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CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment

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Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the limited number of disease-specific studies that offer a high level of evidence. Epileptic spasms are the most common seizure type in CDD and are more often refractory to standard first-line treatment than are spasms of other etiologies. In other seizure types, the effectiveness of antiseizure medications is limited and wanes over time. Ketogenic diet and palliative surgical treatments have both had mixed results in observational studies. When treating refractory seizures in CDD, we recommend carefully balancing seizure control and treatment-related side effects to optimize each individual’s overall quality of life. Clinical trials of medications targeting epilepsy in CDD have been conducted, and additional investigational small molecules, gene therapy, and other disease-modifying therapies are in development for CDD.

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Authors and Affiliations

  1. Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Boston, MA, 02115, USA

    William Hong, Isabel Haviland & Heather E. Olson

  2. Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    Elia Pestana-Knight

  3. Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Judith L. Weisenberg

  4. School of Medicine, Children’s Hospital Colorado, University of Colorado, Aurora, CO, USA

    Scott Demarest

  5. Department of Pediatrics, School of Medicine, University of Colorado, Aurora, CO, USA

    Scott Demarest

  6. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Eric D. Marsh

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  1. William Hong
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  2. Isabel Haviland
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  7. Heather E. Olson
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Correspondence to Heather E. Olson.

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Funding

This review was supported by the National Institute of Neurologic Disorders and Stroke (K23 NS107646-04, principal investigator HEO) and by philanthropic donation for CDD research to support WH’s fellowship in Epilepsy Genetics.

Conflict of interest

WH and IH have no conflicts of interest that are directly relevant to the content of this article. EPK is on the scientific advisory board of Marinus Pharmaceuticals. JLW has received funding from the International Foundation for CDKL5 Research and is a site principal investigator for Marinus Pharmaceuticals. SD has consulted for Upsher-Smith, Biomarin, Neurogene, Marinus, Tysha, and Ovid Therapeutics; has received funding from the National Institutes of Health, the International Foundation for CDKL5 Research, Project 8P, and Mila's Miracle Foundation; and serves on the advisory board for the nonprofit foundations SLC6A1 Connect, Ring14 USA and FamilieSCN2A. EDM is a site principal investigator for trials for Stoke Therapeutics, GW Pharmaceuticals, Zogenix Pharmaceuticals, Acadia Pharmaceuticals, and Marinus Pharmaceuticals; was previously a consultant for Cilpa Pharmaceuticals and Stoke Therapeutics; has received research support from the National Institutes of Health, the Eagles Autism Foundation, the Penn Orphan Disease center, RettSyndrome.org, the International Foundation for CDKL5 Research, and the LouLou Foundation. HEO has consulted for Marinus Pharmaceuticals, Ovid Therapeutics, Zogenix, and Takeda Pharmaceuticals related to CDKL5 deficiency disorder; and has received clinical research funding from the International Foundation for CDKL5 Research and the LouLou Foundation/Orphan Disease Center at the University of Pennsylvania.

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Author contributions

WH: Conceptualization, literature search, data analysis/interpretation, manuscript draft preparation, and critical manuscript revision. IH: Literature search, data analysis/interpretation, manuscript draft preparation, and critical manuscript revision. EPK, JLW, SD, AND EDM: Data analysis/interpretation and critical manuscript revision. HEO: Conceptualization, data analysis/interpretation, manuscript draft preparation, and critical manuscript revision. All authors read and approved the final manuscript and agree to be accountable for this work.

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Hong, W., Haviland, I., Pestana-Knight, E. et al. CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment. CNS Drugs 36, 591–604 (2022). https://doi.org/10.1007/s40263-022-00921-5

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