Unravelling Disease Mechanisms Causing Seizures and Cognitive Dysfunction in Early Infantile Epileptic Encephalopathy (EIEE)

Many epilepsy disorders present in babies in the first year of life and sadly, a significant proportion of these infants have very frequent seizures (which do not respond to medication), make extremely poor developmental progress and have a high risk of premature death. In around half of these patients, a cause cannot be identified and it is likely that many will have an underlying genetic cause where a faulty gene is responsible for the baby's fits. I have recently discovered a new "faulty gene" in some of these children. This project will improve our ability to provide answers for some of these families with children with severe fits. It will also lead to a better understanding of the disease mechanisms that lead to epilepsy.

I plan to investigate a newly discovered gene in children with severe early onset seizures and to answer the following questions:
1. How common are mutations in this gene in patients with early epilepsy?
2. How do faults in this gene cause epilepsy?
3. How do faults in this gene impact learning, memory and behaviour, which are all important problems for children with early onset epilepsy?

Results of the genetic testing will be available for families in the short term. Some of the mechanisms contributing to this type of early onset epilepsy will be elucidated in the medium term. In the longer term, we plan use this knowledge to try and find new drugs and other treatments to try and improve the seizures and long term outcome for these patients.

The early infantile epileptic encephalopathy (EIEE) syndromes are characterised by severe drug-resistant seizures, a poor neurodevelopmental outcome and increased mortality. Several age-dependent electroclinical syndromes are described, including Migrating Partial Seizures in Infancy (MPSI). The disease basis of these disorders is poorly understood.

I have recently identified a novel cause of MPSI due to mutations in an ion transporter gene, MPSI-X. The residues mutated in MPSI-X are highly conserved throughout species and the mutations are not present in ethnically-matched controls. Both the drosophila and mouse knock-out models display an epilepsy phenotype. I hypothesise that in infants with mutations in MPSI-X, there is loss of transporter function, leading to disrupted ion homeostasis, loss of GABA-mediated inhibition and epileptogenesis.

In my proposed fellowship, I will investigate (i) the spectrum of infantile epilepsies caused by MPSI-X (ii) how mutations in MPSI-X cause epilepsy and its associated co-morbidities.

A variety of laboratory techniques including immunoblotting, immunofluorescence, confocal microscopy and a functional transporter assay will be used to study the effects of identified mutations in a cellular disease model. Using an already established knock-out mouse model, in vivo electrophysiological systems and behavioural approaches will be used to phenotype and study the mechanisms of cognitive impairments in MPSI-X knock-out mice.

Academic Impact:
This study aims to investigate the functional effects of mutations in an ion transporter gene. This gene is already known to be important in modulating early brain neurotransmitter responses and neurodevelopment and its role has been studied in chronic pain syndromes and spinal cord injury. However this is the first example of human disease caused by a mutation in this gene and my functional work is therefore likely to have implications for both epilepsy research and also a range of neurological conditions outside the early onset epilepsies.

Industry:
Once I have established the FLIPR thallium-based assay, I am aiming to work towards using this for high throughput drug screening. Identification of compounds that ameliorate abnormal MPSI-X function may have future impact on development of anti-epileptic agents. This approach may lead to collaboration with the private sector/pharmaceutical industry to develop novel drug therapies in the future.

Impact for the patients/families:
The identification of a genetic cause for MPSI will improve diagnosis for patients and may avert unnecessary and invasive investigations. Once work on this novel gene has been peer-reviewed and published, we will add MPSI-X to the growing number of genes tested diagnostically on the GOSH epilepsy multiple gene panel. The psychological benefit for parents and the wider family of receiving an explanation for the difficulties of a severely disabled child should not be under-estimated. In addition, families will have access to genetic counselling which can assist prenatal counselling, prenatal testing and potentially pre-implantation diagnosis.

Impact for wider society:
The EIEE syndromes including MPSI carry a high disease burden and mortality, with high economic costs to society in terms of the care of children with disability and impact on the ability of carers to remain in employment. My ultimate aim is to improve diagnosis, treatment and outcome in these disorders which have significant economic and societal impact.