CDKL5 Deficiency Disorder

CDKL5 deficiency disorder is a rare genetic condition that causes severe seizures starting in early infancy, along with significant delays in development. While there is currently no cure, recent advances have brought the first approved treatment for seizures, and specialized care teams help children manage symptoms and improve their quality of life.

Table of contents

• What is CDKL5 deficiency disorder?
• How common is this condition?
• What causes CDKL5 deficiency disorder?
• Signs and symptoms
• Diagnosis and testing
• Treatment and management
• Inheritance pattern
• Living with CDKL5 deficiency disorder

What is CDKL5 deficiency disorder?

CDKL5 deficiency disorder is a rare neurodevelopmental condition (a condition affecting the development and function of the brain and nervous system) that begins in infancy. The condition is characterized by seizures that start very early in life, followed by significant delays in many areas of development^[1].

The disorder gets its name from the CDKL5 gene, which stands for cyclin-dependent kinase-like 5. This gene provides instructions for making proteins that are essential for normal brain and neuron (nerve cell) development. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding oxygen and phosphate atoms at specific positions^[4].

CDKL5 deficiency disorder was previously classified as an early-onset seizure variant of Rett syndrome because these conditions share common features, including seizures, intellectual disability, and other developmental problems. However, the signs and symptoms associated with CDKL5 deficiency disorder and its genetic cause are now understood to be distinct from those of Rett syndrome, and CDKL5 deficiency disorder is now considered a separate condition^[1].

Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency Disorder (CDD), CDKL5-Related Developmental and Epileptic Encephalopathy

How common is this condition?

CDKL5 deficiency disorder appears to be a rare condition with an estimated occurrence of about 1 in 40,000 to 60,000 live births. Despite being rare, it is one of the most common forms of genetic epilepsy^[1][4].

About 90 percent of those diagnosed with CDKL5 deficiency disorder are girls. The condition mainly affects girls because the CDKL5 gene is located on the X chromosome. Since females have two X chromosomes and males have one X and one Y chromosome, the condition is more likely to be found in girls. However, boys can also have this condition^[1][4].

Although females are more commonly affected than males (the female-to-male ratio is approximately 4:1), the severity of the condition in girls and boys can be equivalent. The severity of the symptoms can vary depending on the type and position of the genetic change, the pattern of X-chromosome inactivation in females, and the presence of postzygotic mosaicism (when some cells have the genetic change while others don’t) in males or females, who can have mild symptoms^[3].

What causes CDKL5 deficiency disorder?

As its name suggests, CDKL5 deficiency disorder is caused by changes (also known as variants or mutations) in the CDKL5 gene. This gene provides instructions for making a protein that is essential for normal brain development and function^[1].

Changes in the CDKL5 gene reduce the amount of functional CDKL5 protein or alter its activity in nerve cells. A shortage (deficiency) of CDKL5 or impairment of its function disrupts brain development, but it is unclear how these changes cause the specific features of CDKL5 deficiency disorder^[1].

Disease-causing changes in the CDKL5 gene include missense variants (spelling errors in the DNA code causing one amino acid to be substituted for another) and truncations or deletions (a shortened version or missing piece of the gene that can lead to the protein not being made)^[2].

The genetic change is usually “de novo,” which means that it is a new mutation in the child’s genes and is not passed down from the parents. Most changes within the CDKL5 gene occur spontaneously. However, there have been rare cases reported in which multiple siblings were affected with the same genetic change within a family^[6][7].

There are currently more than 250 known different mutations that can cause CDKL5 deficiency disorder. Researchers are still working to understand if different mutations lead to different levels of severity^[7].

Signs and symptoms

While every child with CDKL5 deficiency disorder is different in terms of physical symptoms and developmental milestones, the condition includes a number of common identifiable features^[2].

Seizures

Seizures are the hallmark symptom of CDKL5 deficiency disorder. In most cases, seizures usually begin within the first 3 months of life and can appear as early as the first week after birth. About 90 percent of children with this disorder will develop seizures before 3 months of age^[1][2].

