Genetic Health Research (BLC)

The Bruce Lefroy Centre for Genetic Health Research is a research group within the Murdoch Childrens Research Institute, made possible by the generosity of the Lefroy family and friends. The centre benefits from the synergy between the Murdoch Childrens and Victorian Clinical Genetics Services, the major provider of clinical genetics services to Victoria and Tasmania.

The Genetic Health Research team studies genetic diseases of the nervous system including Friedreich ataxia, Parkinson disease, autism, brain malformations, dystonia and Huntington disease. In addition it conducts research into genetic screening. This includes screening for reproductive risks such as cystic fibrosis, Tay Sachs disease and thalassaemia as well as screening for conditions that can affect the health of the screened individual including haemochromatosis.

The main research focus of the Genetic Health Research Group is neurogenetics, and in particular, Friedreich ataxia and Huntington disease, haemochromatosis and community genetics.

Group Leaders: 
Group Members: 
Dr Nicole Cousens
Role: 
Honorary Fellow
Dr Lianne Ioannou
Role: 
Honorary Fellow
Dr Cara Mand
Role: 
Honorary Fellow
Sarah Milne
Role: 
PhD Student
Hwee Ong
Role: 
PhD Student
Dr Sim Yee Ong
Role: 
PhD Student
Geneieve Tai
Role: 
Research Assistant
Dr Kaye Trembath
Role: 
Research Assistant
Dr Adam Vogel
Role: 
Research Officer
Michelle Wolthuizen
Role: 
Project Coordinator
Dr Eppie Yiu
Role: 
Post Doctoral Fellow

Friedreich ataxia

Friedreich ataxia (FRDA) is the most common inherited ataxia and usually begins in childhood. It causes progressive damage to the nervous system and wide-ranging symptoms, including unsteadiness, ultimately resulting in affected individuals requiring a wheelchair. In most individuals, FRDA also affects the heart (cardiomyopathy). The lifespan of affected individuals is markedly reduced. In FRDA, the altered gene is called FXN and this instructs cells to make a protein called frataxin. A DNA expansion in FXN results in lower levels of frataxin protein in people with FRDA compared to unaffected individuals.

Friedreich ataxia clinical studies

Study of resveratrol as a treatment for Friedreich ataxia
The team has shown that resveratrol increases frataxin levels in vitro and in vivo. In the study, people treated with high dose resveratrol had a reduction in oxidative stress markers and improvement in a number of clinical measures.  The group is now working toward a placebo-controlled study.

Study of the impact of Friedreich ataxia on the nervous system, heart and quality of life
The team studies people with Friedreich ataxia on an annual basis to understand the natural history of the disorder on the various body systems affected and perceived quality of life. The group is also the Australasian site for a major international Friedreich ataxia database, the Collaborative Clinical Research Network in Friedreich's Ataxia (USA).

Development of Clinical Management Guidelines for Friedreich ataxia
The researchers have led an international effort to produce clinical management guidelines for Friedreich ataxia.  These are soon to be published and will be revised every two years. This study has been partially funded by FARA (USA).

A functional magnetic resonance imaging (fMRI) study addressing cognitive function in individuals with Freidreich Ataxia
The team is undertaking a four-year longitudinal study to investigate the clinical, neurocognitive, behavioural (motor/cognitive), and neurobiological profile of Friedreich ataxia. This study is funded by the National Health and Medical Research Council (NHMRC).
The team is undertaking a four-year longitudinal study to investigate the clinical, neurocognitive, behavioural (motor/cognitive), and neurobiological profile of Friedreich ataxia. This study is funded by the National Health and Medical Research Council (NHMRC).

The effect of cerebellar abnormality on hearing in individuals with Friedreich ataxia and spinocerebellar ataxia
The group is using neuroimaging techniques to explore the role of cerebellar pathology in the hearing impairment associated with Friedreich ataxia and spinocerebellar ataxia. This study is funded by the National Ataxia Foundation (USA).

The impact of eye movement abnormalities in Friedreich ataxia
The researchers are characterising the neurobehavioural profile of individuals with Friedreich ataxia during an ocular motor task which specifically invokes response inhibition and task switching. In addition, they are exploring the structural and functional neural changes that underlie any impairment in people with FRDA when performing these tasks in order to establish if ocular motor tasks are effective biomarkers of disease severity and progression. This will be useful in establishing the efficacy of therapeutic intervention.

