We know how it feels to receive this diagnosis, and we are here to help.
We understand that this new diagnosis opens up a world of uncertainty, questions, and fears. You are not alone! You will find yourself among friends here, all with the common goal of helping our affected children and loved ones and finding a cure. We have created this list of Frequently Asked Questions that will be a good starting point for learning more about CDKL5.
CDKL5 deficiency disorder is a rare developmental epileptic encephalopathy caused by mutations in the CDKL5 gene, and this can manifest in a broad range of clinical symptoms and severity. The hallmarks are early-onset, intractable epilepsy and neurodevelopmental delay impacting cognitive, motor, speech, and visual function. Although rare, the occurrence is believed to be ~1:40,000 -60,000 live births, making it one of the most common forms of genetic epilepsy.
The CDKL5 gene provides instructions for making proteins that are essential for normal brain and neuron 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 (a phosphate group) at specific positions. Researchers have not yet determined which proteins are targeted by the CDKL5 protein.
CDKL5 was first identified in 2004, it stands for cyclin-dependent kinase-like 5, and its location is on the X chromosome. The X chromosome is one of the sex chromosomes; females have two X’s, and males have one X and one Y chromosome. The letters are an abbreviation of the scientific name of the gene, which describes what it does. The CDKL5 gene was previously called STK9. Many cases have been identified in boys, but because of the location of the gene, CDD mainly affects girls.
Absolutely! The IFCR is working hard to find treatments and a cure for CDKL5. We continue to fund a variety of scientific research projects and our Centers of Excellence provide vital clinical research that is essential for the success of CDD trials, including genetic therapies. Our multidisciplinary teams investigate the symptoms and problems of CDKL5, constructing the natural history of CDD. We are also an International CDKL5 Disorder Database (ICDD) and Loulou Foundation partner.
Yes. The first and only FDA-approved treatment for seizures associated with CDKL5 deficiency disorder (CDD) in patients two years of age and older1 ZTALMY significantly reduced major motor seizure frequency in CDD patients in the pivotal Marigold trial.
Marigold Study – CDKL5 Deficiency Disorder
*This study received FDA approval on March 18, 2022. Watch this short video to learn more about prescription fulfillment process.
Marinus Pharmaceuticals Announces FDA Approval of ZTALMY® (ganaxolone) for CDKL5 Deficiency Disorder in the US.
Genetics & Epidemiology
We do not fully know the cause of CDKL5 deficiency disorder at this time. Mutations have been found in children diagnosed with Infantile Spasms, West Syndrome, Lennox-Gastaut, Rett Syndrome, cerebral palsy, autism, and intractable epilepsy of unknown origin.
Through scientific research and collecting information through the International CDKL5 Disorder Database and at our Centers of Excellence, we are working hard to find all of the pieces of this puzzle. Working together these two research initiatives have formed the International CDKL5 Clinical Research Network (ICCRN). It is important to note that scientists and doctors do not know the full spectrum of CDKL5 disorders at this time. There are likely many people affected by CDKL5 who have mild symptoms and no seizures. With continued research and awareness of CDKL5, we hope to build a more comprehensive understanding of the spectrum of this disorder as we continue the search for a desperately needed cure.
Diagnosis is initially suspected based on symptoms, history, and a physical exam. Your child’s doctor must order the genetic test. Most children will already be under the care of a neurologist, geneticist, or another specialist. The test is a simple blood test that is sent to a laboratory where the genetic sequencing is performed. The result is usually reported in approximately 4-6 weeks from the time of the blood draw.
It appears that most of the mutations are “de novo,” meaning that they occur spontaneously and are not passed down through families. However, there are known families in which multiple siblings are affected with the exact mutation, but neither the mother nor father are confirmed carriers with the current genetic testing technology. However, these mothers are suspected to be germ-line carriers. It is not safe to assume that you are not a carrier based on DNA testing alone. It is best to consult a geneticist to discuss your risk for passing down this genetic mutation.
Although rare, the occurrence estimates are currently ~1:40,000 -60,000 live births, making it one of the most common forms of genetic epilepsy. Now, there are at least two children diagnosed with CDKL5 each week.
While it’s true that the majority of diagnosed children affected by CDKL5 are females, there has been an increase in males diagnosed in recent years. About 90 percent of people diagnosed with CDKL5 deficiency disorder are female. Affected males appear to be similarly affected as females.
Since CDKL5 was discovered only in 2004, we do not have enough data to fully answer this. We do know, however, that the oldest people described in the medical literature with CDKL5 are over 50 years old. There are many others that we know of who are in their mid-30s, 20s, and teens. Most of those newly diagnosed are young children and infants/toddlers but we are starting to see adults in their 40s and 50s diagnosed, too.
While there is no cure for CDD yet, it is also not imminently life threatening. Still, CDD is a complex medical condition with symptoms affecting numerous systems of the body and impacting several essential functions.
