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

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.

Figure 1.

A) A schematic of the CDKL5 protein with variants from individuals with CDD evaluated in the CDKL5 Centers of Excellence. CDKL5 gene image adapted from prior publication. B) 3D protein structure of the CDKL5 gene (Protein Data Bank ID: 4bgq) along with position of population variation (blue spheres) from gnomAD database and variants from the COEs (red spheres). C) Highlight of variants in functional domains in the CDKL5 protein. The missense variants in CDKL5 identified in affected individuals are mapped on the 3D protein structure (protein data bank id: 4bgq) as red spheres (total 23 positions). The yellow-colored region is a nucleotide binding region (aa. 19 – 72) and we observed the disease-associated variant p.Tyr24Cys in this region. The cyan-colored site is a proton acceptor active site (aa. 135) and we observed the disease-associated variant p. Asp135Gly in this site. The green-colored region is a functionally essential DFG motif (aa. 153 – 155) and we observed the disease-associated variant p. Asp153Val in this region. The pink-colored region is the morphology (information content) or consensus sequence of phospho-Tyrosine Y171 (part of Thr-Glu-Tyr motif) (aa. 164 – 178) and we observed the disease-associated variants p.Trp176Arg, p.Tyr177His, p.Arg178Gln in this region.

Figure 1.

A) A schematic of the CDKL5 protein with variants from individuals with CDD evaluated in the CDKL5 Centers of Excellence. CDKL5 gene image adapted from prior publication. B) 3D protein structure of the CDKL5 gene (Protein Data Bank ID: 4bgq) along with position of population variation (blue spheres) from gnomAD database and variants from the COEs (red spheres). C) Highlight of variants in functional domains in the CDKL5 protein. The missense variants in CDKL5 identified in affected individuals are mapped on the 3D protein structure (protein data bank id: 4bgq) as red spheres (total 23 positions). The yellow-colored region is a nucleotide binding region (aa. 19 – 72) and we observed the disease-associated variant p.Tyr24Cys in this region. The cyan-colored site is a proton acceptor active site (aa. 135) and we observed the disease-associated variant p. Asp135Gly in this site. The green-colored region is a functionally essential DFG motif (aa. 153 – 155) and we observed the disease-associated variant p. Asp153Val in this region. The pink-colored region is the morphology (information content) or consensus sequence of phospho-Tyrosine Y171 (part of Thr-Glu-Tyr motif) (aa. 164 – 178) and we observed the disease-associated variants p.Trp176Arg, p.Tyr177His, p.Arg178Gln in this region.

Figure 1.

A) A schematic of the CDKL5 protein with variants from individuals with CDD evaluated in the CDKL5 Centers of Excellence. CDKL5 gene image adapted from prior publication. B) 3D protein structure of the CDKL5 gene (Protein Data Bank ID: 4bgq) along with position of population variation (blue spheres) from gnomAD database and variants from the COEs (red spheres). C) Highlight of variants in functional domains in the CDKL5 protein. The missense variants in CDKL5 identified in affected individuals are mapped on the 3D protein structure (protein data bank id: 4bgq) as red spheres (total 23 positions). The yellow-colored region is a nucleotide binding region (aa. 19 – 72) and we observed the disease-associated variant p.Tyr24Cys in this region. The cyan-colored site is a proton acceptor active site (aa. 135) and we observed the disease-associated variant p. Asp135Gly in this site. The green-colored region is a functionally essential DFG motif (aa. 153 – 155) and we observed the disease-associated variant p. Asp153Val in this region. The pink-colored region is the morphology (information content) or consensus sequence of phospho-Tyrosine Y171 (part of Thr-Glu-Tyr motif) (aa. 164 – 178) and we observed the disease-associated variants p.Trp176Arg, p.Tyr177His, p.Arg178Gln in this region.