Mutations in CDKL5 gene are the cause of the disorder. It remains uncertain, however, how lacking a properly functioning CDKL5 protein disturbs the function of the brain cells. Investigators are trying to understand the mechanisms by which this happens.
Although CDKL5 is a genetic disorder, it appears that most of the mutations are “de novo,” a chance occurrence in the child. However, there is one known case in which multiple siblings were affected with the exact mutation, but neither the mother nor fathers are considered carriers. It is best to consult a geneticist to discuss your individual risk for passing down this genetic mutation.
The main symptom of CDKL5 disorder is early-onset seizures. The hallmark of these seizures is that they seem to be intractable. The seizures are not effectively controlled, even with several antiepileptic drugs in various combinations. Honeymoon periods (seizure-free) with new drugs were observed in some cases. The spectrum of the epileptic seizures in those with CDKL5 mutations is broader, the seizures may appear in many different forms: muscle rigidity, spasms, head-turning, automatisms such as lip smacking, chewing, fidgeting, sleep-related hyperkinetic, sudden myoclonic jerks, becoming rigid for a short period of time, diffuse trembling, facial grimacing, fixed gaze, ‘‘breath-holding/choking’’ episodes or other subtle seizures. Although the infantile spasms, tonic seizures, generalized tonic-clonic seizure, and complex partial seizures seem to be most frequent seizure forms, focal seizures may also occur in patients with this disorder. Most patients have many of the above-mentioned seizure types.
Recently, the literature stated a distinctive seizure type in patients with CDKL5 mutations: Hypermotor-tonic-spasms sequence.
No. It has been documented worldwide the mutation responsible for CDKL5 disorder can strike males, even where there isn't a family history of the rare brain disorder.
CDKL5 presents as a broad constellation of symptoms, with features that closely resemble other established disorders.
It has been identified that mutation in the CDKL5 gene can cause a disorder called X-linked infantile spasm syndrome (ISSX) or West syndrome. However, testing for CDKL5-Related Infantile Spasms should be considered in those with Atypical Rett Syndrome, MECP2-negative Rett Syndrome, X-Linked Infantile Spasms (ISSX, West syndrome, or the Hanefield variant), complex seizures disorders with mental retardation, X-linked Mental Retardation, and Autism Spectrum Disorder.
Common treatment for CDKL5 consists of addressing the symptoms. Since seizures are very common with CDKL5, medications and dietary changes are used to help control episodes. The seizures associated with CDKL5 are difficult to treat and the success is variable. Sometimes, a combination of antiepileptic drugs and other therapies are tried, but there is no identification of the best particular combination of the following:
Most children with CDKL5 also receive on-going treatment in the form of speech and physical therapy, occupational and vision therapy. In addition, music, water and equestrian therapies are very beneficial.
There is rapid and increasing awareness of the condition. Geneticists, neurologists, and paediatricians are increasingly aware, and genetic testing for CDKL5 is commonly requested in patients that seem to fulfill clinical criteria. Scientists have developed a genetic test to complement the clinical diagnosis, which involves searching for the CDKL5 mutation on the child's X chromosome. It is a simple blood test sent off to a laboratory.
How do I connect with other parents of children with CDKL5?
Connect with the CDKL5 Canada Foundation and parents in the CDKL5 community on the following social media networks:
We are the only Canadian organization for CDKL5 Disorder and a member of Canadian Organization for Rare Disorders (CORD).
Other CDKL5 Organizations:
There are many ways to get involved, and all are important. Some people choose to give their time, some their funds, some their talents, and still others their hopes and prayers. We are so grateful to everyone who joins us on our mission!
The need for donations is constant and ever-growing. You can donate directly to CDKL5 Canada HERE or you can contact us to find out other ways to help, such as hosting or participating in a fundraising event.
Almost every cell in our bodies contains 46 chromosomes, which carry our genes. Chromosomes come in pairs, and we inherited one of each pair from our mother and one from our father. The sex chromosomes determine whether we are male or female. Females have 2 X chromosomes, whereas males have one X and one Y. So, for every gene on the X chromosome, females have 2 copies, and males have just one.
