CDKL5 – Developmental and Epileptic Encephalopathy

Cyclin-dependent kinase-like 5 (CDKL5) encodes a serine/threonine kinase expressed predominantly in neurons. Pathogenic CDKL5 variants cause early-onset developmental and epileptic encephalopathy (DEE), characterized by intractable seizures, severe hypotonia, and global developmental delay. This X-linked dominant disorder presents in both sexes, often arising from de novo mutations, and shows frequent skewing of X-inactivation in carrier females.

Genetic studies have identified at least 12 unrelated probands with de novo CDKL5 variants presenting DEE (c.659T>C (p.Leu220Pro), c.119C>T (p.Ala40Val), c.463+5G>A, c.2578C>T (p.Gln860Ter), and others) (PMID:25951140; PMID:30928302). Inheritance is X-linked dominant, with few familial cases reported due to maternal mosaicism or skewed X-inactivation (PMID:25819767). No large pedigrees exist; segregation analyses are limited by de novo occurrence and rarity of multiplex families.

The CDKL5 variant spectrum includes missense substitutions clustered in the catalytic kinase domain and loss-of-function alleles such as nonsense, frameshift, and splice-site mutations. Recurrent variants include c.119C>T (p.Ala40Val) and c.659T>C (p.Leu220Pro), observed in unrelated patients and mosaic individuals, underscoring strong mutational intolerance of the kinase core (PMID:17993579; PMID:25819767).

Functional assays demonstrate that disease-associated CDKL5 mutants fail to localize to the nucleus and exhibit impaired kinase activity toward substrates such as the TEY motif and Amphiphysin 1 (Ser-293). Mislocalized p.Leu220Pro and p.Arg65Gln proteins show defective autophosphorylation and disrupted dendritic arborization in neuronal models (PMID:16935860; PMID:23651931). U1snRNA-based rescue of splice-site mutations restores normal CDKL5 expression, subcellular distribution, and enzymatic function in vitro (PMID:31450582).

Mechanistically, CDKL5 haploinsufficiency disrupts phosphorylation of microtubule-associated proteins (MAP1S) and centrosomal regulators (CEP131, DLG5), impairing neuronal migration, synapse stability, and dendritic morphogenesis. Concordant findings across phosphoproteomic screens and animal models reinforce a loss-of-function paradigm in DEE pathogenesis (PMID:30266825).

No conflicting reports have disproven the CDKL5–DEE link; rather, large cohort and single-cell functional data uniformly support pathogenicity of de novo CDKL5 variants. Emerging genotype-phenotype correlations suggest that variants outside the catalytic domain may exhibit variable expressivity, although the kinase core remains the primary pathogenic hotspot.

Integration of genetic and experimental data establishes a strong gene-disease association for CDKL5 in DEE, guiding early genetic testing in cryptogenic infantile epileptic encephalopathy. Key Take-home: CDKL5 variant screening is essential for accurate diagnosis, prognostication, and precision therapeutic planning in early-onset DEE.

References

• Epilepsy Research • 2015 • Epileptic Encephalopathy is a heterogeneous condition in which cognitive, sensory and/or motor functions deteriorate… PMID:25951140
• Journal of Medical Genetics • 2008 • Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. PMID:17993579
• International Journal of Molecular Sciences • 2019 • Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy. PMID:31450582
• The EMBO Journal • 2018 • Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase. PMID:30266825
• Pediatric Neurology • 2019 • Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review. PMID:30928302

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