NeurometPlus

Incidence

CDKL5 stands for cyclin-dependent kinase-like 5 and mutations in this gene were first identified as disease-causing in 2004. The CDKL5 gene is located on the X chromosome. Although many identified patients are males, because of the location of the gene, this disorder mainly affects females at 4:1 ratio. However. affected males may have more severe symptoms than females. Although rare, the occurrence could be between ~1:40,000 and 1:60,000 live births, although an Australian population-based study suggested a lower incidence. Most of the CDKL5 gene mutations are “de novo”, meaning that they occur spontaneously.

Clinical Characteristics

CDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy (DEE) caused by changes (mutations) in the CDKL5 gene. The CDKL5 gene provides instructions for making a protein that is essential for normal brain development. CDD has been classified as a DEE because the genetic change causes both the epileptic activity as well as the severe impairment of development. The hallmarks of CDD are the onset of seizures at a very early age, (usually about 3 months but can be as early as the first week of life) and severe neurodevelopmental delay impacting cognitive, motor, speech, and visual function. CDD can manifest in a broad range of clinical severity and is often associated with other symptoms such as gastrointestinal and sleep disturbances. Seizures are a major problem for patients with CDD because they are usually severe and difficult to control with medication. Multiple different types of seizures occur and include infantile spasms, myoclonic seizures and tonic-clonic seizures. Core symptoms include: Epileptic seizures starting early in life, epileptic spasms often occurring without hypsarrhythmia, multiple different types of seizures, limited ability to walk, limited hand skills, purposeless hand movements (stereotypies), poor muscle tone (hypotonia). They also have inability to speak but may use complex gestures/vocalization, lack of eye contact (cortical visual impairment), teeth-grinding (bruxism), constipation, sleep difficulties and intellectual disability. Other symptoms include breathing irregularities (such as hyperventilation, as seen in Rett\'s syndrome), respiratory infections, vomiting, gastroesophageal reflux, scoliosis. They show some characteristics such as a sideways glance and habit of crossing legs and behavioral symptoms such as anxiety and social avoidance.

Precipitants

Unknown.

Provocation Tests

Unknown.

Diagnostic Procedures

Diagnosis is initially suspected based on clinical presentation and confirmed by molecular genetic testing for CDKL5 mutations or multigene panel testing for early onset epilepsy. However some CDKL5 mutations/variants are not disease-causing but benign, so to confirm a diagnosis the mutation has to be considered disease-causing.