Not everyone will have all the signs/symptoms listed here, and some may have
other symptoms not mentioned.
- Epileptic seizures starting early in life
- Epileptic spasms often occurring without hypsarrhythmia
- Multiple different types of seizures
- Cortical Visual Impairment (Lack of eye contact)
- Limited ability to walk
- Inability to speak but may use complex gestures/vocalization
- Limited hand skills
- Sleep difficulties
- Purposeless hand movements (stereotypies)
- Teeth-grinding (bruxism)
- Poor muscle tone (hypotonia)
- Intellectual disability
- Breathing irregularities (such as hyperventilation)
- Respiratory infections
- Gastroesophageal reflux
- Characteristics such as a sideways glance and habit of crossing legs
- Behavioral symptoms such as anxiety and social avoidance
The majority of people diagnosed with CDKL5 do have seizures. However, some have never had a seizure. Most children affected by CDKL5 suffer from seizures that begin in the first hours, days, weeks, or months of life. Children diagnosed with CDKL5 disorder may have seizures starting within hours of birth, or as late as eight months to 2 years of age. Some mothers have described feeling seizures even in the prenatal period.
Individuals with CDKL5 have a wide variety of seizures. Sometimes they can have several different kinds of seizures all on the same day. Others may experience only one type of seizure at a time, and then as they grow, the seizures type may change. Many children have seizures in their sleep, and many experience acute sleep startles (sometimes identified as actual seizures on EEG).
It can be challenging to understand what the seizure terminology means. Doctors have described more than 30 different types of seizures, divided into two major categories — focal seizures and generalized seizures. However, there are many kinds of seizures in each of these categories. Not all seizures are easy to define as either focal or generalized. Some people have seizures that begin as focal seizures but then spread to the entire brain. Other people may have both types of seizures but with no apparent pattern.
Focal seizures, also called partial seizures, occur in just one part of the brain. These seizures are frequently described by the area of the brain in which they originate. For example, someone might be diagnosed with focal frontal lobe seizures or a temporal lobe seizure.
In a simple focal seizure, the person will remain conscious but experience unusual feelings or sensations that can take many forms. The person may experience sudden and unexplainable feelings of joy, anger, sadness, or nausea. He or she also may hear, smell, taste, see or feel things that are not real.
In a complex focal seizure, the person has a change in or loss of consciousness. His or her consciousness may be altered, producing a dreamlike experience. People having a complex focal seizure may display strange, repetitious behaviors such as blinks, twitches, mouth movements, or even walking in a circle. These repetitive movements are called automatisms. More complicated actions, which may seem purposeful, can also occur involuntarily.
Generalized seizures are a result of abnormal neuronal activity on both sides of the brain. These seizures may cause loss of consciousness, falls, or massive muscle spasms. There are many kinds of generalized seizures.
In absence seizures, the person may appear to be staring into space and/or have jerking or twitching muscles. These seizures are sometimes referred to as petit mal seizures, which is an older term.
Tonic seizures cause stiffening of muscles of the body, generally those in the back, legs, and arms. Clonic seizures cause repeated jerking movements of muscles on both sides of the body.
Myoclonic seizures cause jerks or twitches of the upper body, arms, or legs.
Atonic seizures (aka drop seizure, or drop attack) cause a loss of normal muscle tone. The affected person will fall down or may drop his or her head involuntarily.
Tonic-clonic seizures cause a mixture of symptoms, including stiffening of the body and repeated jerks of the arms and/or legs as well as the loss of consciousness. Tonic-clonic seizures are sometimes referred to by the older term of grand mal seizures.
A wide variety of anti‐seizure therapies have been tried by many of our children, with varying degrees of success.
- Anti‐epileptic drugs (AED’s)
- Ketogenic diet/modified Atkins diet.
- Vagal nerve stimulator (VNS)
- Neurosurgery, such as corpus callosotomy
- Various dietary changes/modifications
In general, the seizures associated with CDKL5 are difficult to treat, but there are several anti-seizures medications that are being tried in the population. The families of children with CDKL5 have reported periods of time that their kids have been seizure‐free, a so-called “honeymoon period” (lasting anywhere from a few weeks to a few years), after starting a new medication, but often the seizures return and may take on a different form.
Cortical/Cerebral Visual Impairment (CVI) is a brain-based visual impairment caused by damage to the visual pathways or visual processing areas of the brain—and it’s the leading cause of blindness in children.
One study shows that CVI-related vision problems impact 1 in 30 kids in mainstream classrooms. CVI is common in children with Cerebral Palsy, Down Syndrome, Autism, and neurodevelopmental conditions. An individualized multisensory approach to learning and intervention, rooted in comprehensive assessment, empowers life-changing access.
Every individual with CVI, no matter their zip code or how their CVI manifests, has a right to early diagnosis, effective vision services, and accessible educational programs.