The types of seizures change with age and may follow a predictable pattern. The most common types include^[1]:

• Generalized tonic-clonic seizures, which involve a loss of consciousness, muscle rigidity, and convulsions
• Tonic seizures, which are characterized by abnormal muscle contractions or stiffening of the entire body
• Epileptic spasms, which involve short episodes of muscle jerks, often appearing as a bending of the body and straightening of the limbs
• Myoclonic seizures, which cause quick, jerking movements

Seizures with multiple distinct phases are common, such as the hypermotor-tonic-spasms sequence. Seizures occur daily in most people with CDKL5 deficiency disorder, although they can have periods when they are seizure-free. Seizures in this disorder usually do not get better with treatment and tend to be difficult to control with medications^[1][2].

Developmental and motor delays

Development is significantly impaired in children with CDKL5 deficiency disorder. Most have severe intellectual disability and little or no speech. The development of gross motor skills (such as sitting, standing, and walking) is delayed or not achieved. About one-third of affected individuals are able to walk independently^[1].

Fine motor skills (such as picking up small objects with the fingers or grasping) are also impaired. About half of affected individuals have purposeful use of their hands. Children may not meet developmental milestones such as crawling, walking, or talking at the usual age^[1][7].

Vision problems

Most people with this condition have vision problems, specifically cortical visual impairment (difficulty interpreting vision in the brain, even though the eyes are structurally normal). Children may have poor eye contact and visual fixation^[1][2].

Muscle tone abnormalities

Children with CDKL5 deficiency disorder typically have hypotonia (low muscle tone), which contributes to delayed motor development. Over time, some children may develop high muscle tone in the legs^[2].

Movement disorders

Movement disorders are common and include chorea (involuntary jerky movements), dystonia (involuntary muscle contractions), and repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking^[1][3].

Additional symptoms

Other common features of CDKL5 deficiency disorder include^[1][2]:

• Impaired language, communication, and social skills
• Autistic features (though many children don’t meet formal criteria for autism spectrum disorder)
• Teeth grinding (bruxism)
• Disrupted sleep and difficulty sleeping
• Feeding difficulties and swallowing problems (many children need a feeding tube)
• Gastrointestinal problems including constipation and gastroesophageal reflux (backflow of acidic stomach contents into the esophagus)
• Growth restriction and impaired growth
• Episodes of irregular breathing
• Scoliosis (side-to-side curvature of the spine), hip dysplasia, or other orthopedic complications from low muscle tone

Less common features

Some people with CDKL5 deficiency disorder may have distinctive facial features including a high and broad forehead, large and deep-set eyes, a well-defined space between the nose and upper lip (philtrum), full lips, widely spaced teeth, and a high roof of the mouth (palate). Other physical differences can include an unusually small head size (microcephaly) and tapered fingers^[1][2].

Features overlapping with Rett syndrome and other neurodevelopmental disorders may include cold hands and feet, unexplained laughing or screaming spells, and irregular breathing (periods of fast or slow breathing)^[2].

Diagnosis and testing

Diagnosis is initially suspected based on symptoms, medical history, and a physical examination. Most children will already be under the care of a neurologist, geneticist, or another specialist when testing is ordered^[4].

The diagnosis of CDKL5 deficiency disorder is established in a female with suggestive clinical findings and a heterozygous (having one changed copy) CDKL5 genetic change identified by molecular genetic testing. In males, the diagnosis is established with suggestive clinical findings and a hemizygous (having only one X chromosome with the changed gene) CDKL5 genetic change^[3].

The genetic test is a simple blood test. Your child’s doctor must order the genetic test to confirm the diagnosis^[4].

During the first visit, your child’s provider will ask about symptoms, how long they’ve had them, and take a detailed medical history. A physical exam will check overall health, followed by a neurological exam to see how the brain is working^[14].

Additional tests may be used to take pictures of the brain, such as an MRI (magnetic resonance imaging) or electroencephalogram (EEG), which records the electrical activity of the brain^[14].

Treatment and management

There is currently no cure for CDKL5 deficiency disorder. Treatment is focused on managing symptoms and improving quality of life. The management of individuals with this condition is complex and requires multiple specialty evaluations^[3].

Approved treatment for seizures

In 2022, the U.S. Food and Drug Administration approved Ztalmy® (ganaxolone) as the first and only treatment specifically for seizures associated with CDKL5 deficiency disorder in patients two years of age and older. This liquid anti-seizure medication is taken daily and has been shown to significantly reduce major motor seizure frequency in patients with CDKL5 deficiency disorder^[4][14].

