One unlucky letter causes an infant epilepsy

Women in Science

A 20 year old mystery was solved this week with the discovery that an epilepsy that affects infants is caused by the change of a single letter in one gene. Seizures in infancy are not rare, but this familial epilepsy occurs in probably 60 families across Australia. It can also cause a movement disorder later in life.

The discovery was made by teams from the University of South Australia led by Associate Professor Leanne Dibbens and the Florey Institutes/University of Melbourne led by Professor Ingrid Scheffer. She is the 2012 Asia-Pacific L’Oréal-UNESCO For Women in Science Laureate and will receive her award in Paris in March.

Prof Scheffer first started looking at benign familial infantile epilepsy some twenty years ago. “I have now met many families where several members had seizures beginning at around 6 months and the inheritance pattern looked like it was due to a single gene. Sometimes the baby’s parents had a movement disorder that often had not been diagnosed. ” she says.

“Fortunately, while this form of epilepsy can be terrifying for both infant and parents it is self-limiting. Children grow out of it and it doesn’t affect their intelligence. However it can reappear in later childhood or adolescence as a movement disorder. When you try to move a limb, it has a ‘mind of its own’ and moves in an odd direction. For one of my patients this often happens when the light changes at a pedestrian crossing and he goes to cross the road.”

“Another of my patients is a dancer. Just before she starts to dance she has learnt to prepare her body by making a first movement then waiting for a moment for the abnormal movement and sensation to pass.”

Prof Scheffer and colleagues have been keen to identify the cause of the condition.

15 years ago the mutation was pinned down to chromosome 16 but neither they, nor many other researchers worldwide could identify the gene until last year.

A Chinese team looking at a movement disorder found that it was due to a mutation which adds just one more code (C) to a twelve code sequence on chromosome 16 affecting a gene called PRRT2. Their publication (Chen et al, Nature Genetics 2011) gave Scheffer and her colleagues the clue they needed.

“We went straight to the families we know with the condition,” she says. “We found a mutation in the PRRT2 gene in 19 of the 23 families, and 15 had the exact same mutation with the extra C despite being of many different nationalities. This suggests it is a mutation ‘hotspot’.”

“Now we’ve identified the mutation we can screen infants and predict the risk of seizures. We know that this gene makes a protein called proline rich transmembrane protein 2. That means we can hone in on what’s happening biochemically and start to develop targeted treatments for the condition.”

The research was published on Friday, 13 January 2012 in the American Journal of Human Genetics.

Ingrid is one of five L’Oréal-UNESCO For Women in Science Laureate for 2012. Each will receive US$100,000 in recognition of her contribution to the advancement of science at the Awards Ceremony on 22 March 2012 at the UNESCO Headquarters in Paris.


About Professor Ingrid Scheffer:

About Associate Professor Leanne Dibbens

University of Melbourne media release:


PRRT2 mutations cause Benign Familial Infantile Epilepsy (BFIE) and Infantile Convulsions with Choreoathetosis (ICCA) syndrome

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder of infancy with autosomal dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes Proline Rich Transmembrane protein 2, in fourteen of seventeen families (82%) with BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families with Infantile Convulsions and Choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 causes both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy both in terms of age of expression (infantile versus later childhood) and in anatomical substrate (cortex versus basal ganglia).

Authors and affiliations

Sarah E. Heron,1 Bronwyn E. Grinton,2 Sara Kivity,3 Zaid Afawi,4 Sameer M. Zuberi,5 James N. Hughes,6 Clair Pridmore,7 Bree L. Hodgson,1 Xenia Iona,1 Lynette G. Sadleir,8 James Pelekanos,2,9 Eric Herlenius,10 Hadassa Goldberg-Stern,3 Haim Bassan,11 Eric Haan,12 Amos D. Korczyn,4 Alison E. Gardner,13 Mark A. Corbett,13 Jozef Gécz,6,13,14 Paul Q. Thomas,6 John C. Mulley,6,14,15 Samuel F. Berkovic,2* Ingrid E. Scheffer,2,16,17 Leanne M. Dibbens.1,17

1 Epilepsy Research Program, School of Pharmacy and Medical Sciences, University

of South Australia, Adelaide, South Australia 5000, Australia.

2 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health,

Heidelberg, Victoria 3084 Australia.

3 Schneider Children’s Medical Center of Israel, Petach Tikvah 49202, Israel.

4 Tel-Aviv University, Tel-Aviv 69978, Israel.

5 Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow G3 8SJ, United Kingdom.

6 School of Molecular and Biomedical Science, the University of Adelaide, Adelaide, South

Australia 5005, Australia.

7 Department of Neurology, Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia.

8 Department of Paediatrics, University of Otago, Wellington 6242, New Zealand.

9 Academic Discipline of Paediatrics and Child Health, The University of Queensland, Brisbane St Lucia, Queensland 4072, Australia.

10 Neonatal Research Unit, Department of Women’s and Children’s Health, Astrid Lindgren Children’s Hospital, Karolinska Institutet, Stockholm SE-171 77, Sweden.

11 Pediatric Neurology and Development Unit, Dana Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel.

12 South Australian Clinical Genetics Service, SA Pathology at Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia.

13 Neurogenetics Program, SA Pathology at Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia.

14 School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia 5005, Australia.

15 Department of Genetic Medicine, SA Pathology at Women’s and Children’s Hospital, North Adelaide, South Australia 5006, Australia.

16 Florey Neuroscience Institutes and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, Victoria 3052, Australia.

17 These authors contributed equally to this work