Michael Neff

Background: Cyclin-dependent like kinase 5 (CDKL5) Deficiency Disorder is an X-linked mutation that leads to severe developmental delays, spontaneous seizures, and early death in infants.^6,7,8 CDKL5 is a serine threonine kinase that is a key regulator of early neuronal development that controls the aggregation of glutamatergic receptors, GABA-A receptors, and regulation of actin-microtubule growth dynamics.^1,2,4,6 Currently, 84% of patients with CDKL5 deficiency disorder possess uncontrolled spontaneous drug resistant seizures that severely lowers the prognosis and quality of life outcomes.^5,8,9 Neurosteroids are currently being proposed as a novel treatment option for CDKL5 deficiency disorder due to their intrinsic GABAergic and other regulatory properties to mitigate the loss of CDKL5 regulation.^3,5,8

Objective: In this review, we explore the pathogenic mechanisms that CDKL5 Deficiency Disorder enacts on CNS and a novel neurotherapeutic that is first in class to receive FDA approval for the treatment of the etiology.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords/Phrases: “CDKL5 Deficiency Disorder”, ” Neurosteroids”, “Drug-Resistant Seizures”, and “Ganaxolone”.

Results: Animal model studies indicated that the loss of actin-microtubule regulation from the CLIP170 protein due to mutation in CDKL5 can be restored to the active conformation through the use of exogenous neurosteroid administration with both structural and phenotypic benefits.^3,4 CDKL5 deficiency correlated strongly with the loss of the enzyme PSD95, a protein vital in the aggregation of glutamatergic receptors containing the GluA2 subunit. PSD95 expression was restored through the administration of an exogenous neurosteroid.^2,9 Additionally, the loss of gephyrin expression in CDKL5 KO was correlated to a loss of synaptic GABA-A receptors that was subsequently restored via a neurosteroid.^3,4 These initial promising results lead to the MARIGOLD phase III trial of the neurosteroid ganaxolone (GX) as an adjunctive treatment in children with spontaneous drug resistant seizures related to CDKL5 deficiency disorder. Results from the trial showed a significant decrease in the median 28-day seizure frequency (-30.7%) in the treatment group compared to placebo (-6.9%).⁵

Conclusions: These studies indicate that mutation in CDKL5 causes significant loss of function of the post/presynaptic membranes leading to dysregulation of excitatory/inhibitory signaling in neurodevelopment. CDKL5 loss is also associated with aberrant neuronal growth due to dysregulation of actin-microtubule regulatory proteins. These deficits were successfully mitigated through the use of exogenous neurosteroid administration with phenotypic benefits, including a reduction in spontaneous drug-resistant behavioral seizures.

Works Cited:

1. Yennawar M, White RS, Jensen FE. AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder. J Neurosci. 2019;39(24):4814-4828. doi:10.1523/JNEUROSCI.2041-18.2019
2. Wang HT, Zhu ZA, Li YY, et al. CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures. Epilepsia. 2021;62(2):517-528. doi:10.1111/epi.16805
3. De Rosa R, Valastro S, Cambria C, et al. Loss of CDKL5 Causes Synaptic GABAergic Defects That Can Be Restored with the Neuroactive Steroid Pregnenolone-Methyl-Ether. Int J Mol Sci. 2022;24(1):68. Published 2022 Dec 21. doi:10.3390/ijms24010068
4. Barbiero I, Zamberletti E, Tramarin M, et al. Pregnenolone-methyl-ether enhances CLIP170 and microtubule functions improving spine maturation and hippocampal deficits related to CDKL5 deficiency. Hum Mol Genet. 2022;31(16):2738-2750. doi:10.1093/hmg/ddac067
5. Knight EMP, Amin S, Bahi-Buisson N, et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial [published correction appears in Lancet Neurol. 2022 Jul;21(7):e7]. Lancet Neurol. 2022;21(5):417-427. doi:10.1016/S1474-4422(22)00077-1
6. Jakimiec M, Paprocka J, Śmigiel R. CDKL5 Deficiency Disorder-A Complex Epileptic Encephalopathy. Brain Sci. 2020;10(2):107. Published 2020 Feb 17. doi:10.3390/brainsci10020107
7. Van Bergen NJ, Massey S, Quigley A, et al. CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development. Biochem Soc Trans. 2022;50(4):1207-1224.doi:10.1042/BST20220791
8. Olson HE, Daniels CI, Haviland I, et al. Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder. J Neurodev Disord. 2021;13(1):40. Published 2021 Sep 16. doi:10.1186/s11689-021-09384-z
9. Wang HT, Zhu ZA, Li YY, et al. CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures. Epilepsia. 2021;62(2):517-528. doi:10.1111/epi.16805