioning of peripheral glands. Conclusion: We documented a down regulation of all steroidogenesis in PCDH19-related epilepsy. Particularly we found allopregnanolone and pregnaenolone solphate sulfate deficiency. Allopregnanolone is a GABA-A receptor modulators influencing the neuronal excitability, thus representing a realistic therapeutic target for PCDH19-related epilepsy.
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