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Pediatr Neurol. 2019 Feb 23. pii: S0887-8994(19)30012-8. doi: 10.1016/j.pediatrneurol.2019.02.015. [Epub ahead of print]

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.

Author information

1
Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts. Electronic address: Heather.Olson@childrens.harvard.edu.
2
Children's Hospital Colorado, University of Colorado, School of Medicine, Aurora, Colorado; Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado.
3
Cleveland Clinic Neurological Institute Epilepsy Center, Cleveland Clinic Neurological Institute Pediatric Neurology Department, Neurogenetics, Cleveland Clinic Children's, Cleveland, Ohio.
4
Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
5
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
6
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
7
Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.
8
UCL Great Ormond Street NIHR BRC Institute of Child Health, London, UK.
9
Department of Neurology, NYU Langone Health, New York, New York.
10
Children's Hospital Colorado, University of Colorado, School of Medicine, Aurora, Colorado; Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado; Department of Pharmacology, University of Colorado, School of Medicine, Aurora, Colorado; Department of Neurology, University of Colorado, School of Medicine, Aurora, Colorado; Department of Otolaryngology, University of Colorado, School of Medicine, Aurora, Colorado.

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.

KEYWORDS:

CDKL5 deficiency disorder; Clinical trials; Developmental encephalopathy; Epilepsy genetics; Epileptic encephalopathy

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