Edited by Katheryn Elibri Frame, DO, President of IFCR

The CDKL5 International Database is a vitally important research tool in which all families (worldwide) affected by CDKL5 are encouraged to participate.  IFCR has partnered with researchers Stephanie Fehr, Helen Leonard and Jenny Downs at the Telethon Institute for Child Health Research (Australia) in the development of the database because we recognize its importance in research, treatments, interventions and clinical trials.  The database has been active for just over one year now, and as the number of patients being reported continues to grow, a better understanding of the clinical picture of CDKL5 is starting to emerge.  Recently, Stephanie Fehr reported some results at the European Rett Syndrome Meeting in Maastricht, the Netherlands in October 2013*  and IFCR is pleased to share highlights of these presentations with you.  We will be sharing information from the database over the next several months as it becomes available, so please check back frequently to learn the latest news.  This current news release will touch on the areas of epilepsy, gastrointestinal issues and physical development.  The database is comprehensive and addresses many more areas of CDKL5, and those results will be shared by researchers in the future.

So why is this database and patient participation so important?   CDKL5 is still so new and rare that the only way to truly understand this disorder and all the complications, treatments, interventions and natural progression of this disorder is to compile the data from as many patients as possible so it can be thoroughly evaluated.   Research can then be directed in a more meaningful and targeted approach, and the information contained in the database is critical for any clinical trials in the future.   Once we understand the spectrum of CDKL5 and have a good picture of what is happening in the lives of those affected, only then can we begin to make widespread and meaningful changes that can improve the quality of lives for those affected.  We highly encourage all families to take part in this project so that all children and adults living with CDKL5 have the best chance for treatments and a cure. Please visit CDKL5 International Research Database to learn more about participating in this important research! Description and Treatment of Epilepsy in CDKL5 Epilepsy is the most common symptom of CDKL5 disorder and early onset refractory epilepsy continues to be one of the identifying characteristics of this disorder.  The study sample consisted of 111 participants (99 females, 12 males) ranging in age from 3 months to 30 years old, and all but one female had epilepsy. The age of onset of epilepsy is 1 day old to 15 months, with the median age being 6 weeks old.  Most children were diagnosed as having seizures at the time of the first episode, however the rest had a delayed diagnosis of epilepsy, from one day to 26 months beyond the initial event, the median wait time was 4 weeks. These first seizure types were mostly described as generalized, and the large majority of children were diagnosed with one seizure type at onset, although a few had two or three different seizures types at onset.   The various seizure types seen in order of most frequent are: Tonic-clonic (43%) Infantile spasms (30%) Focal seizures (23%) Myoclonic (19%) Tonic (11%) Absence (5%) Atonic (1%) Clonic (1%) A honeymoon period longer than two months where the child was free from seizures occurred in 44% of those surveyed.  The median time was 6 months, but the range was from 2 months to over 6 years. When asked about current seizure type and frequency at the time of the survey, the majority still had only one seizure type, however the trend was increasing towards almost 50% developing two or three types.   Importantly, 14% reported being seizure free!  The most frequent types seizures also changed: Tonic-clonic (43%) Myoclonic (36.5%) Tonic (30%) Absence (24%) Infantile spasms (23%) Focal seizures (15%) Atonic (9.5%) Clonic (4%) Anti-Epileptic Drugs (AED’s) in CDKL5 are common.  Approximately 50% are taking three or more AED’s at the same time in attempt to control the seizures, and fewer than 20% are only taking one AED.  A total of 25 different AED’s were used among the 93 participants where the name of the drug was known. However, in addition to AED’s there are other modalities used as treatment options such as the ketogenic diet, vagal nerve stimulator (VNS), and neurosurgery.  Fifty-four percent had tried the Ketogenic diet, and of those almost 65% reported some improvement in seizure frequency, severity, duration and overall behavior.  However only 30% continued with the diet for various reasons. Regarding the VNS, 22% had a VNS inserted between the ages of 18 months and 19 years old, and 59% of those patients were reported to have some improvements in seizure frequency, duration, severity and behavior.  