Severity Assessment in CDKL5 Deficiency Disorder

S. Demarest, Elia M. Pestana-Knight, Heather E. Olson, J. Downs, Eric D. Marsh, Walter E. Kaufmann, Carol Anne Partridge, H. Leonard, Femida Gwadry-Sridhar, Katheryn Elibri Frame, J. Helen Cross, Richard F.M. Chin, S. Parikh, Axel Panzer, Judith Weisenberg, K. Utley, Amanda Jaksha, Sam Amin, Omar Khwaja, O. Devinsky & 3 others Jeffery L. Neul, Alan K. Percy, T. A. Benke

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)38-42
Number of pages5
JournalPediatric Neurology
Volume97
DOIs
Publication statusPublished - 1 Aug 2019

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Epilepsy
Natural History
Consensus
Cyclin-Dependent Kinase 5
Clinical Trials
Rett Syndrome
Inborn Genetic Diseases
Group Processes
National Institutes of Health (U.S.)
Research
Cognition
Industry
Parents
Research Personnel
Mutation
Therapeutics

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Demarest, S., Pestana-Knight, E. M., Olson, H. E., Downs, J., Marsh, E. D., Kaufmann, W. E., ... Benke, T. A. (2019). Severity Assessment in CDKL5 Deficiency Disorder. Pediatric Neurology, 97, 38-42. https://doi.org/10.1016/j.pediatrneurol.2019.03.017
Demarest, S. ; Pestana-Knight, Elia M. ; Olson, Heather E. ; Downs, J. ; Marsh, Eric D. ; Kaufmann, Walter E. ; Partridge, Carol Anne ; Leonard, H. ; Gwadry-Sridhar, Femida ; Frame, Katheryn Elibri ; Cross, J. Helen ; Chin, Richard F.M. ; Parikh, S. ; Panzer, Axel ; Weisenberg, Judith ; Utley, K. ; Jaksha, Amanda ; Amin, Sam ; Khwaja, Omar ; Devinsky, O. ; Neul, Jeffery L. ; Percy, Alan K. ; Benke, T. A. / Severity Assessment in CDKL5 Deficiency Disorder. In: Pediatric Neurology. 2019 ; Vol. 97. pp. 38-42.
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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.",
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Demarest, S, Pestana-Knight, EM, Olson, HE, Downs, J, Marsh, ED, Kaufmann, WE, Partridge, CA, Leonard, H, Gwadry-Sridhar, F, Frame, KE, Cross, JH, Chin, RFM, Parikh, S, Panzer, A, Weisenberg, J, Utley, K, Jaksha, A, Amin, S, Khwaja, O, Devinsky, O, Neul, JL, Percy, AK & Benke, TA 2019, 'Severity Assessment in CDKL5 Deficiency Disorder' Pediatric Neurology, vol. 97, pp. 38-42. https://doi.org/10.1016/j.pediatrneurol.2019.03.017

Severity Assessment in CDKL5 Deficiency Disorder. / Demarest, S.; Pestana-Knight, Elia M.; Olson, Heather E.; Downs, J.; Marsh, Eric D.; Kaufmann, Walter E.; Partridge, Carol Anne; Leonard, H.; Gwadry-Sridhar, Femida; Frame, Katheryn Elibri; Cross, J. Helen; Chin, Richard F.M.; Parikh, S.; Panzer, Axel; Weisenberg, Judith; Utley, K.; Jaksha, Amanda; Amin, Sam; Khwaja, Omar; Devinsky, O.; Neul, Jeffery L.; Percy, Alan K.; Benke, T. A.

In: Pediatric Neurology, Vol. 97, 01.08.2019, p. 38-42.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Severity Assessment in CDKL5 Deficiency Disorder

AU - Demarest, S.

AU - Pestana-Knight, Elia M.

AU - Olson, Heather E.

AU - Downs, J.

AU - Marsh, Eric D.

AU - Kaufmann, Walter E.

AU - Partridge, Carol Anne

AU - Leonard, H.

AU - Gwadry-Sridhar, Femida

AU - Frame, Katheryn Elibri

AU - Cross, J. Helen

AU - Chin, Richard F.M.

AU - Parikh, S.

AU - Panzer, Axel

AU - Weisenberg, Judith

AU - Utley, K.

AU - Jaksha, Amanda

AU - Amin, Sam

AU - Khwaja, Omar

AU - Devinsky, O.

AU - Neul, Jeffery L.

AU - Percy, Alan K.

AU - Benke, T. A.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

KW - CDKL5

KW - Cortical visual impairment

KW - Epilepsy

KW - Intellectual disability

KW - Rare disorder

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DO - 10.1016/j.pediatrneurol.2019.03.017

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Demarest S, Pestana-Knight EM, Olson HE, Downs J, Marsh ED, Kaufmann WE et al. Severity Assessment in CDKL5 Deficiency Disorder. Pediatric Neurology. 2019 Aug 1;97:38-42. https://doi.org/10.1016/j.pediatrneurol.2019.03.017