Rett syndrome (RTT) is a severe neurodevelopmental disorder, the Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. A number of different genes, including the CDKL5 gene, are located on the X-chromosome. We are sorry, but there is still no official definition in the Unified Medical Language System (UMLS).
CDKL5 stands for cyclin‐dependent kinase‐like 5, this gene was previously called STK9. The CDKL5 gene leads to the production of a protein, which is particularly abundant in the neurons of the brain and of fundamental importance for the correct developement and functioning of the nervous system. If the CDKL5 gene gets lost or is mutated, the resultant absence of the CDKL5 protein or the production of a protein that is not correctly working, or is not working at all, causes the early onset of neurological symptoms that in general manifest during the first months of life.
Although little is known about the protein’s function, it may play a role in regulating the activity of other genes, including the MECP2 gene (of Rett Syndrome). The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a phosphate group at specific positions. Researchers have not yet determined which proteins are targeted by the CDKL5 protein.
Most of the children affected by CDKL5 cannot walk, talk or feed themselves, and many are confined to a wheelchair , dependent on others for everything. Many also suffer with scoliosis, visual impairment, sensory issues and various gastrointestinal difficulties. It is important to note that we don’t know the full spectrum of CDKL5 disorders at this time. It is likely that there are many people affected by CDKL5 who have mild symptoms and no seizures.
Dr. Hanefeld described for the first time in 1985 some of these cases in female patients affected by one of the Rett syndrome variants characterized by infantile spasms and an abnormal brain activity (hypsarythmia). Subsequently, the definition “early seizure onset variant” or “Hanefeld variant” has been extended to include patients with atypic Rett forms characterized by the onset, during the first weeks or months of life, of epileptic crises that often are drug resistant. Mutations in the CDKL5 gene have also been identified in patients with X-linked infantile spasms syndrome (ISSX) or West syndrome, mental retardation and autism. Even if these disorders affect mainly girls, several males have now been described with mutations in CDKL5 and with a clinical picture similar to that of the female patients.
The incidence of a CDKL5 mutation in the population is unknown at this time.
There are more than 100 cases of CDKL5 mutations that have been reported in the medical and scientific literature. However, we know that there are likely more than 600 documented cases worldwide, and that number is growing rapidly. More and more children and adults are being tested and diagnosed, as doctors and geneticists become more familiar with CDKL5.
Even if these disorders affect mainly girls, several males have now been described with mutations in CDKL5 and with a clinical picture similar to that of the female patients.
At this time, we do not know what is life expectancy. Since CDKL5 was discovered only in 2004, we do not have enough data to answer this. What we do know, however, is that the oldest patients described in medical literature with CDKL5 are 41 years old. There are many others that we know of who are in their mid 20’s, and many in their teens. Most of those newly diagnosed are young children and infants/toddlers.
Not everyone will have all the signs listed here and may have other symptoms not mentioned, furthermore different seizure types can be found in the same patient and change with time:
- Epileptic seizures starting in the first five months of life.
- Infantile spasms (in about 50%)
- Many different types of epilepsy usually including myoclonic jerks, focal crises and generalized tonic-clonic seizures
- A small head (microcephaly) in about 50%
- Hand wringing movements or mouthing of the hands
- Marked developmental delay
- Limited or absent speech
- Hypersensitivity to touch, for example dislike of hair brushing
- Lack of eye contact or poor eye contact
- Gastro‐esophageal reflux
- Small, cold feet
- Breathing irregularities such as hyperventilation
- Grinding of the teeth
- Episodes of laughing or crying for no reason
- Low/Poor muscle tone
- Very limited hand skills
- Some autistic‐like tendencies
- Cortical Visual Impairment (CVI), aka “cortical blindness”
- Eating/drinking challenges
- Interruptive sleep
- Characteristics such as a sideways glance, and habit of crossing legs
Different symptoms are associated with CDKL5 mutations as described, they are all in general accompanied by severe neurological symptoms often drug resistant.
Patients treated with anti-epileptic drugs often benefit from a period in which the drugs work efficiently but that, unfortunately, is followed by a reappearance of the crises. The available data describing neuronal imaging and EEG analyses do still not allow defining typical alterations of the disorder. Together with the epilepsy, patients with CDKL5 mutations often suffer from a psychomotor delay, stereotypic hand movements, autistic features, poor language development, and severe muscular hypotonia.
Compared to persons affected by classic Rett syndrome patients with CDKL5 variant are characterized by the absence of a period of normal development, 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. At this time, CDKL5 appears to be distinct from, but closely related to, Rett Syndrome. There is still a great deal of research that needs to be done to understand the connection between CDKL5 and MeCP2.
Dysfunctions of the autonomous nervous system like respiratory problems and cold extremities can be present in CDKL5 patients while they are a more constant feature of Rett syndrome patients. Often the children with CDKL5 mutations have particular facial characteristics such as big well-defined eyes, a prominent lower lip and protruding upper teeth.
CDKL5 presents as a broad constellation of symptoms, with features that closely resemble other established disorders, such as West Syndrome, Lennox‐Gastaut (LGS), Early onset Epilepsy of Infancy, and Autism.
PATHOGENESIS - The causes
It appears that most of the mutations in CDKL5 gene arise “de novo”, meaning that they occur spontaneously at the moment of the conception, and are not passed down through families. However, there is one known family in which multiple siblings were affected with the exact mutation, but neither the mother nor father are considered carriers. It is best to consult a geneticist to discuss the own individual risk for passing down this genetic mutation.
