What is CDKL5 Disorder?

CDKL5 disorder is a rare X-linked genetic disorder first identified in 2004. An x-linked disorder means that the gene carrying the problem is found on the x chromosome. CDLK5 stands for cyclin-dependent kinase-like 5 and is a gene located on the X chromosome. A woman contributes two X chromosomes to her child and the father contributes one X chromosome and one Y chromosome.

  • The CDLK5 gene tells the body how to make a protein that’s needed for normal brain development.
  • Most people affected by a CDKL5 disorder have seizures that begin within the first months of life. Problems with the baby’s development then occur, leading to severe developmental delay. Medically, the term used to describe this combination of problems is epileptic encephalopathy.

How does CDKL5 disorder present?

CDLK5 disorder is 5 times more common in females than males. However males with the disorder are affected more severely than females.

Recent studies have shown the main features of CDKL5 disorder include:

  • Seizures starting in the first 3 to 6 months of life.
  • Problems with development of the nervous system, including cognitive development.
  • Stereotyped repetitive hand movements.

How is CDKL5 disorder diagnosed?

Children suspected of having a CDKL5 disorder should be seen by a child neurologist. The diagnosis is initially suspected based on history, symptoms, and physical examination. CDKL5 disorder is then confirmed by genetic blood testing that can show the change or mutation on the CDKL5 gene. MRI testing may be done.

Different types of EEG (electroencephalography) testing may be done at different times for the child with CDKL5 disorder.

  • Most commonly, the EEG during a seizure may be normal or slightly abnormal early in the disorder. Sometimes background activity is slow and seizure discharges can be seen in one or more areas.
  • A burst suppression — literally a pattern on the EEG that displays flat EEG waves separated by brief periods of activity — pattern has also been reported early on.
  • Infantile spasms and an atypical hypsarrhythmia pattern on EEG may be seen over time in 75% of children.
  • More changes may occur in the EEG over time. For example seizures involving different brain areas and seizures that are harder to control with medications.

MRI (magnetic resonance imaging) testing usually shows nonspecific changes in the brain, such as cortical atrophy (smaller areas than normal) and hyperintensities (areas that look brighter than usual) in the temporal lobe. We are not sure exactly what these changes may mean.

What other medical issues are seen in people with CDKL5 disorder?

Children with CDKL5 disorder can have many problems and typically cannot walk, talk, or feed themselves.

  • Respiratory (breathing), cardiac (heart), gastrointestinal (stomach), visual (seeing), and sleep difficulties are often present.
  • Speech is limited or absent.
  • Scoliosis (curvature of the spine), apraxia (difficulty making purposeful movements), and low muscle tone are other symptoms seen.
  • Poor fine motor skills and hand wringing movements or mouthing of the hands are common.
  • Feeding challenges and grinding of the teeth are also present.

What is the spectrum of CDKL5 disorder?

The full spectrum or extent of CDKL5 disorder is not known at this time. CDKL5 genetic changes or mutations have been found in children diagnosed with many other neurologic disorders, including infantile spasms, Lennox Gastaut syndrome, Rett Syndrome, West Syndrome, and autism.

What seizures types are present in CDKL5 disorder?

Seizures are a major feature in children with CDKL5 disorder. Early onset seizures can happen within the first hours, days, weeks, or months. 

  • Seizure types include infantile spasms, myoclonic, tonic, and tonic-clonic seizures.
  • In the beginning, seizures occur during sleep but with time often appear during waking hours as well. It is common for these first seizures not to be seen on EEG; however this does not mean that CDKL5-related seizure activity is absent.
  • Status epilepticus and nonconvulsive status epilepticus (seizures that are too long or periods of repeated seizures) can occur.

How are seizures in treated?

Seizures in CDLK5 disorder are difficult to treat, but it is important to note that some people do well on anticonvulsant monotherapy (one drug at a time), while others need adjunctive therapy (more than one medication).

  • No single seizure medication has proven to be most effective in controlling seizures in these children. It is fairly typical for a child to require many medication trials.
  • Steroid treatment and the ketogentic diet have been used in the treatment course of some children.
  • Vagus nerve stimulation is also often considered with CDKL5-related seizures.
  • If all other therapies have failed and a seizure focus can be isolated, surgery may be an option in some situations.

Who should be on your health care team?

The degree of disability and individual health needs varies for people with CDKL5 disorder. Medical management of CDLK5 disorder is symptomatic and supportive. If a child is diagnosed with CDKL5 disorder, they will require the support of a multidisciplinary team including a pediatrician and a child neurologist or epileptologist, along with help from nursing, nutrition, social work, and occupational, speech and physical therapists.

Although no cure for CDKL5 disorder currently exists, there is ongoing research aiming to better understand how CDKL5 mutations affect brain function so that potential treatments can be developed.

Authored by: Elaine Kiriakopoulos MD, MSc | Drug Resistant and Rare Epilepsies Editor on 6/2015