May 2012

Scientists at UCD Develop New Diagnostic Test for Rare Liver Disorder

Thu, 24 May 12 09:00

Liver BiopsyDr. Sally-Ann Lynch, Consultant Geneticist at Our Lady’s Children’s Hospital Crumlin and a member of the UCD research group, said the findings will have a positive impact for a small but vulnerable group of children.

“This disorder, known as infantile hepatopathy affects approximately 1 in 2,500 live births and can be life-threatening. Children who present with symptoms of this disorder are usually very sick, and the use of biopsies is a painful, stressful and sometimes risky procedure. This new test is a non-invasive diagnostic tool, and an excellent example of research translating directly to a clinical setting,” said Dr. Lynch.

Using a combination of genetic analysis techniques, the research team identified a mutation in the LARS gene - an enzyme involved in generating essential cell proteins - that causes rare infantile liver disease. First author on the study Dr. Jillian Casey from UCD School of Medicine said that while there is currently no cure for infantile hepatopathy, this discovery is an encouraging step towards the development of more effective forms of treatment.

“To develop better therapeutic treatments we first need to understand the disease mechanism. The symptoms of this infantile liver disorder include anaemia, developmental delay and seizures. When we see multi-system symptoms of this nature, it suggests a dysfunction in the mitochondrion, the so-called ‘power house’ of the cell. Our research rules that out, and identifies instead a mutation in the protein-making LARS gene as the primary cause. That knowledge will inform the future development of how we treat patients,” said Dr. Casey.

These ancient protein-making molecules have been implicated in a number of human disorders including neurological diseases, muscle disorders and cancers. This is the first time that one of these molecules has been associated with a liver disease.

This study is part of a broader initiative, led by Dr. Sean Ennis from UCD School of Medicine, the goal of which is to discover the genetic causes of rare diseases and advance the progression towards diagnostics, prevention and treatment.

Scientific Journal Article:

Title: “Identification of a mutation in LARS as a novel cause of infantile hepatopathy”

Publication:  Molecular Genetics and Metabolism May 2012.

Symptoms of Infantile Hepatopathy

Symptoms typically develop in infancy and include failure to thrive, poor feeding, vomiting and jaundice. It is a life-long relapsing remitting disorder, which becomes highly symptomatic when the body experiences even mild physiological stress such as flu.

Genetic Analysis Technique Explained

Homozygosity mapping: A technique that identifies segments of DNA - inherited from both parents - that is shared by all patients experiencing a particular disorder, but not shared by unaffected family members.

Exome Sequencing: An efficient strategy to selectively sequence the protein-coding regions in the genome in one experiment. The protein-coding regions only represent 1-1.5% of the total genome sequence, but 85% of disease-causing mutations are located in these regions.

Research Group:

Jillian Casey (University College Dublin and National Children's Research Centre), Ellen Crushell (Temple Street Children's University Hospital), SallyAnn Lynch (Temple Street Children's University Hospital and Our Lady's Children's Hospital Crumlin), Billy Bourke (University College Dublin and Our Lady's Children's Hospital Crumlin), Paul McGettigan (University College Dublin), Niamh Lynam-Lennon (Trinity College Dublin), Michael McDermott (Institute of Molecular Medicine, Trinity College Dublin), Regina Regan (University College Dublin), Judith Conroy (University College Dublin), Jacinta O'Sullivan (Institute of Molecular Medicine, Trinity College Dublin), Sean Ennis (University College Dublin and National Centre for Medical Genetics).

Funders:

Children’s Fund for Health, Temple Street Children’s University Hospital, Dublin, Ireland, EMBARK (Irish Research Council for Science, Engineering and Technology), National Children’s Research Centre (Our Lady’s Children’s Hospital, Ireland) and the Health Research Board (Ireland).