CDKL5 Deficiency Disorder (CDD) is a rare genetic condition affecting brain development. This neurodevelopmental disorder stems from specific changes within the CDKL5 gene. Individuals with CDD experience a range of neurological challenges that become apparent early in life.
The Role of the CDKL5 Gene
The CDKL5 gene directs the production of the CDKL5 protein. This protein functions as a kinase, an enzyme that modifies other proteins by adding phosphate groups at specific locations. The CDKL5 protein is particularly active in the brain and plays a role in neuronal maturation and synaptic regulation.
The CDKL5 protein influences the formation, growth, and movement of nerve cells, along with their division. It also contributes to the transmission of chemical signals at synapses, the connections between neurons. This protein is found in both the nucleus and cytoplasm of neurons, with its nuclear presence being important for gene regulation.
Symptoms and Characteristics of CDD
A common early sign of CDKL5 Deficiency Disorder is the onset of seizures, appearing within the first three to six months of life. These seizures can be challenging to control and manifest in various forms, including epileptic spasms, tonic seizures (characterized by muscle stiffening), myoclonic seizures (brief, jerking movements), and generalized tonic-clonic seizures. Many individuals experience multiple seizure types.
Alongside seizures, individuals with CDD experience significant neurodevelopmental delays that affect cognitive, motor, speech, and visual functions. Children may not reach developmental milestones such as crawling, walking, or talking at expected ages. Many affected individuals also exhibit low muscle tone (hypotonia), which impacts motor skill development.
Cortical visual impairment (CVI) is a common feature, affecting at least 75% of individuals with CDD. This condition involves difficulties in the brain’s ability to process visual information, leading to impairments in visual fields, acuity, contrast sensitivity, and depth perception. Sleep disturbances are also frequently reported, with challenges in falling asleep, staying asleep, frequent night awakenings, and reduced total sleep time.
Gastrointestinal issues, such as constipation and gastroesophageal reflux, are often present, and feeding difficulties can be severe enough to necessitate tube feeding for some children. Repetitive, purposeless movements, referred to as stereotypic hand movements, are another characteristic. These can include hand clapping, hand licking, hand sucking, and teeth grinding. The severity and combination of these symptoms can vary significantly among individuals with CDD.
Genetic Causes and Diagnosis
CDKL5 Deficiency Disorder arises from a genetic change in the CDKL5 gene, which is located on the X chromosome. In most instances, this genetic alteration is de novo, meaning it occurs spontaneously in the affected individual and is not inherited from either parent. However, in rare cases, the mutation can be inherited from a mother who carries the variant in some of her cells without showing overt symptoms.
The disorder is observed more frequently in females, with approximately 90% of diagnosed individuals being girls. This pattern is due to the gene’s location on the X chromosome; females have two X chromosomes, while males have only one.
The diagnosis of CDD is initially suspected based on a thorough clinical evaluation, including a review of symptoms, medical history, and a physical examination. Confirmation of the diagnosis requires genetic testing, typically performed using a blood or saliva sample. This testing involves gene sequencing or other methods to identify specific mutations or larger deletions or duplications in the CDKL5 gene. Results from genetic testing are usually available within four to six weeks.
Management and Therapeutic Approaches
Currently, there is no cure for CDKL5 Deficiency Disorder, so management focuses on addressing the wide range of symptoms to improve quality of life. A multidisciplinary team of specialists, which may include neurologists, geneticists, gastroenterologists, and rehabilitation therapists, collaborates to create a personalized care plan.
Seizure control is a primary concern, as the seizures are often severe and difficult to manage with conventional antiepileptic drugs. Various medications may be prescribed, often in combination, to help reduce seizure frequency and intensity. The FDA approved ganaxolone, known by the brand name ZTALMY, for treatment. This neuroactive steroid is the first medication specifically approved for seizures associated with CDD in patients aged two years and older, working by enhancing the activity of GABA, an inhibitory neurotransmitter in the brain.
Beyond medication, other strategies like the ketogenic diet and vagus nerve stimulation may be considered for seizure management. Developmental therapies are also integral to care. Physical therapy helps with motor skills, mobility, and balance, while occupational therapy focuses on fine motor skills and daily activities such as feeding and dressing. Speech therapy is provided to support communication development and address feeding or swallowing difficulties. Comprehensive support for other health issues, including gastrointestinal problems and sleep disturbances, is also integrated into the overall management plan.