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About Us

CDKL5 Europe is a group of patient organisations and family contacts, to support families and research for those living with CDKL5 in Europe.

The aims of CDKL5 Europe are:

  • To make the CDKL5 Disorder better known to the public, professionals, carers, and those directly affected across Europe
  • To improve communication within the European CDKL5 Disorder community
  • To promote, as a representative European organisation, the interests of people with the CDKL5 Disorder and their families
  • To expand CDKL5 Europe to all European countries and to assist, if necessary, in the creation of national associations
  • To promote research into the CDKL5 Disorder through collaboration with the scientific community.

CDKL5 Europe will be expanded in the coming months to provide a comprehensive list of contacts of Scientists; Researchers; Doctors; and private sector companies from Europe with an interest in CDKL5.

Research

10 years ago, in 2004, CDKL5 Mutations were first discovered.  Since then, research has been slow to gather momentum. However, Europe is fast becoming the centre of CDKL5 Research. There is now a strong focus within the European Community for Researchers, Scientists and Patient organisations to work together, and to identify where they can look to collaborate in applying for Research grants.  Collaborative working is already happening within the CDKL5 European Community.  With the Horizon 2020 Initiative and other European sources of funding, CDKL5 Research will be gathering pace in the next 12-18 months.  This section will provide you with summaries of research conferences, as well as bringing you up-to-date with what research is being done and where.
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Mapping pathological phenotypes in a mouse model of CDKL5 Disorder

Posted: Saturday 31st May 2014

Mapping pathological phenotypes in a mouse model of CDKL5 Disorder 

PLOS 2014.   Link to text

This is a paper from Italy on a Cdkl5 knockout mouse model. The authors present a number of studies on the cellular and behavioural aspects of Cdkl5 deficient mice. Absence of the Cdkl5 protein in the mice was confirmed using 2 standard techniques - western blotting and immunofluorescence.

Cell biology 

Localisation of the Cdkl5 protein - further immunofluorescent studies also showed a number of features. In normal (wild-type) mice, the Cdkl5 protein is found both in the nucleus of neurons and in their cytoplasm. Furthermore, there is a specific type of neuron - called a pyramidal neuron - and although the Cdkl5 protein is present in the cytoplasm of pyramidal neurons of the cortex, it seems to be more prominent in the cytoplasm of pyramidal neurons in a specific area of the brain called the hippocampus -which is located under the cerebral cortex.

Dendrites - which are the branched projections of neurons, are particularly important as Cdkl5 activity seems to focus within these structures. Dendritic arborisation (the complexity of their appearance and therefore function) was found to be significantly reduced in knockout mice, and this was associated with a reduction in the thickness of the cortex and of the hippocampus.

Signalling - cell signalling (also known as signalling pathways) are the many complex processes that control and co-ordinate the different activities of cells. Some signalling factors known to be affected in Rett syndrome were examined in Cdkl5 knockout mice. One such factor, called BDNF, was found to be normal, as were levels of the Mecp2 protein itself. However, another signalling factor, known as “Akt” was found to be reduced along with levels of phosphorylated “ribosomal protein S6”  - also called  “rpS6” - a protein that is a component of  ribosomes, the protein factories that convert RNA into proteins - see The Genetics of CDKL5.

Cdkl5 and Mecp2 - Previous studies have shown a link between Cdkl5 and Mecp2 (Rett) function in the brain. The authors of this study were able to show that they probably also have distinct functions in the brain as well.

Clinical

Behaviour - a number of behavioural tests were performed on the knockout mice and their responses compared to normal (wild-type) mice. Abnormal clasping was seen in a significant number of the knockout mice whereas no or very low levels were seen in the wild-type mice. Knockout mice showed significantly decreased locomotion in a familiar home-cage environment but normal locomotion in a new unfamiliar environment, suggesting that the capacity for locomotion itself may not be the source of their deficit.  Knockout mice also showed a reduction in head tracking (their responses to visual stimuli) which appeared to be due to deficient visual processing in their visual cortex that is, their eyes are working but their brains can’t fully organise the visual signals - presumably representing cortical visual blindness.

