CDKL5 – CDKL5 Deficiency Disorder

CDKL5 Deficiency Disorder (CDD) is a severe X-linked dominant developmental and epileptic encephalopathy characterized by early infantile-onset, drug-resistant seizures (HP:0001250), profound global developmental delay (HP:0001263), severe intellectual disability (HP:0001249), hypotonia (HP:0001252), and frequent cortical visual impairment (HP:0100704). The incidence is estimated at 1:40,000–60,000 live births, with a marked female predominance and often more severe course in affected males.

CDD is caused predominantly by de novo CDKL5 variants, with over 300 unrelated probands described carrying truncating, missense, splice-site, and structural alterations that consistently reproduce the CDD phenotype ([PMID:30928302]). Inheritance is X-linked dominant with rare reports of post-zygotic mosaicism; no multi-generation segregation has been documented, reflecting the high rate of de novo mutational events.

The CDKL5 variant spectrum includes frameshift and nonsense mutations concentrated in the N-terminal catalytic domain, pathogenic missense substitutions affecting critical residues, and rare multi-exonic duplications or pericentric inversions. A representative recurrent truncating variant is c.197_198delCT (p.Leu67GlnfsTer23), identified in a patient with continuous spike-and-wave during sleep ([PMID:31046567]).

Functional studies establish a loss-of-function mechanism: missense and truncating variants impair CDKL5 autophosphorylation, reduce kinase activity toward substrates such as MECP2 and amphiphysin-1, and disrupt subcellular localization ([PMID:20861382]). Splicing mutations at +5 nucleotides can be corrected by engineered U1snRNA to restore normal CDKL5 expression and activity in cell models ([PMID:30266825]).

Animal models corroborate human findings: Cdkl5 knockout and knock-in mice exhibit early seizures, hypotonia, cognitive and motor deficits, reduced dendritic arborization, and autonomic dysfunction. A humanized E364X knock-in mouse displays cerebellar GABAergic hypofunction and sex-dependent alterations in GABA receptor expression, validating haploinsufficiency and identifying novel therapeutic targets ([PMID:39583831]).

Phenotypic variability includes rare individuals with CDD who never develop seizures yet manifest intellectual and motor delays with preserved EEG, as in the p.Ser215Arg hypomorphic variant, questioning whether seizures are universally mandatory in CDD ([PMID:32034940]).

CDD represents a definitive gene-disease association under ClinGen criteria, with strong genetic and functional concordance. CDKL5 testing is essential for infants presenting with early-onset refractory epilepsy and neurodevelopmental impairment, and advancing mechanistic insights supports the development of targeted therapies and outcome measures.

Key Take-home: Loss-of-function CDKL5 variants cause a definitive X-linked dominant developmental and epileptic encephalopathy, with robust genetic and experimental evidence guiding diagnosis and therapeutic innovation.

References

• Pediatric Neurology • 2019 • Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review. PMID:30928302
• Neurocase • 2019 • A new cause of developmental and epileptic encephalopathy with continuous spike-and-wave during sleep: CDKL5 disorder. PMID:31046567
• American Journal of Medical Genetics Part A • 2020 • Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory? PMID:32034940
• The Journal of Neuroscience • 2010 • CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling. PMID:20861382
• The EMBO Journal • 2018 • Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase. PMID:30266825
• Heliyon • 2024 • A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling. PMID:39583831

Evidence Based Scoring (AI generated)