CDKL5 Deficiency Disorder

A rare, severe developmental and epileptic encephalopathy that begins in early infancy and is characterized by multiple types of drug-resistant seizures, plus neurodevelopmental delays that impact cognitive, motor, speech, and visual function.

What is CDD? 

Cyclin-dependent kinase like-5 (CDKL5) deficiency disorder is a genetic condition that is caused by changes (pathogenic variants) in the CDKL5 gene, which is located on the X chromosome.^1,2 The CDKL5 gene instructs the body how to make the CDKL5 protein which is required for normal brain development and function.²   It is characterized by seizures that begin in infancy, followed by significant delays in many aspects of development.^1,2

The full extent of CDD is not known; however, CDKL5 gene mutations have been found in children diagnosed with Infantile Spasms, West Syndrome, Lennox-Gastaut syndrome, Rett Syndrome, cerebral palsy, autism, and intractable epilepsy of unknown origin.^2,4
 

Who does CDD affect? 

• Prevalence: Rare condition affecting approximately between 1 in 40,000 to 60,000 live births.^1-3 

• Ethnicity: Impacts people of many different ethnicities.²

• Gender: Affects four times as many females than males.^1,2 The course of the disease is usually more severe among males and is often fatal in the first or second decade of life.^1,3 

• Family: Although CDD is generally not inherited from either parent (de novo mutations), cases of family history of CDKL5 mutations have been reported.²
   

What are the symptoms?

CDD leads to a broad, complex range of clinical symptoms that can differ in severity between patients.⁴ Early manifestation and diagnosis have a huge impact on the quality of life of patients and their families, as timely identification allows for earlier intervention and support.⁵

Seizures
In more than 90% of patients, seizures begin in the first year of life and often as early as at six weeks of age and persist into adulthood.^5,6 Despite available medication, CDD remains drug resistant and most patients continue to experience 1 to 5 seizures per day.^5,6 The type of seizures experienced can vary throughout a CDD patient’s lifetime.^5,6

• At disease onset: Most common seizure types include tonic seizures, infantile (or epileptic) spasms, generalized tonic-clonic seizures, and focal seizures.^5,6
• Over time: Epileptic spasms, tonic, myoclonic, and generalized tonic-clonic become the most common seizure types.^5,6

Intellectual and Developmental problems
Developmental milestones are severely delayed in affected individuals including: ^1,5

• Little or no development of speech.²
• Musculoskeletal problems such as scoliosis.²
• Delays or failure to achieve gross motor skills and the use of larger muscles needed for whole-body movements such as sitting, standing, and walking.^1,2
• Challenges with fine motor skills, the coordination of smaller muscles for everyday tasks such as the ability to pick up small objects.²

Non-seizure symptoms
Other non-seizure symptoms can include problems with vision, breathing, sleeping, feeding, and teeth grinding.² Gastrointestinal symptoms are also common and may include constipation, reflux, and air swallowing.^2,3
 

Impact on caregivers

Frequent and severe epileptic episodes and non-seizure symptoms such as increased sleep disturbance and behavioral issues can significantly impact family and caregiver’s quality of life.⁷ These individuals often have to give up their careers to provide their children with a wide range of treatment and multidisciplinary care to manage the symptoms of CDD.⁷ As the diagnosis of CDD and the subsequent access to syndrome-specific family support are often considerably delayed, this can further amplify the emotional burden of the condition on those supporting patients.⁸

How is CDD managed?

Current management of the condition is primarily symptom-based and requires a multidisciplinary approach to care, including physiotherapy, occupational therapy, speech therapy, and nutritional guidance.⁹

• Seizures show high drug resistance and are often difficult to control.¹⁰ 47% of individuals (N=122) are on three or more antiseizure medications (ASMs), with six ASMs being the median number of medications taken throughout a patient’s life.^*10 Despite this, many patient’s seizures remain uncontrolled.¹⁰
• Other treatment options include dietary therapy, neurostimulation or callosotomy.⁶

* Data taken from a cohort of the international CDKL5 disorder database