HYPOTHESIS OF MOLECULAR PATHWAYS
As most genes, the CDKL5 gene brings to the synthesis of a protein with the same name: the CDKL5 protein. Functional studies of this protein were started only in 2005. Here we summarize only the principal information that has been gathered till now. Technically, CDKL5 is a kinase or, with other words, it is a protein capable of adding a phosphate group to other proteins. The targets of a kinase are not random but very specific. What does the addition of a phosphate group mean? It is a way of regulating the functions of the target protein. As an example, we can imagine a car with properties like a certain speed, a certain energetic consumption, and a certain degree of pollution. Our kinase could be imagined to be the car mechanics that by tightening and loosening screws and bolts can improve or worsen the above mentioned capacities of the car. CDKL5 performs exactly the same role in our cells: it is a protein that through its activities changes the way other proteins work. Where does it do this? Probably it exerts its functions in a large number of different tissues and cells; in fact, we know that CDKL5 is expressed basically everywhere. However, in the brain its levels are significantly higher than in other tissues suggesting a particular role in this organ. We also know that CDKL5 levels increase in the brain in concomitance with neuronal maturation and remain high throughout adult life. These data suggest that . We still do not know how many and which target proteins are regulated by CDKL5. However, strong evidence indicates that MeCP2, which is mutated in most cases of classic Rett syndrome, is a target of CDKL5. This explains why classic Rett syndrome and the disorders associated with CDKL5 mutations share some overlapping features. We still cannot say with certainty that CDKL5 regulates MeCP2 functions in the brain and what are the consequences of this. There is still no mouse model with mutations in CDKL5 useful for studying the disease. However, neurons without CDKL5 have been generated in the laboratory and they have an abnormal morphology that makes researchers hypothesize that these neurons cannot sustain the communication that normally occurs between these cells. It is worth mentioning that our brain contains billions of neurons that each establishes contacts with a huge number of different neurons leading to an extremely complex network that is fundamental for learning, memory, response to stimuli, coordination of movements, emotions etc etc. Moreover, without CDKL5 during brain development the neurons seem not to be located correctly in time and space, which again indicate that there might be an aberrant communication among the neurons.
The initial diagnosis is a clinical one or, with other words, based on the clinical symptoms presented by the patient the doctors hypothesize that the CDKL5 gene might be mutated and therefore they request a molecular analysis. A blood sample of the patient is sent to a specialized laboratory where a specific DNA sequencing analysis is performed. The entire part of the CDKL5 gene that leads to the synthesis of the CDKL5 protein is being sequenced and compared to that of a control sample of a healthy person. The presence of an alteration of the gene normally requires the same analysis of the parents’ DNA. If, as mentioned, the genetic alteration of CDKL5 is present only in the patient the molecular diagnosis, confirming the clinical one, is obtained. If the patient turns out to be negative (no mutations are found) the clinical diagnosis may still be valid. In fact, presently, the CDKL5 gene is considered mutated in approximately 15% of patients with a clinical picture like that described above. Whenever the patient does not have a mutation in the CDKL5 gene the DNA is normally analyzed with other molecular genetic techniques to discover other chromosomal defects or mutations in other genes. Today there is still a significant number of patients that suffer from the described severe clinical picture but in which no genetic alterations have been found to explain the disease.
The disease has been identified only recently and the information so far available is still rather scarce. First of all, we do not know if the disease is neurodegenerative or if it regards neurodevelopment or maintenance of the neurons. This knowledge, together with a clear understanding of the role of CDKL5 in the normal brain, will allow us to have a better comprehension of which direction to follow to cure or ameliorate the symptoms characterizing patients with mutations in CDKL5.
A wide variety of anti‐seizure therapies have been tried by many of our children, with varying degrees of success. They include:
- anti‐epileptic drugs
- Ketogenic diet/modified Atkins diet.
- Vagal nerve stimulator (VNS)
- Neurosurgery, such as corpus callostomy
- Various dietary changes/modifications
There are several common therapies out there that have helped many children with CDKL5 make strides. Most success has come from early intervention, but it is never too late to try new therapies. Most of the children receive physical, occupational, and speech therapies. There are also many places across the country that specialize in intensive forms of these therapies. Aqua therapy, hippotherapy, and music are also common therapies for our children.
HOPE FOR THE NEXT FUTURE
First of all, it is important to keep in mind that the history of Rett syndrome research helps delineating the direction to follow when studying CDKL5. Therefore, summarizing some of the principal steps, we can imagine that it will be necessary to:
- Generate a mouse model devoid of CDKL5;
- Use techniques allowing the genetic manipulation of CDKL5 in the mouse to understand in which brain areas CDKL5 exert its main functions;
- Use gene therapy approaches on mouse models to understand if the disorder is reversible;
- Find the target proteins of CDKL5 to understand the defects associated with their deregulation and if therapeutic approaches (drugs and others) exist that will correct these dysfunctions;
- Find the proteins regulating CDKL5 functions and understand if their therapeutic modulation can revert defects associated with CDKL5;
- Identify the genes that are deregulated in the absence of CDKL5 and understand if their therapeutic modulation can revert defects associated with CDKL5;
- Clarify which are the molecular defects associated with some pathogenic mutations to understand if it is possible to associate particular mutations with specific clinical traits.
Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases. 2012
link to CDKL5.com
link to lalberodigreta.org
link to hindawi.com
This last link is about Rett Syndome:
link to prorett.org