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

Severity Assessment in CDKL5 Deficiency Disorder.

Author information

1
Children's Hospital Colorado and University of Colorado School of Medicine Aurora, Colorado; Department of Pediatrics, Aurora, Colorado.
2
Cleveland Clinic, Neurological Institute Cleveland, Ohio; Epilepsy Center, Cleveland, Ohio.
3
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital Boston, Massachusetts.
4
Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia; School of Physiotherapy and Exercise Science, Curtin University, Perth, Western Australia, Australia.
5
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
6
M.I.N.D. Institute, Department of Neurology, University of California Davis Health System, Sacramento, California; Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
7
CDKL5 UK, Somerset, UK.
8
School of Physiotherapy and Exercise Science, Curtin University, Perth, Western Australia, Australia.
9
Department of Computer Science, University of Western Ontario and Pulse Infoframe, London, Ontario, Canada.
10
CDKL5 Research Collaborative, Dexter, Michigan.
11
UCL Great Ormond Street Institute of Child Health & NIHR GOSH BRC, London, UK.
12
University of Edinburgh and Royal Hospital for Sick Children, Edinburgh, UK.
13
Epilepsy Center, Cleveland, Ohio.
14
DRK Westend Clinic Berlin, Berlin, Germany.
15
Neurology, Division of Pediatric Neurology, Epilepsy Section, Washington University School of Medicine, St. Louis Children's Hospital, St Louis, Missouri.
16
International Foundation for CDKL5 Research, Wadwsorth, Ohio.
17
University of Bristol, UK.
18
Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development NORD, Basel, Switzerland.
19
Department of Neurology, New York University, New York, New York.
20
Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Tennessee.
21
University of Alabama at Birmingham, Pediatrics, Neurology, Neurobiology, Genetics, and Psychology, Birmingham, Alabama.
22
Children's Hospital Colorado and University of Colorado School of Medicine Aurora, Colorado; Department of Pediatrics, Aurora, Colorado; Department of Pharmacology, Aurora, Colorado; Department of Neurology, Aurora, Colorado; Department of Otolaryngology, Aurora, Colorado. Electronic address: tim.benke@ucdenver.edu.

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

PMID:
31147226
PMCID:
PMC6659999
[Available on 2020-08-01]
DOI:
10.1016/j.pediatrneurol.2019.03.017

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