People with CVI struggle with visual attention and visual recognition resulting in a lack of access for understanding the world around them. Some people see the world as distorted and unrecognizable. Others can focus but might struggle to understand what they see. A crowded setting, a hot day, or fatigue has the potential to make vision use nearly impossible.
Unfortunately, many parents of CDKL5 children have experienced this same thing. They have described nights where their child has “all-night parties” in their room. Typically, the child is awake all night, and some are content and able to entertain themselves throughout the night.
Others are agitated and restless during these phases.
Some children may outgrow this phenomenon as they get older. In the meantime, please discuss this with your child’s medical team as there are interventions that can be trialed. Some parents have tried natural sleep aids such as melatonin. It is important to talk with your child’s doctor before starting any kind of over-the-counter sleep aid, as there may be drug interactions with your child’s seizure medications.
Therapies can have a tremendous impact on our children’s progress and quality of life. Some kids slowly learn to walk as a result of intensive physical therapy. It can take four or more years to reach major motor milestones, so if you think your child might achieve any goal you are working toward, don’t give up. Be patient and allow your therapy focus to shift, and do not be afraid to take a break or revisit certain skills later.
Physical and Occupational Therapy – to improve muscle tone and motor skills
Speech Therapy – to work on communication either orally or with technology
Vision Therapy – to improve the brain’s ability to interpret vision
You are your child’s best advocate. It is important to find medical and therapy providers who will collaborate with you, answer your questions, and explain things in a way you can understand. Prepare a list of the questions and issues you want to address, and make sure all questions are answered before you leave an appointment. Don’t be afraid to ask the doctor or therapist to explain something again in a different way—it’s essential that you understand their advice and instructions and leave with everything that you need.
Keep a list of your child’s medical conditions and providers with their contact information. Have a system for keeping track of appointments and therapies. Keep a record of their daily schedule, including feeding, that can be seen by anyone who cares for them.
Mutations in the CDKL5 gene have been identified in girls diagnosed with a variant form of Rett syndrome (RTT). This form of the disorder, often severe, includes many of the features of classic Rett syndrome (including developmental problems, loss of language skills, and repeated hand wringing or hand washing movements), but also causes recurrent seizures beginning in infancy. Also, in Rett Syndrome, regression or loss of skills or function often takes place, and this is not common in CDKL5. Usually, there is no regression; instead, developmental milestones are late or not acquired.
CDKL5 is distinct from but closely related to Rett Syndrome. There is still a lot of research necessary to understand the connection between CDKL5 and MeCP2 fully.
CDKL5 presents as a broad spectrum of symptoms, with features that are closely associated with other neurological disorders, such as Rett Syndrome (RTT), Infantile Spasms(ISSX), West Syndrome, Lennox‐Gastaut (LGS), Early-onset Epilepsy of Infancy, and Autism.
CDKL5 and Rett Syndrome
See previous FAQ question.
Infantile Spasms (West Syndrome)
Infantile Spasms (ISSX) is a rare seizure disorder in infants and early childhood. In CDKL5, it tends to start at a very early age: usually by three months, but certainly by six months of age. The seizures primarily consist of a sudden bending forward of the body with stiffening of the arms and legs; some children arch their backs as they extend their arms and legs. Spasms tend to occur upon awakening or falling asleep, or after feeding, and often occur in clusters, from one up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day; other subtle presentations of infantile spasms are episodes that appear to be a bit like choking, becoming rigid or stiff for a short time, unusual facial grimacing, or other subtle seizures.
West Syndrome is composed of a triad of:
- Infantile spasms
- Intellectual disability, or developmental regression
- Hypsarrhythmia: In simple terms, it is very chaotic and disorganized brain waves with no recognizable pattern, compared with a normal EEG which shows a clear separation between each signal and a visible pattern.
The syndrome is age‐related, generally occurring between the third and the twelfth month, generally manifesting around the fifth month.
LGS is characterized by multiple types of seizures and an abnormal EEG with generalized slow spike‐wave discharges. Seizures are often resistant to therapy. The most common seizure types are tonic-axial, atonic, myoclonic, and generalized tonic-clonic. Absence status, tonic status, and non‐convulsive status epilepticus can occur.
CDKL5 and Autism
Autism and Autism spectrum disorders (ASDs) are a group of severe neurodevelopmental disorders with rising prevalence in which individuals show deficits in social interaction, impaired communication, repetitive behavior, and restricted interests and activities.
Many children with CDKL5 have autistic features and tendencies, together with their seizures and other physical symptoms. To date, we are aware of one person with a CDKL5 mutation in a girl with high functioning Autism only. She has no other physical symptoms of CDKL5 and has never had seizures. She shares the same CDKL5 mutation as her identical twin sister who has been diagnosed with Atypical Rett Syndrome and older brother diagnosed with West Syndrome.