PhD candidate’s research helps find cause of disorder

University of Otago Dunedin School of Medicine PhD candidate Amy Jones has helped to discover the...
University of Otago Dunedin School of Medicine PhD candidate Amy Jones has helped to discover the cause of a rare genetic condition in children. PHOTO: GERARD O’BRIEN
What started out as a study of a child with seizures and delayed development, has grown into a global study which has allowed researchers to find the cause of the unusual and incredibly rare genetic condition.

The discovery is now giving hope to families with the condition and others with related disorders.

Lead author and University of Otago Dunedin School of Medicine PhD candidate Amy Jones has been working on the research with academics from across the United States, South Africa, the United Kingdom and Europe to study the role of glutamine in brain development.

By analysing the effects genetic variants had on brain cells, they found the cause of a new rare condition — Glutamine Synthetase Stabilisation Disorder — which causes seizures and delayed development.

"Eight other individuals from around the world with disrupted brain development and severe epilepsy, had their DNA sequenced and causative genetic variants were found", she said.

"These variants were all positioned at the start of the same gene, prompting us to ask why."

Molecular experiments revealed the genetic variants had the effect of producing a stabilised enzyme that produced the small molecule glutamine in an unregulated fashion.

"Typically, genetic disorders result from genetic variants that disable a gene, so it was surprising that in this case, there was an increase in stability of the enzyme.

"In some ways, these variants can be thought to be taking the handbrake off the enzyme and letting it free-wheel in an unregulated fashion."

The children in the study were previously treated according to their symptoms, rather than from an understanding of the cause of their condition.

There are thousands of similar rare disorders, affecting 8% of the population, and defining their causes was the first step to creating specific treatments to enable more effective management of them.

She said the discovery told researchers that the production of glutamine needed to be maintained within a very tight specific range during brain development.

"Too much and too little damages the developing brain", she said.

Senior author and University of Otago Curekids paediatric genetics Professor Stephen Roberston described the study as "an excellent example of finely tuned precision medicine".

"Defining their causes is the first logical step to formulating treatments specific to them, to enable more effective management of the disorders."

Ms Jones said it was important new disorders were discovered and understood.

"This work on a rare disorder also contributes to the collective knowledge of critical components of healthy brain development."

She hoped the findings would enable other individuals who fit the clinical profile, but who had not had a diagnosis yet, to be tested for this disorder.

"It is very likely there are individuals with this disorder that aren’t yet diagnosed."