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Published on: August 1, 2017
Severity Assessment in CDKL5 Deficiency Disorder
Scott Demarest1, Elia M Pestana-Knight2, Heather E Olson3
1Children's Hospital Colorado and University of Colorado School of Medicine Aurora, Colorado; Department of Pediatrics, Aurora, Colorado.
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.
Insights
A new severity assessment tool was developed for CDKL5 deficiency disorder (CDD), a severe genetic epilepsy. This tool aids in monitoring patient progress and advancing clinical trials for this rare neurological condition.
Area of Science:
- Genetics and Neurology
- Rare Disease Research
- Clinical Assessment Tool Development
Background:
- Cyclin-dependent kinase-like 5 (CDKL5) mutations cause CDKL5 deficiency disorder (CDD), a genetic condition characterized by severe epilepsy and developmental impairments.
- CDD is a frequent genetic cause of epilepsy in early life, affecting cognitive, motor, visual, and autonomic functions.
- A standardized severity assessment is currently lacking, hindering clinical course monitoring, natural history definition, and clinical trial readiness.
Purpose of the Study:
- To develop a comprehensive severity assessment tool for CDKL5 deficiency disorder.
- To establish a standardized method for evaluating disease severity and monitoring patient progression.
- To facilitate clinical trial readiness and natural history studies for CDD.
Main Methods:
- Development involved clinical and research expertise from international consortia (International Foundation for CDKL5 Research Centers of Excellence, NIH Rett and Rett-Related Disorders Natural History Study).
- A modified Delphi process with multiple iterations was employed, engaging clinicians, researchers, industry, patient groups, and parents.
- The assessment was refined through feedback and piloting with families at international meetings.
Main Results:
- A 51-item severity assessment was finalized, covering epilepsy, motor, cognitive, behavioral, visual, speech, and autonomic domains.
- The assessment includes parental ratings on therapy effectiveness and overall child and family functioning.
- The tool provides a comprehensive description of CDD manifestations.
Conclusions:
- A severity assessment for CDKL5 deficiency disorder was rapidly developed through multi-stakeholder consensus.
- Ongoing validation is necessary to support its use in future clinical trials.
- The consensus methodology used may serve as a model for developing assessments in other rare disorders.
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