Other research which is connected in some way to CDKL5 .....

9. Neonatal Exposure to Antiepileptic Drugs Disrupts Striatal Synaptic Development
Annals of Neurology 2012.     Link to text.                                                                                                             

This is a very interesting piece of research from Georgetown University in Washington, DC, on the effects of exposure to anti-epileptic drugs (AED) during critical periods of brain development. This is a laboratory-based study on rats. The authors initially discuss how the developing brain is highly vulnerable to modifications of the molecular environment of neurons and that even transient interventions during sensitive developmental periods can have long-lasting functional consequences. In relation to AED’s, they note that phenobarbital (PB) exposure during gestation or early infancy has been associated with reduced intelligence quotient and decreased regional brain volumes in humans.  There is also some evidence that exposure to PB might contribute to the increased risk for neuropsychiatric disorders associated with early life seizures. Unfortunately, the interpretation of results from clinical studies is limited because of the difficulty in distinguishing the long-term effects of drug treatment from the effects associated with the underlying condition. However, despite this and other evidence, PB still remains the drug of choice in the first-line treatment of early-onset epilepsy.

In this study, the researchers look at striatal medium spiny neurons (MSN) which are a specific type of neuron found in a part of the brain called the Corpus Striatum. They play a key role in initiating and controlling movements of the body, limbs, and eyes. The authors studied the effects of PB and 2 other AED’s (phenytoin and lamotrigine) on the development of MSN’s in rats that were exposed to the drugs very early in life corresponding to their neonatal period. They looked at the electrical and histological effects, as well as some clinical effects.

Electrical studies – their results provide the first evidence that neonatal exposure to AED’s not only stunts the development of synapse function between neurons but may also produce a neurotoxic effect on surviving neurons which may in turn affect their function.
Histological studies – these showed that the appearance of dendritic spines were subtly altered in the brains of rates treated with PB. Spine width was slightly reduced and there were also relatively more dendritic filodopia – immature spines - which may represent failure to establish synapse formation.
Clinical studies – rats were exposed to what is called a “reversal learning task” a validated test of cognitive function and behaviour. Those rats treated with PB showed impaired reversal learning compared to control rats.

The authors go on to propose a potential mechanism of action for the detrimental effects observed with these AED’s which is distinct from their anti-epileptic activity. The 3 AED’s studied all have this property whereas other AED’s, such as Levetiracetam (Keppra) do not. The authors therefore conclude that AED’s used for the first line treatment of seizures in the newborn should be selected more carefully.

Note – a very interesting study for us personally as Ellie was put on relatively high doses of phenobarbitone at the age of 5 weeks on the basis that it was a “safe” drug. When we arrived in Australia her blood levels were checked and the local lab in Adelaide contacted us in a bit of a panic as her levels were so high. The idea that some AED’s used as first-line treatment in the first few months of life may actually be causing harm is something that clearly needs exploring further. The authors here make the point that although their study focused on neurons in one specific part of the brain, the AED’s studied have effects across many other parts of the brain and so there is potential for more widespread changes. For a genetic condition like CDKL5, we would obviously need further studies to differentiate the effects of the drugs from the effects of the underlying mutation. Further research beckons…..

8. Sleep, Plasticity and the Pathophysiology of Neurodevelopmental Disorders: The Potential Roles of Protein Synthesis and Other Cellular Processes.   Brain Sciences 2014.          Link to article                                                   

This is an interesting review from the US about sleep and its relationship to the development of memory and learning. The “laying down” of memory processes can be categorized into three stages - encoding, consolidation and retrieval, and sleep is clearly more than just having a few zzzzz’s after a good night out!  In normal development, sleep appears to be important for the consolidation of various types of memory and therefore can affect the development of learning. Sleep may be particularly important for memory consolidation during the periods of intense learning that occur throughout early development.

