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

Pediatr Neurol. 2019 Aug;97:18-25. doi: 10.1016/j.pediatrneurol.2019.02.015. Epub 2019 Feb 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alternative Splicing
  • Anticonvulsants / therapeutic use
  • Corpus Callosum / surgery
  • Developmental Disabilities / etiology
  • Diet, Ketogenic
  • Electroencephalography
  • Epileptic Syndromes* / genetics
  • Epileptic Syndromes* / pathology
  • Epileptic Syndromes* / therapy
  • Gastrointestinal Diseases / etiology
  • Humans
  • Models, Molecular
  • Movement Disorders / etiology
  • Mutation
  • Precision Medicine
  • Protein Conformation
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Spasms, Infantile* / genetics
  • Spasms, Infantile* / pathology
  • Spasms, Infantile* / therapy
  • Vagus Nerve Stimulation
  • Vision Disorders / etiology

Substances

  • Anticonvulsants
  • Protein-Serine-Threonine Kinases
  • CDKL5 protein, human

Supplementary concepts

  • CDKL5 deficiency disorder