Severity Assessment in CDKL5 Deficiency Disorder

• Authors: Scott Demarest, Childrens Hospital Colorado; Elia M. Pestana-Knight, Cleveland Clinic; Heather O. Olson, Boston Childrens Hospital; Jenny Downs, University of Western Australia; Eric D. Marsh, Childrens Hospital of Philadelphia; Walter Kaufmann, Emory University; Carol-Anne Partridge, CDKL5 UK; Helen Leonard, Curtin University; Femida Gwadry-Sridhar, University of Western Ontario; Katheryn Elibri Frame, CDKL5 Research Collaborative; J. Helen Cross, UCL Great Ormond Street Institute of Child Health; Richard F. M. Chin, University of Edinburgh; Sumit Parikh, Epilepsy Center; Axel Panzer, DRK Westend Clinic Berlin; Judith Weisenberg, Washington University; Karen Utley, International Foundation for CDKL5 Research; Amanda Jaksha, International Foundation for CDKL5 Research; Sam Amin, University of Bristol; Omar Khwaja, Roche Innovation Center Basel; Orrin Devinsky, New York University; Jeffery L. Neul, Vanderbilt University; Alan K. Percy, University of Alabama Birmingham; Tim A. Benke, Childrens Hospital Colorado
• Journal Title: Pediatric Neurology
• Volume: Volume 97
• Publisher: Elsevier Science Inc. | 2019-08-01, Pages 38-42
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.pediatrneurol.2019.03.017
• Subjects: Biology, Neuroscience; Biology, Genetics; Health Sciences, Rehabilitation and Therapy; Psychology, Developmental
• Keywords: Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; Pediatrics; Neurosciences & Neurology; CDKL5; Rare disorder; Severity assessment; Epilepsy; Cortical visual impairment; Intellectual disability; Rett syndrome; Functional abilities; Infantile spasms; Mutations; Epilepsy; Phenotype; Onset; Gene; Encephalopathies; Genotype

Abstract

Background: Pathological mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder (CDD), a genetic syndrome associated with severe epilepsy, cognitive, motor, visual and autonomic disturbances. CDD is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor clinical course, 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 NIH 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, speech and autonomic function. Parental ratings of therapy effectiveness, child and family functioning are also included. Conclusions: A severity assessment was rapidly developed with input from multiple stake-holders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of the severity assessment may be applicable to similar rare disorders.