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Review
. 2019 Aug:97:38-42.
doi: 10.1016/j.pediatrneurol.2019.03.017. Epub 2019 Mar 27.

Severity Assessment in CDKL5 Deficiency Disorder

Scott Demarest  1 , Elia M Pestana-Knight  2 , Heather E Olson  3 , Jenny Downs  4 , Eric D Marsh  5 , Walter E Kaufmann  6 , Carol-Anne Partridge  7 , Helen Leonard  8 , Femida Gwadry-Sridhar  9 , Katheryn Elibri Frame  10 , J Helen Cross  11 , Richard F M Chin  12 , Sumit Parikh  13 , Axel Panzer  14 , Judith Weisenberg  15 , Karen Utley  16 , Amanda Jaksha  16 , Sam Amin  17 , Omar Khwaja  18 , Orrin Devinsky  19 , Jeffery L Neul  20 , Alan K Percy  21 , Tim A Benke  22
Affiliations
Review

Severity Assessment in CDKL5 Deficiency Disorder

Scott Demarest et al. Pediatr Neurol. 2019 Aug.

Abstract

Background: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness.

Methods: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input.

Results: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included.

Conclusions: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.

Keywords: CDKL5; Cortical visual impairment; Epilepsy; Intellectual disability; Rare disorder; Severity assessment.

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Conflict of interest statement

Declaration of interest:

Scott Demarest: Consulting for Upsher-Smith and BioMarin. All remuneration has been made to his department.

Elia M. Pestana Knight: None

Jenny Downs: Consultancy for Avexis, Anavex, GW and Marinus. Any remuneration has been made to her department.

Heather Olson: None

Eric D. Marsh: Funding from the NIH, Rettsyndrome.org, and Rett Syndrome Research Trust, Site PI on studies from GW pharma, Zogenix Pharma, Marinus pharma, consultant to Stoke therapeutics.

Walter E. Kaufmann: None

Carol-Anne Partridge: None

Helen Leonard: None

Femida Gwadry-Sridhar: None

Katheryn Elibri Frame: None

J. Helen Cross: J Helen Cross has participated as a clinical investigator for Zogenix, GW Pharma, Marinius Pharmaceuticals and Vitaflo. She has been a member of advisory boards and speaker for Eisai, GW Pharma, Nutricia and Zogenix. All remuneration has been made to her department.

Richard F. M. Chin: None

Sumit Parikh: None

Axel Panzer: None

Judith Weisenberg: None

Karen Utley: None

Amanda Jaksha: None

Sam Amin: None.

Omar Khwaja: None

Orin Devinsky: Consultancy/advisory: Privateer Holdings/Tilray, Egg Rock/Papa & Barkley, Receptor Life Sciences, Empatica, Tevard, Engage, Rettco, Pairnomix/Q-state, Zogenix and GW Pharmaceuticals.

Jeffery L. Neul: Funding from the NIH, Consultancy with Acadia, AveXis, Biohaven, GW Pharmaceuticals, Neuren, Newron, Takeda, Teva

Alan K. Percy: Consultancy for Anavex, AveXIs, and GW Pharmaceuticals; Clinical Trial with Newron Pharmaceuticals

Tim A. Benke: Consultancy for AveXis, Ovid, Takeda and Marinus. All remuneration has been made to his department.

Figures

Figure 1:
Figure 1:. Modified Delphi process for CDD-SA development.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
Figure 2:
Figure 2:. CDD-SA.
The Final CDD-SA with brief instructions on completion.
See this image and copyright information in PMC

References

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