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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy.
• It is characterized by early-onset epilepsy, hypotonia, intellectual and motor disabilities, and visual impairment.
• CDD arises from pathogenic variants in the CDKL5 gene.

Purpose of the Study:

• To review the clinical presentations and genetic variations associated with CDD.
• To propose minimum diagnostic criteria for CDD.
• To explore the molecular basis of CDD and its implications for precision therapy.

Main Methods:

• Systematic literature review of CDD cases.
• Analysis of clinical data from CDKL5 Centers of Excellence.
• Review of genetic variant types and their impact on CDKL5 protein function.

Main Results:

• Pathogenic variants in CDKL5 include deletions, truncations, splice variants, and missense variants.
• Missense variants are concentrated in the kinase domain or affect splice sites.
• CDKL5 protein plays crucial roles in neuronal development, including proliferation, migration, and synapse formation.

Conclusions:

• CDD presents with a distinct spectrum of early-onset neurological and developmental challenges.
• Standardized diagnostic criteria are needed to improve identification and management.
• Understanding CDKL5's molecular function opens avenues for targeted and disease-modifying therapeutic interventions, with ongoing clinical trials.