CDKL5 – Rett syndrome

Cyclin-dependent kinase-like 5 (CDKL5) on Xp22 encodes a serine/threonine kinase whose heterozygous de novo variants cause an early-onset seizure variant of Rett syndrome. In the initial report, a family of three affected siblings with infantile spasms and Rett-like features harbored a c.183delT (p.Met63CysfsTer13) variant that segregated with disease and was absent in unaffected relatives (PMID:15492925). Subsequent screening of >160 female patients negative for MECP2 mutations identified >80 distinct CDKL5 variants—including frameshifts, splice-site and missense changes—associated with early seizures, developmental stagnation, hand stereotypies, and severe intellectual disability (PMID:15689447).

Inheritance is X-linked dominant with most variants arising de novo. Familial segregation has been observed in twin pairs and multiplex pedigrees, confirming pathogenicity of truncating alleles and splice-site changes. For example, recurrent frameshifts such as c.2635_2636del (p.Leu879fs) and missense mutations within the kinase domain occur in independent cohorts, with consistent absence in unaffected carriers (PMID:15917271).

Functional studies reveal that CDKL5 interacts with MeCP2 and phosphorylates both itself and MeCP2, indicating a shared neurodevelopmental pathway. Rett-associated CDKL5 mutants show impaired in vitro kinase activity and mislocalization, while CDKL5 knock-down in neuronal cultures impairs dendritic arborization and migration—phenotypes rescued by wild-type CDKL5 expression (PMID:15917271; PMID:20861382).

No credible conflicting evidence has been reported, and genotype–phenotype correlations (e.g., p.Ala40Val associated with milder features) refine clinical expectations. Diagnostic criteria for the early-onset seizure variant of Rett emphasize epilepsy onset between 10 days and 5 months, severe hypotonia, and hand stereotypies (PMID:19362436).

Integration of genetic and experimental data supports a Definitive gene–disease association. CDKL5 testing is recommended for patients with Rett-like features and early infantile seizures when MECP2 mutations are absent. Early molecular diagnosis can inform prognosis and guide inclusion in clinical trials.

Key Take-home: CDKL5 mutations define an X-linked dominant, early-onset seizure variant of Rett syndrome and should be included in diagnostic gene panels for infantile epileptic encephalopathies.

References

• American Journal of Human Genetics • 2004 • Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation PMID:15492925
• Journal of Medical Genetics • 2005 • CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome PMID:15917271
• The Journal of Neuroscience • 2010 • CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling PMID:20861382
• Journal of Medical Genetics • 2005 • CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms PMID:15689447
• Brain & Development • 2010 • Early-onset seizure variant of Rett syndrome: definition of the clinical diagnostic criteria PMID:19362436
• American Journal of Medical Genetics Part A • 2012 • Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships PMID:22678952

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