Seizures - None of the knockout mice showed evidence of spontaneous seizures - as with other knockout mice. However, when epileptic producing drugs were given they did show abnormal EEG responses compared to wild-type mice.

Mapping phenotypes - we know that different parts of the brain are involved in different functions (speech, hearing, vision, movement, etc). Different parts of the brain are also characterised by different types of neurons. In the final part of their paper, the authors describe the development of so called “conditional” knockout mice, in which the Cdkl5 gene has been selectively removed from specific types of neurons found in different areas of the brain. The idea here was to see whether some of the characteristics we see in the CDKL5 disorder could individually be mapped to different types of neurons. The researchers found that deficits in behaviour were associated with absent Cdkl5 in one type of neuron in the forebrain, while limb control and eye tracking changes occurred with Cdkl5 deficiency in a different type of neuron of the motor and visual cortical pathways. The authors suggest that therapies aimed at re-expressing CDKL5 in cortical pyramidal neurons may be successful in reversing the most debilitating behavioural phenotypes of the disorder - possibly a plug for PRT !

Overall, the authors concluded that their knockout mouse models exhibits several core features of the CDKL5 disorder and therefore serve as useful animal models of the disorder. The authors go on to discuss the signalling pathways that may be involved and suggest that the down regulation of the “rpS6” pathway may be a common signalling deficit in both the CDKL5 disorder and Rett syndrome, indicating that defective translational regulation, in other words - a problem with the control of protein production -  is a potential core mechanisms for the common pathological features of both disorders. However, their studies also suggest that Cdkl5 and Mecp2 may, in addition, act through different signaling mechanisms to affect common targets.

Note - this is great stuff and covers various aspects which is a little difficult to do justice to.  Large parts of the paper are fairly technical as the authors are obliged to describe the techniques involved in developing their mouse model and their subsequent cellular studies. Some of their results corroborate the results of previous studies and there are also some new findings presented. The work they present on signalling is particularly technical but extremely important. What they are saying here is - right, we know where the Cdkl5 protein is in the brain, now let's see what other pathways are missing as a result of its deficit. I imagine that studying related signalling pathways will be the way a lot of future research into CDKL5 will go. We may also see more mouse models of specific mutations being produced soon - let's hope!! Finally, the study represents the combined efforts of various individuals from a number of centres in Italy and Switzerland.I think it is to their credit that this work has been published as an open-access article.

 

Thanks to Martyn Newey Trustee of CDKL5 UK for providing this review which is also hosted on his informational website www.supporting-cdkl5.co.uk

Mutations in the C-terminus of CDKL5: proceed with caution

Posted: Saturday 31st May 2014

Mutations in the C-terminus of CDKL5: proceed with caution

European Journal of Human Genetics 2013.    Link to abstract

This study from France looks at mutations affecting the last 3 exons (19 - 21) of the CDKL5 gene.   The authors investigated 30 female patients with a clinically heterogeneous phenotype, ranging from nonspecific mental retardation to a severe neonatal encephalopathy. They were all screened for CDKL5 mutations which 2 were found to have. The first was a 2 year old girl who had severe encephalopathy with severe developmental delay, and seizures with apneas that started at the age of 3 months. She had a previously unreported mutation affecting exon 20. The second was an  11 year old female who presented with moderate developmental delay,  intellectual disability, speech delay and a number of other features. She was found to have a mutation in exon 21 that had previously been reported. 

In each case parental screening identified that the asymptomatic father of each female also carried the same mutation.  The 11 year old was subsequently found to have a deletion involving the SOX5 gene on chromosome 12. The authors also review the literature where mutations affecting exons 19 - 21 have been reported. Their interpretation of these cases lead them to discuss the possibility that mutations in this region of the CDKL5 gene may not be pathogenic. The authors therefore suggest that screening for mutations in exons 19 - 21, and specifically after codon 938, may not be useful in establishing a diagnosis of atypical Rett syndrome.