Since we only need one copy of each gene on the X chromosome to survive, a female will have one of her two X chromosomes “inactivated” in each cell in her body. The process is supposed to be random, meaning that the likelihood of the maternal or the paternal X chromosome will be inactivated is roughly equal. Occasionally however, there is “skewing” of the X-inactivation pattern such that the same X is inactivated in the majority of cells.
There is some evidence that the severity of disorders caused by a mutation in a gene on the X chromosome is related to the pattern of X-inactivation (random or skewed). There is a blood test that can determine the pattern, but unfortunately it is not reliable enough to be able to predict disease severity with accuracy.
Although every cell in our bodies theoretically should have the exact same DNA sequence, occasionally we find that a person has a gene mutation in some, but not all, of his or her cells. This is known as “mosaicism.” Usually this means that no mutation was present at conception, but as an embryo made up of just a few cells, a mutation occurred. From then on, the mutation was present in some of the cells of the body, but not others.
How mosaicism is related to severity of a genetic condition depends on the percentage of abnormal cells and their tissue distribution (where in the body they ended up). For genetic mutations affecting the brain, like CDKL5, it can be impossible to predict the outcome based on a blood test, because the cells in the blood do not necessarily reflect the cells in the brain.
In general though, it is believed that having a mosaic form of a genetic condition is less severe than having the mutation in every cell. For disorders caused by genes on the X chromosome that mostly affect girls, like CDKL5, mosaicism is one possible explanation why boys can survive with the condition, despite having only one X chromosome.
This is a common misperception, even among doctors. Rett syndrome is a diagnosis made because of specific clinical features, namely:
Relatively normal development for the first year of life, followed by a period of regression (loss of previously learned skills), and then a period of stabilization
Partial or complete loss of acquired purposeful hand skills (eg self-feeding)
Partial or complete loss of acquired speech
Difficulty learning to walk or abnormal walking
Repetitive hand movements such as hand wringing, squeezing, mouthing or rubbing
Over 95% of girls with “typical” Rett syndrome have a mutation in the MECP2 gene on the X chromosome.
“Atypical Rett syndrome” is a term used to describe patients with some, but not all, symptoms of Rett syndrome. Girls with atypical Rett syndrome are less likely to have a mutation in MECP2. A very small number of girls with atypical Rett syndrome have a mutation in CDKL5. Usually these girls have the “early seizure variant” (also called the Hanefeld variant) type of atypical Rett syndrome. However, it seems from what we know so far that most girls with a mutation in CDKL5 don’t fit the criteria set out for Rett syndrome (even the atypical form).
The “germ line” refers to the cells that are found in the ovary (eggs) or testes (sperm). Another word for these cells is “gametes.” They have half the amount of genetic information of the rest of the body’s cells (known as “somatic cells”) because their job is to unite with a gamete from the opposite sex and form an early embryo (zygote).
Germ line mosaicism is when a person carries a genetic mutation in their eggs or sperm, but not in the rest of the body. So, you can do a DNA test using a blood sample, but no mutation will show up. But, since it is present in some of the eggs or sperm, the mutation can be passed to offspring. It’s quite rare for this to happen, and difficult to prove.
As far as we know, this is extremely rare. At least 2 families have been reported with more than one affected child. The vast majority of families have only one affected child and no family history. This likely means that most of the time, the mutation that arises in the CDKL5 gene happens in either the egg or the sperm from one parent.
This is usually offered to both parents when the child is a girl (when the child is a boy, we know he cannot have inherited the mutated gene from his father, because the X chromosome always comes from the mother). We usually expect that neither parent will carry the mutation, because they are not affected. However, rare exceptions can exist. There are 2 scenarios:
Gonadal (or germline) mosaicism in either parent (see question #14)
Favourable X-inactivation pattern in the mother, who is a carrier (see question #11).
In both cases above, the chances of having a second affected child is very difficult to predict. However, prenatal diagnosis could be offered in subsequent pregnancies to determine whether the fetus has the mutation.