What did the project achieve?
“This study has helped to improve our understanding of the genetic causes of Landau Kleffner syndrome, which we hope will ultimately lead to the development of effective new treatments,” says Dr Adeline Ngoh of the UCL Great Ormond Street Institute of Child Health. “Our results have also already enabled us to give more accurate information about the expected long-term outcomes to some of our patients and their families, enabling early access to the support they need to reach their full potential.”
Landau Kleffner syndrome (LKS) is a very rare brain condition that causes children to lose their ability to talk and understand speech. Many will also experience seizures, learning, movement and behaviour problems. A child’s symptoms usually start when they are between three and six years old – and can impact hugely on their quality of life.
Although the underlying cause of LKS is unknown in most cases, faults in a gene called GRIN2A have been identified in some children with the syndrome. This gene carries the instructions to make a protein that is responsible for transmitting electrical signals in the brain and has an important role in learning and memory.
The team identified gene faults in the GRIN2A gene in seven out of 45 patients with LKS. Most of these would be expected to lead to reduced levels of the protein product in cells. Two changes are likely to lead to structural alterations, with this study demonstrating that these reduce the ability of the protein to transmit electrical signals.
“As a result of this study, these seven children now have an accurate diagnosis, which will help support genetic counselling for their families,” says Dr Ngoh.
“Through our laboratory experiments, we established that some of these faulty proteins are not transported to the cell surface. We also showed that cells with these gene faults don’t have any detectable electrical signals – and so aren’t working as they should.”
The study also provided the opportunity to look at the clinical features and long-term outcomes of 90 LKS patients treated over the last 30 years, which is one of the largest groups reported worldwide.
“Although around half of people with LKS can lead independent lives as adults, we discovered that there are certain indicators – including the age that children start to lose their speech, a below-average IQ, and subtle movement symptoms – that are linked with worse long-term outcomes in adulthood,” says Dr Ngoh. “This means we can help ensure that the children who are likely to have poorer outcomes gain access to additional support as soon as possible.”
This research was completed on
Research Training Fellowship*: Dr Ngoh
Children with a rare brain condition called Landau Kleffner syndrome (LKS) – which is estimated to affect up to one in every 300,000 children – may one day benefit from research by Dr Adeline Ngoh of University College London’s Institute of Child Health.1 When they’re between three and nine years old, children with this condition lose the ability to talk and understand speech, which can have devastating consequences. Many also experience seizures. Dr Ngoh is investigating what causes LKS. She hopes to give children and their families a better understanding of why they’ve been affected. Ultimately, her work may also lead to the development of new treatments.
How are children’s lives affected now?
“Children with LKS develop normally for the first few years of life, but then lose their ability to understand speech and to speak meaningfully,” says Dr Ngoh. “Many children also start to have seizures.”
“Children with LKS no longer understand what is being said to them, and other people can’t understand what the children are trying to say, as their speech does not make sense,” continues Dr Ngoh. “Even everyday sounds such as a telephone ringing may lose their meaning.”
“Sadly, children with LKS can lose confidence and become frustrated or withdrawn,” says Dr Ngoh. “Many develop behavioural problems, and some develop symptoms within the autistic spectrum. Children’s education and social interactions can be severely affected.”
“Despite the disability that LKS causes, not much is known about the condition”, says Dr Ngoh. “Unfortunately, families often have to live with many unanswered questions, there’s a lack of treatment options and long-term disability is common.”
How could this research help?
“I’m investigating the genetic causes of LKS,” says Dr Ngoh. Little is known about this at the moment.
“At Great Ormond Street hospital, we have treated over 70 children with LKS,” says Dr Ngoh. “We plan to find out how many of our patients have changes, or mutations, in a gene called GRIN2A, which has already been linked to the condition in a minority of cases.2 We are also looking for other genetic changes that might be linked to the condition. Identifying disease-causing genes would provide families with definitive answers when they ask ‘Why has our child developed LKS?’ and ‘What are our chances of having more children with the condition?’”
“We are also investigating how changes in the GRIN2A gene – and any other genes we identify – might lead to children’s symptoms,” says Dr Ngoh. “Improving our understanding of the disease processes involved may one day lead to the development of better treatments.”
1. Kaga M, et al. Epidemiological study of Landau Kleffner syndrome (LKS) in Japan. Brain Dev 2014; 36(4): 284-6.
2. Carvill GL et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013; 45:1061-6. doi: 10.1038/ng.2726. Epub 2013 Aug 11.
*Research Training Fellowships:
Each year, Action Medical Research awards these prestigious grants to help the brightest and best doctors and scientists develop their career in medical research.
|Dr SF Adeline Ngoh MBBS MRCPCH
|Dr Manju A Kurian MBBChir MRCPCH PhDProfessor Dimitri M Kullmann BA(Hons) DPhil MBBS FRCP MRCPProfessor Robert J Harvey BSc (Hons) PhD
|Developmental Neurosciences, University College London, Institute of Child Health
|Project Location Other
|Clinical and Experimental Epilepsy, Institute of Neurology, University College LondonDepartment of Pharmacology, School of Pharmacy, University College London
|9 February 2015
|Project start date
|2 March 2016
|Project end date
|1 April 2018