In 2005, Australian researchers first identified and described CDKL5 Deficiency Disorder, an ultra-rare genetic condition marked by frequent seizures that begin soon after birth and never let up – leading to severe disability. Almost two decades on, there’s no cure or reliable treatment, but work at Telethon Kids Institute is helping scientists across the globe inch their way towards clinical trials which could, at last, provide relief for children and families.
We call them milestones – the developmental checkpoints that signal our children are progressing as expected as they bump, tumble and strut their way through life.
Whether it’s smiling, crawling, walking, or talking, they’re big, bold milestones we mark on calendars, record in scrapbooks, or brag about on social media.
But for some kids, especially those with severe disability like that caused by the incredibly rare CDKL5 Deficiency Disorder (CDD), progress tends to be far more subtle – smaller improvements over time measured not in milestones, but ‘inchstones’, as disability advocates and researchers call them.
These less obvious changes are especially important when it comes to testing new treatments in clinical trials, providing vital clues that indicate whether the treatment is effective
or not.
But a lack of tested outcome measures attuned to the nuances of children with severe disability is hampering efforts to find answers for these children and their families.
“We can’t properly test new treatments and cures for children with severe disability until we understand how to measure those small changes, or inchstones,” said Associate Professor Jenny Downs, Head of Disability at Telethon Kids Institute.
CDKL5, in particular, is such a severe condition that when assessed using currently available measures, the children inevitably end up with scores at the low end of the range. That means we can’t tell if they’ve undergone changes or not – whether they’re getting better or worse.
Associate Professor Jenny Downs
It’s a flaw Associate Professor Downs and other researchers are working hard to fix in time for the crop of potential CDKL5 treatments expected to make it to trial stage over the next few years.
“At the moment there are a lot of potential new medicines on the horizon, including gene therapy,” she said. “We want to be absolutely ready for clinical trials of these treatments, and part of being ready for clinical trials is having the right outcome measures.”
Together with fellow Telethon Kids researchers Helen Leonard, Peter Jacoby and Jacinta Saldaris, Associate Professor Downs is working with a team at the University of Colorado, the Children’s Hospital in Philadelphia, and CDKL5 Centre of Excellence Clinics across the United States to develop a suite of more finely calibrated outcome measures.
In this project – funded by the prestigious National Institutes of Health in the US – the team is developing, refining and testing new measures for clinical severity, gross motor and hand function, communication and quality of life (using a quality-of-life tool developed by Associate Professor Downs).
“For example, sitting is often measured for periods of ten seconds, so we are testing new items that involve sitting and necessary assistance for shorter period of times,” Associate Professor Downs said.
“And when it comes to communication, there are so many ways children express who they are, what they like or want, and how they want to connect with other people, despite severe disability. So one of the real challenges for us is to develop a new communication scale that captures a greater depth of communication, rather than just focusing on milestones such as babbling or using words.
“With more thoughtful measures, we might be able to document a child who can communicate a range of different emotions and messages through different types of body language or sounds.”
Associate Professor Downs is also part of the global Inchstone Project – a consortium of patient advocacy groups and researchers focused on accelerating development of outcome measures for people with severe developmental and epileptic encephalopathy disorders such as CDKL5.
It’s so important, not just for these trials but for the daily lives of these children, that we have measures that can better reflect how these children are progressing.
Associate Professor Jenny Downs
“Families do not want medicines thrown out because we have not understood the effects on their children.
“Likewise, if a measure of more finely graded skills indicates that skills have been lost, then we can be clear that we definitely do not want that new medicine.”
Did you know?
- CDKL5 Development Disorder (CDD) is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, which provides instructions for making proteins that are essential for normal brain and neuron development. Diagnosis is via genetic testing.
- CDD causes early onset seizures (usually within the first three months of life), and can lead to severe intellectual and motor impairment, abnormal muscle tone, gastrointestinal and feeding difficulties, and sleep and respiratory problems.
- Although a genetic disorder, the mutation that causes CDD occurs randomly.
- CDD is so rare there are fewer than 40 known cases in Australia, and fewer than 1,000 known cases around the world – although there may be more cases where access to genetic testing is poor.
- The circumstances of each case vary depending on the child’s specific mutation on the CDKL5 gene – to date there are more than 200 known mutations.