Additional seizure management

Since seizures in CDKL5 deficiency disorder are highly refractory (difficult to control), a reasonable goal is to manage rather than stop seizures. Other anti-seizure medications are commonly prescribed, with the four most frequently used being broad-spectrum medications. In studies, about 14-48% of individuals achieved a 2-week response to treatment, and 5-36% achieved a sustained 3-month response^[9].

Cannabis derivatives have been tried in over one-third of individuals for attempted seizure control^[9].

In combination with medications, about 50% of individuals are treated with ketogenic diet (a special high-fat, low-carbohydrate diet) for attempted seizure control^[9].

Surgical approaches have been used in limited cases and include vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers are too limited to assess response^[9].

Families should have a Seizure Action Plan so that everyone who cares for the child knows what to do when they have a seizure^[15].

Multidisciplinary care team

Because CDKL5 deficiency disorder can affect different areas of the body, children typically have a care team of experts from many specialties. The team may include^[14][15]:

• Pediatric neurologists
• Genetic counselors
• Gastroenterologists (for feeding issues, constipation, and reflux)
• Pulmonologists (for breathing and lung problems)
• Cardiologists
• Pediatric ophthalmologists (eye specialists)
• Pediatric physical therapists
• Pediatric occupational therapists
• Pediatric speech-language pathologists
• Dietitians and nutritionists
• Social workers

Management of other symptoms

Nearly one-third of individuals receive medication for sleep disturbances, 13% for behavioral dysregulation and movement disorders. About 43% have gastrostomy tubes (feeding tubes) to help with nutrition and feeding difficulties^[9].

Gastrointestinal issues such as constipation, acid reflux, diarrhea, and intestinal gas are common and may require management by a gastroenterologist. With the risk of aspiration of liquids, food, or saliva, lung infections including viruses can quickly become serious and require immediate medical attention^[15].

CDKL5 Centers of Excellence

Several specialized centers have been designated as CDKL5 Centers of Excellence by the International Foundation for CDKL5 Research. These centers provide coordinated, multidisciplinary care and participate in clinical research to advance understanding of the condition. Referral to one of these centers may allow families to coordinate care more easily^[3][14].

Emerging therapies

Additional disease-specific and disease-modifying treatments are in development. Clinical trials for CDKL5 deficiency disorder are emerging, including genetic therapies. Families should ask their provider if their child qualifies for any available clinical trials^[4][9][14].

Inheritance pattern

This condition is inherited in an X-linked dominant pattern. The CDKL5 gene is located on the X chromosome, which is one of the two sex chromosomes^[1].

In females (who have two X chromosomes), a genetic change in one of the two copies of the CDKL5 gene in each cell causes the disorder. In males (who have only one X chromosome), a change in the only copy of the gene causes the disorder^[1].

A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons, only to their daughters^[1].

Living with CDKL5 deficiency disorder

Children with CDKL5 deficiency disorder will have the condition for their entire lives. The severity of the disorder varies, but most children require significant support and care. While there is no cure yet, the condition is not imminently life threatening when properly managed^[7][15].

It’s important to understand that no one knows exactly what caused the CDKL5 gene to mutate. Parents did not do anything during pregnancy to cause this condition, and they couldn’t have done anything to prevent it^[15].

The range of symptoms is wide, and the number of symptoms a child will experience and the degree to which they experience them will be unique to each child. Some well-meaning doctors may give predictions about what a child will never be able to do. However, some children have learned to walk and to communicate, and early therapeutic intervention can be helpful. It’s important not to set limits before trying^[15].

Parents are their child’s best advocates. It is important to find medical and therapy providers who will collaborate, answer questions, and explain things in a way that’s easy to understand. Keeping organized records of medical conditions, providers, appointments, therapies, and daily schedules can help manage the complexity of care^[15].

The International Foundation for CDKL5 Research (IFCR) provides resources, support, and information for families. They work to fund research projects and maintain Centers of Excellence that provide clinical research essential for the success of clinical trials. Support groups and connections with other CDKL5 families can provide valuable emotional support and practical advice^[4].