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WHAT is the Hanefeld variant of Rett syndrome and the other pathologies associated with the CDKL5 gene?

A number of different genes, including the CDKL5 gene, are located on the X-chromosome.

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 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 onset of neurological symptoms that in general manifest during the first months of life.

Dr. Hanefeld described for the first time in 1985 some of these cases in female patients affected by one of the Rett syndrome variants (link) 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.
Different symptoms are associated with CDKL5 mutations; as described, they are all in general accompanied by severe, often drug resistant, epileptic crises that appear in the first weeks after birth.
Here we resume some of the most frequent symptoms characterizing patients with CDKL5 mutations. However, it is important to stress that they are not all always present.

Among the most frequent neurological symptoms are the epileptic crises that can be of various types (infantile spasms, generalized tonic-clonic seizures, focal crises, myoclonic epilepsy etc). Different seizure types can be found in the same patient and change with time. 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 mutations are characterized by the absence of a period of normal development, they maintain a partial use of the hands and have poor eye contact.
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.

Immagine ottenuta da sequenza di diagnosi molecolare del DNA.  In alto (la chiamerei fig 1) è rappresentato porzione di una sequenza normale del gene Cdkl5 (successione dei nucleotidi-lettere) GGAAAACA. In basso (la chiamerei fig 2) è riportata la sequenza dello stessa porzione di Cdkl5 ma caratterizzata da una mutazione patogenica. La sequenza è ora diventata  GGAAGACA, ovvero l'elettroferogramma evidenzia una lettera A  mutata in G.

-              The cause
In general, mutations in CDKL5 are considered the cause of the disease if the are present in the child but not in the healthy parents. Therefore, these mutations arise “de novo” at the moment of the conception.

-              The diagnosis
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 cure

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.




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 CDKL5 functions are important when, after birth, we start acquiring and elaborating information from the external environment to learn and memorize. 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.

 Neuroni isolati da embrioni murini coltivati in laboratorio. Silenziando il gene CDKL5 vengono generati neuroni senza la proteina. A sinistra è mostrato un neurone normale con tutte le sue ramificazioni mentre a destra si può notare la diminuzione di ramificazioni ottenuta in assenza di CDKL5.



- 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.

Thanks to 

Prof. Nicoletta Landsberger PhD Labroratory of Genetic and Epigenetic Control of Gene Expression –
Department of Structural and Functional Biology University of Insubria - Busto Arsizio (Varese) Italy, and Prof. Charlotte Kilstrup-Nielsen PhD for the helpful collaboration.


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