New research discovery: major cause found and a genetic test for startle disease now a possibility | Action Medical Research

New research discovery: major cause found and a genetic test for startle disease now a possibility

24 July 2012

Two recent papers in the Journal of Biological Chemistry1,2 have identified novel changes in a key gene in startle disease, a rare illness in newborn babies.

Babies with startle disease, also known as hyperekplexia, react in an exaggerated way when startled. They become rigid and unable to move, and sometimes stop breathing, which can prove fatal. Things that prompt the startle reaction include sudden, unexpected noise, movement and touch, and unexpected sight of people or objects.

Symptoms often fade by the time babies reach their first birthday, but they can continue throughout childhood and into adulthood, with some children experiencing severe breathing problems and others having learning difficulties.

With funding from children’s charity Action Medical Research, Professor Robert Harvey at UCL School of Pharmacy, London, and Professor Mark Rees and Dr Rhys Thomas at the Institute for Life Science in Swansea, are looking for more changes in genes that cause startle disease.

Around three fifths of cases remain unexplained, suggesting there are some genes for startle disease that have yet to be discovered.3,4 The research could lead to a new genetic test and more effective treatment for babies and children worldwide.

Mutations in the GlyT2 gene have been identified by Professor Harvey and team as a second major cause of the disease. Previously, mutations in the GLRA1 gene were thought to be the only major cause.

However, in the first new study1, mutations in the gene that encodes GlyT2 were found in 21 people from the UK, Australia, Canada, France, Italy, Jordan, the Netherlands, Portugal, Spain and the USA. Newborn babies with this mutation were also found to have a high rate of breathing and learning difficulties.

These mutations disrupt how GlyT2 works, leading to chemical changes at nerve junctions (synapses). This causes the symptoms seen in these newborn babies.

Professor Rees commented: “This study underpins the importance of multi-institutional research into rare paediatric disorders.” He said that the careful recruitment of those affected to the research, and clinical monitoring over 20 years, is now helping to map the disorder and develop care tailored to each person.

In a further study2 led by Dr Beatriz López-Corcuera at the Universidad Autónoma de Madrid, in collaboration with Professor Harvey’s team, the first common dominant GlyT2 mutation was identified in people from Spain and the UK. Children with the Y705C mutation had a range of symptoms, including abnormal startle response and breathing, malformed facial features, delayed motor development or intellectual disability.

Professor Harvey explained: “The Y705C mutation impairs the action of GlyT2 in a number of unique ways which may explain the diverse symptoms of individuals with this mutation.”

He concluded: “Taken together, these new findings suggest that that genetic screening for hyperekplexia should encompass both presynaptic and postsynaptic causes of disease. We would like to thank Action Medical Research and the Medical Research Council for supporting our research into this rare disorder.”

- ENDS -

Case study: Scarlett (Grimsby, Lincs)
New mothers expect to go home from hospital with their healthy baby the next day. But Scarlett Fifield’s introduction to home life took five weeks.

Seizures started when she was just three hours old and got progressively worse. “Those first few weeks with a new baby are meant to be the happiest time of your lives, but we were going through hell,” her mum Abbie says.

Scarlett was diagnosed with hyperekplexia - or startle disease - when she was two weeks old. While in hospital Scarlett had her first apnoea attack where the muscles and soft tissues in the throat collapse, obstructing breathing. “This was so very frightening to watch. Our baby went blue and shook from head to toe,” says her mum.

“Once Scarlett was diagnosed we were so happy. We had found out what was wrong and the appropriate treatment could begin so she could come home safely.”

“This startle disease research will potentially save other sick and vulnerable babies the trauma that Scarlett went through and may even save a baby’s life,” says her mum.


BBC News - 'She went blue and shook from head to toe'


1. Harvey RJ, MI Rees, Thomas RH, et al. Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease. Journal of Biological Chemistry , June 14, 2012, doi: 10.1074/jbc.M112.372094 jbc.M112.372094.
2. Lopez-Corcuera B, Harvey RJ, MI Rees, et al. A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2. Journal of Biological Chemistry, June 29, 2012, doi: 10.1074/jbc.M111.319244 jbc.M111.319244.
3. Harvey RJ, Topf M, Harvey K, Rees MI (2008) The genetics of hyperekplexia: more than startle! Trends in Genetics 24: 439-447.
4. Thomas RH, Stephenson JBP, Harvey RJ, Rees MI (2010) Hyperekplexia: Stiffness, startle and syncope. Journal of Pediatric Neurology 8: 11-14.

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Action Medical Research - the leading UK-wide medical research charity dedicated to helping babies and children - is celebrating 60 years of vital research in 2012. We’ve been funding medical breakthroughs since we began in 1952 and have spent more than £100 million on research that has helped save thousands of children’s lives and changed many more. Today, we continue to find and fund the very best medical research to help stop the suffering of babies and children caused by disease and disability. We want to make a difference in:

• tackling premature birth and treating sick and vulnerable babies
• helping children affected by disability, disabling conditions and infections
• targeting rare diseases that together severely affect many forgotten children.

But there is still so much more to do. Make 2012 a special year and help fund more life-changing research for some of the UK’s sickest babies and children.

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