CDKL5 Deficiency Disorder Without Epilepsy

Area of Science:

• Genetics
• Neurology
• Developmental Biology

Background:

• Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe neurodevelopmental disorder characterized by early-onset epilepsy.
• The classical CDD phenotype includes intractable seizures, severe intellectual disability, and motor impairments.

Observation:

• This study reports on eight patients (two new, six previously published) with CDD features but no history of epilepsy.
• These patients exhibited milder gross motor delays, autism spectrum disorder, and absence of visual cortical impairment.
• Electroencephalography revealed normal results in adults but interictal epileptiform discharges in a pediatric case.

Findings:

• The identified CDKL5 variants included both damaging (nonsense, frameshift) and missense types.
• Some variants were de novo, while others were maternally inherited from asymptomatic mothers with skewed X-chromosome inactivation.
• No clear genotype-phenotype correlation was found for this milder CDD presentation without epilepsy.

Implications:

• These findings expand the known clinical spectrum of CDKL5 deficiency disorder.
• The possibility of a milder CDD phenotype without epilepsy should be considered in the differential diagnosis of neurodevelopmental disorders.
• Further research is needed to understand the genetic and molecular mechanisms underlying this epilepsy-absent CDD variant.