The drive for sleep at any point in time is determined by two processes: a circadian process that mainly controls REM sleep and a homeostatic process that is mainly confined to the description of non-REM sleep. There are a number of substances implicated as being sleep regulators, including adenosine, prostaglandins, nitric oxide and cytokines. There are also a number of cellular processes involved and one hypothesis suggests that sleep is required for synaptic pruning – NB) disorders of synaptic pruning have been implicated in neurodevelopmental disorders. 

Having reviewed the normal processes of sleep, the authors discuss the disturbance of sleep in neurodevelopmental disorders, pointing out that recent data has revealed that sleep abnormalities are among the most prevalent and common symptoms and may contribute to the progression of these disorders. The authors review a number of neurodevelopmental disorders including Autism, Fragile X Syndrome, Rett syndrome, Prader-Willi and Angelman’s Syndrome, where sleep disorders have been reported. They then go on to discuss the cellular consequences of normal and prolonged wakefulness and their effects on plasticity of the brain. The authors also point out that sleep has been thought of as a symptom of a wide variety of psychiatric and neurological disorders and that if the “primary” disorder was treated then the sleep disorder would resolve. However, this view is being replaced with the idea that the disordered sleep is not merely a symptom but that it can also play a role in the progression of the primary disorder. As the authors again point out, cell signaling and cortical connections are often altered in neurodevelopmental disorders so that the effects of any “perturbations” on neurons will be unpredictable. The combination of abnormalities of sleep and the altered brain conditions that are present might therefore lead to “synergistic and deleterious” effects. Finally, the authors note that there are very few sleep-dependent memory studies in patients with neurodevelopmental disorders or studies in any subject group that test whether social skills-learning is sleep-dependent.

Note – Theories around sleep and the disturbance of sleep in relation to memory and learning remain contentious as there appears to be conflicting experimental evidence. However, this is a good review around the subject and although CDKL5 isn’t specifically mentioned, we all know how relevant this is to us. A difficult subject to study as there are many forms of memory and learning. The authors point out that more research into sleep disturbance in individuals with neurodevelopmental disorders is needed. Although future therapeutic strategies are discussed, this paper isn’t giving us any practical answers yet into how we might deal with sleep disturbance. It is, however, making a very good case that managing and trying to improve sleep patterns should be a priority. There is quite a lot more technical stuff in the review so certainly worth a read.

7. Gastrointestinal problems in children with a CDKL5 Disorder: a parent-led survey.     
CDKL5 UK  Poster Presentation at the 3rd European Rett Syndrome Conference, Maastricht October 2013.      Link to poster

6. Treatment of Neurodevelopmental Disorders in Adulthood.
The Journal of Neuroscience 2012.                    Link to article

This is an excellent review of a concept that appears to be growing in popularity. Neuronal plasticity is defined as “the capacity of neurons and neural circuits in the brain to change structurally and functionally in response to experience”. During our development, it was thought that there was a “critical period of plasticity” after which, the brain became less responsive (eg. it is easier to learn a foreign language as a child than as an adult). However, studies looking at the visual cortex in mouse models have shown that the state of plasticity observed in the “critical period” can be reactivated in adulthood through drug treatment and specific environmental manipulation - also called environmental enrichment (EE). Combine this with appropriate rehabilitation and it is then possible to demonstrate recovery of function to a certain extent. 

The authors review some of the evidence that suggests that the phenotypes associated with neurodevelopmental disorders might be improved, even in adulthood, with these approaches. They also focus on 2 particular conditions, Fragile X Syndrome and Neurofibromatosis type 1, both of which are genetically inherited conditions. They review experimental data on adult mouse models that have demonstrated the reversal of some of the features of the underlying condition. They conclude by saying that this line of research may eventually lead to the development of treatments that might alleviate or cure symptoms and disabilities that occur secondary to neurodevelopmental disorders.

Note - Although CDKL5 is NOT specifically mentioned in this review, it is still pretty exciting stuff!  Clearly there is a long way to go with this line of research, and as always, the big question will be can results from animal studies be translated to humans? If it does become possible to induce a state of plasticity such that a ”learning programme” can be instituted to improve cognitive function, then, this would go a long way to helping many adults and children  with conditions like CDKL5.