It was not reported in this current release of data the percentage of children who were treated with both the ketogenic diet and a VNS.  A small number of children underwent neurosurgery, such as corpus callosotomy, functional hemispherectomy, or temporal or frontal lobectomy.  Outcomes from surgical interventions on seizures and behavior was not reported in this presentation. For those individuals who reported currently being seizure-free, they each had a different treatment regimen, including combination of AED’s with or without the Ketogenic diet or VNS. Motor Development in CDKL5 There is variability within the CDKL5 disorder in regards to gross motor abilities, as reported by parents. Most children’s abilities were impaired, while a small number were able to complete all aspects of the gross motor scale independently, even run. Based on a sample size of 116 children (102 females and 14 males) from 17 different countries, and ages ranging from 4 months to 29 years (median age 6 years) for females and 2 years to 22 years 8 months (median age 9 years 2 months) for males: rolling over: approx 84% of girls can roll over vs 35% for boys sitting:  55% of girls can sit independently vs 23% of boys crawling: nearly 21% of the girls could crawl vs 10% of boys stand independently:  almost 20% of girls can stand independently walking independently: almost 18.8% of girls can walk independently run independently: 8% of girls can run as reported by their caregivers. Most males needed maximal support to sit, stand, transition and walk, but in this study, three boys learned to stand with support, two of whom also learned to walk with support.  It is very important to note the small sample size of males in this study.  A better understanding of the gross motor abilities of males affected by CDKL5 will become clear as the number of males diagnosed and participating in the database grows.  Anecdotal reports outside of the official database of boys walking, talking, climbing and running are beginning to emerge. Gastrointestinal Problems identified in CDKL5 Disorder Consistent with the picture in other neurological disorders gastrointestinal symptoms occur frequently in the CDKL5 disorder, affecting both males and females.    This study had 102 participants, from 13 different countries, included in this analysis (89 females and 13 males). Ages ranged from 7 months to 29 years 10 months (mean 8.2 years, median 6.9 years). There was an equal amount of males and females (85%) reported to have ever experienced a gastrointestinal issue in their life.  At the time of reporting, however, 65% of females and 61% of males were currently experiencing a GI problem.  Around 20% of individuals appear to have resolved GI problems. The odds of having a reported gastrointestinal problem was greater in children over the age 4 years old, although 40% did report some GI problems under the age of 4. The most common problems are constipation (75.5%) and reflux (67.6%), followed by slow gut motility (26%) and air swallowing (18.8%). Almost 60% were taking at least one medication for a GI problem, most commonly for reflux and constipation. Feeding difficulties such as trouble swallowing, chewing and high risk of aspiration were reported in more than half of the girls and nearly all of the boys. The need for surgical intervention for GI problems is high, with 32% of all participants having one or more surgical procedures.  However, it was disproportionately higher among males needing intervention,  69.2% (9/13) males vs 27% (24/89) females.    Gastrostomy (feeding tube such as G-tube or J tube) insertion was the most common with 31 (30.4%) individuals (22 females and 9 males) having had a gastrostomy,  and in 12 instances this was accompanied by a Nissen fundoplication procedure. The most common reasons reported for needing a feeding tube were: Feeding difficulties (~76%) To give medication (60%) To gain weight (50%) Making feeding easier (50%) To improve health (~47%) To reduce respiratory infections (eg, aspiration) (~40%) To administer the Ketogenic diet (30%) Too tired to eat (30%) Other (20%) Abdominal bloating (~5%) *References 1. Treatment regimens for epilepsy in children and adults with the CDKL5 disorder; Stephanie Fehr, Jenny Downs, Helen Leonard, David Forbes, Nick de Klerk, John Christodoulou and Simon Williams; podium presentation at the European Rett Syndrome conference, Maastricht, October 2013 2.Development and current gross motor function in children and adults with the CDKL5 disorder; Stephanie Fehr, Helen Leonard, David Forbes, Simon Williams, John Christodoulou and Jenny Downs; poster presentation at the European Rett Syndrome conference, Maastricht, October 2013 3.Prevalence of gastrointestinal problems in children and adults with the CDKL5 disorder;  Stephanie Fehr, David Forbes, Jenny Downs, Simon Williams, John Christodoulou and Helen Leonard; poster presentation at the European Rett Syndrome conference, Maastricht, October 2013