Note - a nice little study validating the previous paper from Williamson (below) suggesting that the main CDKL5 protein in the human brain is translated from exons 2 - 18 and part of intron 18.

 

Thanks to Martyn Newey Trustee of CDKL5 UK for providing this review which is also hosted on his informational website www.supporting-cdkl5.co.uk

 

Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene

Posted: Saturday 31st May 2014

Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene 

Developmental Medicine & Child Neurology 2012.   Link to text                                                   

This is a small study from the Netherlands looking at sleep and respiratory disturbances in 4 females with CDKL5 mutations. Their ages ranged from 2 to 15 years. The 3 younger children (ages 2, 4 and 5) had mutations affecting exons 5 and 9 and had severe phenotypes. The 15 year old had a mutation affecting exon 18 and a milder phenotype, being able to walk and having less severe seizure activity. The study involved the use of a questionnaire (Sleep Disturbance Scale for Children) and Polysomnography. REM sleep is thought to be the most important phase of our sleep cycle. In young children about 50% of sleep is spent in the REM phase while this drops to about 20% in adults. The 3 youngest in this study all spent less than 20% in REM with one recorded as having no REM sleep. Sleep efficiency - the percentage of time in bed spent asleep - was reduced in all 4 females - mainly due to frequent and long-lasting awakenings. Apnoea is the term for cessation of breathing, and it has a number of causes. Respiratory centres in the brain are responsible for controlling and driving the effort to breath, and central apnoea occurs when these control centres don’t function properly. Two of the females, the youngest and oldest, had central apnoea, which occurred during the awake state. The authors conclude by suggesting that Polysomnography  should  more-or-less be mandatory for the assessment of sleep and respiratory disturbances in children with a CDKL5 disorder.

Note - Whilst we recognise the pattern of sleep disturbances described in this study (yawn...don't we just...), we have not seen respiratory disturbances in Ellie, although I think others have in their children. As the authors themselves admit, this is a very small study which also has incomplete data. It is therefore difficult to draw any wider conclusions.  It does, however, establish some baseline data for children with CDKL5 mutations that may be of use in later studies.

 

Thanks to Martyn Newey Trustee of CDKL5 UK for providing this review which is also hosted on his informational website www.supporting-cdkl5.co.uk

View complete list of scientific papers and studies

Recent News

CDKL5 Europe Awareness Video - Magic
8th June 2014
Magic - "Is in my Eyes"   We hope you like the CDKL5 Europe Awareness video we have created.  Featuring our children from all over Europe for June which is International CDKL5 Awareness Month.  
Read More

CDKL5 Europe Awareness Video - Magic

Posted: Sunday 8th June 2014

Magic - "Is in my Eyes"

 

We hope you like the CDKL5 Europe Awareness video we have created.  Featuring our children from all over Europe for June which is International CDKL5 Awareness Month.

 

CDKL5 Europe - Together we're stronger
1st June 2014
At the request of the scientific community, and following on from a successful European CDKL5 Conference, attended by a large number of European Families, we decided that it was time for formally launch CDKL5 Europe.  ...
Read More

CDKL5 Europe - Together we're stronger

Posted: Sunday 1st June 2014

At the request of the scientific community, and following on from a successful European CDKL5 Conference, attended by a large number of European Families, we decided that it was time for formally launch CDKL5 Europe.  CDKL5 Europe is not a formal foundation at present, but it is currently co-ordinated by CDKL5 UK who are a registered charity in the UK.  The dedicated parents from all over Europe have decided to come together and collaborate to have a central place where we can represent the voice of the families in Europe living with a loved one with CDKL5 Disorder.  We hope that this collaboration will also extend to researchers, scientists, medical and social professionals from all over Europe. With a European focus on Rare Diseases there are a lot of opportunities that we have in terms of funding for CDKL5 research.  Through CDKL5 Europe we hope to bring about change, we believe knowledge is power, and with our motto, Together we're stronger, we hope that the future of our children is in our hands.  Collaboration is already happening with Patient organisations and the scientific world working side-by-side all over Europe through the Horizon 2020 initiative, to read more about it visit their website

View complete list of news articles

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