5. Proximal large bowel volvulus in children: 6 new cases and review of the literature. 
Journal of Pediatric Surgery  2012.                    Link to abstract

This is a review from 3 centres in the UK, Ireland and Hungary of an extremely rare condition that affects the bowel. A volvulus is a condition where the bowel twists on its mesentry (a fold of tissue that attaches it to the wall of the abdomen). This can then cause obstruction of the bowel and can even result in irreversible damage to the blood supply of the bowel. If diagnosed early enough it is possible to treat the condition without surgery although most patients do require some sort of surgical procedure. The authors review 36 cases that have previously been reported and an additional 6 cases of their own. Males and females were equally affected but 29 (69%) were described as having neurodevelopmental delay. The mean age of the group was 10 years (range 0 to 18 years). The presenting symptoms were colicky abdominal distension (100%), abdominal pain (98%), vomiting (83%) and constipation (69%). All but one of the patients with constipation had neurodevelopmental delay. All 42 patients required surgery and there were 6 (14%) deaths. The authors also noted that neurodevelopmental delay and severe chronic constipation were the commonest associated disorders. They suggest that in mentally impaired children, insufficiently treated chronic constipation results in a heavy and extremely dilated bowel that stretches the bowel mesentry and allows a volvulus to occur. They also point out that although children with a volvulus present with pain, distension and vomiting, these symptoms also frequently occur in children with neurodevelopmental delay and constipation without volvulus, and should respond to enemas and laxatives. The rarity of volvulus and the inability of a child with neurodevelopmental delay to adequately communicate their symptoms, may explain why there may be a delay in establishing the diagnosis.

Note - The first thing to say is that this is an extremely rare condition in children. The authors found only 36 reported cases in the English literature from 1965 to 2010. Although any child can be affected by this condition, it would appear that children with neurodevelopmental delay are more prone, presumably due at least in part to problems with communication - an issue which I am sure we all recognise. They do not, however, specify the nature of the neurodevelopmental delay present in the children of this study. Many of us will be only too familiar with the problems around bowel function and constipation - see Living with CDKL5,  so as I stated there, it is very important that parents and carers keep a close eye on this issue, and in my view, do not delay in involving your family doctor / specialist physician if you have a concern. Also - see article below regarding GI disorders....


4. Validation of high-resolution DNA melting analysis for mutation scanning of the CDKL5 gene:
Identification of novel mutations.
Gene  2012.                    Link to abstract

This study from France describes the validation of a technique called high-resolution melting analysis (HRMA) used to detect genetic mutations. HRMA was developed in the US by the University of Utah in conjunction with Idaho Technology, and introduced in 2003. The authors point out that hitherto, identification of mutations in CDKL5 has been time consuming, laborious and expensive. Their study reports the validation of HRMA and the results of a comparison with another technique called denaturing high performance liquid chromatography (dHPLC). Their results showed that point mutations and small insertions and deletions can be reliably detected by HRMA, and compared to dHPLC, HRMA profiles are more discriminating. They conclude for mutation screening, HRMA appears cost-effective, easy to set up, highly sensitive, non-toxic and rapid. The technique is ideally suited for large genes with mutations located along the whole coding sequence, such as occurs with the CDKL5 gene.

Note - I read this with interest because Ellie, like many other children who were eventually diagnosed with a CDKL5 disorder, initially had a false-negative result. As technology advances we would hope that testing for all mutations becomes more sensitive and reliable, quicker and cheaper.

3. A survey of parents of children with cortical or cerebral visual impairment.    
Journal of Visual Impairment and Blindness 2010.                     Link to text

This study summarises the results of a survey of 80 parents who have children with Cortical or Cerebral Visual Impairment (CVI). The various aetiologies (causes) are reviewed along with rehabilitation and intervention strategies. The most effective rehabilitation is said to be that which involves parents and other family members. Motion, particularly of a coloured object is the most important factor in improving the visual response. The survey also looks at 3 issues - how do parent's receive the diagnosis of CVI, what educational support do children with CVI receive, and what do parents of children with CVI feel about the support they and their children receive.

