CDKL5 Deficiency Disorder


CDKL5 deficiency 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. CDKL5 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 CDKL5 gene tells the body how to make a protein that’s needed for normal brain development.

Most people affected by a CDD 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 developmental and epileptic encephalopathy (DEE).

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

  • Seizures starting in the first 3 to 6 months of life (some seizures may begin as early as the first week of life).
  • Problems with development of the nervous system, including cognitive development.
  • Stereotyped repetitive hand movements.

The full extent of CDKL5 Deficiency Disorder (CDD) 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.

Although rare, CDD may occur in 1 in 60,000 live births. CDKL5 variants have been identified in many ethnic groups, with 4 times as many females than males being affected.

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

The most common seizure types are epileptic spasms (which can present with a pattern called hypsarrhythmia on the EEG), tonic, myoclonic, and generalized tonic-clonic seizures. About a third of individuals can have seizures with multiple phases. Clonic, atonic, and absence seizures occur in individuals with CDD, but are less common.

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.

Children with CDKL5 deficiency disorder (CDD) can have many problems. Non-seizure symptoms reported in individuals with CDD include:

  • Respiratory (breathing), cardiac (heart), gastrointestinal (stomach), visual (seeing), and sleep difficulties.
  • Speech is limited or absent.
  • Limited ability to walk, scoliosis (curvature of the spine), apraxia (difficulty making purposeful movements), and low muscle tone (hypotonia).
  • Poor fine motor skills and hand wringing movements or mouthing of the hands.
  • Feeding challenges and grinding of the teeth.
  • Loss of developmental milestones (regression) in some individuals.

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

Most of the CDKL5 gene variants that have been reported are “de novo.” This means that they occur spontaneously are not passed down through families. However, rare families in which multiple siblings are affected with the same variant do exist, and in these cases the CDKL5 gene variant likely occurred in a small number of cells in one parent’s body or in their reproductive cells.

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

  • 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 (a pattern on the EEG that displays flat EEG waves separated by brief periods of activity) has also been reported early on.
  • Infantile spasms and an atypical hypsarrhythmia (type of 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.

Seizures in CDKL5 deficiency disorder (CDD) are difficult to treat and often require multiple anti-seizure medications as well as other approaches.

  • Ganaxolone is now the first anti-seizure medication that has received FDA approval for CDD.
  • 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.

What Is the Outlook for CDD?

An early diagnosis is helpful so that an individual with CDD can establish care with a multidisciplinary team dedicated to supporting therapies and addressing any health concerns related to the diagnosis.

The history of CDKL5 deficiency disorder (CDD) is incomplete and research is ongoing to improve understanding of the long-term outlook for patients diagnosed with CDD. The International CDKL5 Disorder Database was established in September 2012 and gathers data from families throughout the world who have children with CDD.

The CDKL5 Centers of Excellence, established by the International Foundation for CDKL5 Research (IFCR), delivers multidisciplinary clinical care and collects clinical or research data on patients with CDD in the U.S.

Authored By:

Dr. Heidi Grabenstatter, PhD
Dr. Helen Leonard, MPH, MBChB
Elaine Kiriakopoulos MD, MSc

on Friday, June 24, 2022

Reviewed By:

Beth Sheidley MS, CGC
Heather Olson, MD, MS
Isabel Haviland, MD
Lindsay Swanson, MS, CGC

on Friday, June 24, 2022


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