Note - This article has been written by parents of children with Cortical Visual Impairment (CVI) . This is not something that  we read so much about in CDKL5 articles, as the focus tends to be on seizures, developmental delay and mobility. However, children with CDKL5 certainly do suffer from CVI and although this article covers a broad spectrum of issues, many are relevant to us which I think is very helpful.


2. Gastrointestinal Disorders in Children with Neurodevelopmental Disabilities.                                                                          
Developmental Disabilities Research Reviews 2008.                    Link to abstract

As the title suggests, this article reviews the various gastrointestinal problems that children with neurodevelopmental disabilities can suffer. It systematically describes problems from the mouth and swallowing, through to the lower bowel and constipation. Underlying causes are discussed and the various treatment options reviewed.   The author points out how difficulties with eating may be confused with behavioural food avoidance or aversion, and that abdominal discomfort can present as chronic irritability, crying or dystonic (involuntary twisting or repetitive) movements of the face and neck. More than 80% of children with gastro-oesophagel reflux will have recurrent vomiting. Constipation is discussed and defined as opening of bowels less frequently than 3 times per week or the regular need for laxatives. Constipation is a common problem in children with disabilities and can go unrecognised for years. Treatment requires a consistent approach by willing parents and carers.

Note - Although this review tends to refer frequently to children with cerebral palsy,  many of the problems discussed will apply to children with CDKL5. I have highlighted 2 particular issues that are discussed, gastro-oesophageal reflux  and constipation, as these will be familiar to most of us. There is one particular telling line in the discussion about gastro-oesophagel reflux, which says  "It is ironic that the learning deficit that usually accompanies neurological impairment also impairs the ability of the individual to communicate the main symptom... which is pain."    A good and very useful review article - I have a full copy if anyone would like to read it


1. Melatonin therapy for circadian rhythm sleep disorders in children with multiple disabilities: what have we learned in the last decade?        Developmental Medicine & Child Neurology 2004.                    Link to text

Sleep is thought to be a learned neurological process that develops in response to cues from the environment. This is a process that we all go through, but which is impaired in children with neurodevelopmental problems. As a result they can retain their fragmented "baby" pattern of sleeping, potentially throughout their life. Circadian rhythm sleep disorders (CRSD) occur when there is a dissociation between sleep-wake  behaviour and the environment. Parents should promote the sleep learning process through "highly regulated strict sleep hygiene".  Melatonin is produced by the pineal gland in the brain, and although previous research has established that it can induce and maintain sleep,  it's exact mechanism of action remains unclear. It does not promote sleep in the same way as a hypnotic (sleeping tablet) does,  but may act by inhibiting neuronal excitability in the central nervous system. Exposure to light tends to decrease melatonin secretion while darkness promotes it. CRSD's tend to be associated with disturbance in melatonin secretion. There are also non-circadian rhythm sleep disorders due to pain from such things as reflux or orthopaedic problems, or from nocturnal seizures or related drug treatment. In the treatment of CRSD it is important to choose the correct melatonin formulation depending of the particular sleep disorder. Discontinuation for a few days is also recommended as children can acquire normal sleep patterns over time. Some studies suggest that children with neurodevelopmental disabilities, who have CRSD  can show a 70-90% quick response. However, not all children respond equally and there may be some with certain conditions who may not benefit. No major side-effects of melatonin have been reported in paediatric studies. 

Note -   This review contains a lot of information about sleep disorders and the role of melatonin. One of the authors published the original study on the role of melatonin in sleep disorders, and so the enthusiasm for melatonin is understandable. They do state that much of the skepticism regarding melatonin was based on lack of quality control, unsubstantiated benefit claims, misconceptions about the action of melatonin and oversimplification about the relationship between melatonin and CRSD's.  Perhaps the most relevant points for parents and carers are made in the first few paragraphs where they state that the majority of children with neurodevelopmental disabilities are said to have long-standing sleep disorders, and that the management is often neglected due to the inadequate training of doctors in these problems.

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