Evaluation of upper limb function in people with Friedreich ataxia
The team is exploring factors such as spasticity and weakness which contribute to reduced upper limb function in people with Friedreich ataxia. This information is critical to designing appropriate intervention aimed at improving function.

Examination of lower limb spasticity in Friedreich ataxia
This cross-sectional study seeks to examine lower limb spasticity in Friedreich ataxia in order to offer new insight as to the best approach and timing of spasticity management.

Does physical rehabilitation maintain or improve the functional independence in people with Friedreich ataxia- a randomised controlled trial
This study will evaluate the efficacy and timing of outpatient physical rehabilitation in maintaining or improving the functional independence of people with FRDA. Given there is currently no intervention that can halt the progression of FRDA, exploring interventions to maintain function is critical to patient care.

Swallowing in Friedreich ataxia
The team is investigating the incidence and nature of swallowing disorders (dysphagia) in people with Friedreich ataxia, as well as the relationship between dysphagia and progression of the condition. Findings from this study will elucidate the natural history of dysphagia in Friedreich ataxia, and inform management and therapeutic intervention strategies. This project is measuring the effect of Friedreich ataxia on swallowing over a two-year period. Dysphagia is debilitating, contributing to both morbidity and mortality, hence this project is essential to understand the natural course of swallowing difficulties in people with Friedreich ataxia in order to improve their quality of life.

A cardiac MRI study in Friedreich ataxia
This study, funded by the Friedreich Ataxia Research Alliance (USA), is a collaboration with the Philadelphia Friedreich ataxia group.  Individuals will have cardiac MRI and the various parameters that are measured will be correlated with other clinical features of Friedreich ataxia as well as a number of biochemical biomarkers.

Pre-symptomatic genetic testing for Friedreich ataxia
Pre-symptomatic testing of children for adult onset genetic conditions is generally not recommended as it is considered that the child should be able to decide whether or not to have testing when they reach maturity to do so.  Friedreich ataxia can develop in childhood through to adulthood so this issue is more complex in this condition compared to conditions that always have onset in adulthood.  The group is exploring these issues through interviews with young people at risk of Friedreich ataxia, parents of children with Friedreich ataxia and health professionals.

Social function, psychological health and personality in individuals with Friedreich ataxia
While some research has been done into the prevalence of mood disorders in people with Friedreich ataxia, little is understood about personality and social function. There is extremely limited information available on how social function may be impacted by this condition. This study will investigate social skills, personality and psychological health of adults with Friedreich ataxia. The relationship between these outcomes and factors such as gender, age at onset, illness severity, comorbid conditions, and genetic mutations will be examined.

Friedreich ataxia laboratory research

Bone marrow transplant and lentiviral gene therapy for Friedreich ataxia
This National Health and Medical Research Council (NHMRC)-funded project aims to examine bone marrow transplantation and inactivated viruses (called lentiviral vectors) as ‘Trojan horses’ to deliver frataxin to different disease models of Friedreich ataxia (figure 2). The overall goal of this project is to develop safe and effective cell and gene therapies for Friedreich ataxia. Ultimately, restoring function to even a small percentage of cells could positively affect the surrounding microenvironment and improve overall outcome.

Epigenetic studies in Friedreich ataxia
This project investigates the epigenetic changes in FRDA and other repeat-associated neurological diseases and will provide insight into the role epigenetic disruption plays in modulating disease outcome. It could also identify novel biomarkers for predicting and monitoring disease progression.

The impact of FXN point mutations
This project aims to examine the impact of disease-causing gene mutations on the function of frataxin and the clinical outcome that results.

Huntington disease clinical studies

Predictive testing for Huntington disease – why do people choose to have or not to have genetic testing?
Only about 15 per cent of people at risk of Huntington disease and similar genetic disorders choose to have predictive testing.  Little is known about why 85 per cent choose not to have predictive testing.  This questionnaire study will examine the reasons why people do and do not have predictive testing and explore psychosocial differences between the two groups.

What are the needs of young people who have family members affected by Huntington disease?
Young people at risk of Huntington disease face numerous challenges, both from being at risk of the condition and having affected family members.  This questionnaire study will explore what challenges are faced by such young people and identify where interventions could make a positive difference.

Does premorbid activity affect age of onset of Huntington disease?
The team has previously found that leading a passive lifestyle contributes to an earlier age of onset of Huntington disease. This study, through the European Huntington Disease Network, is studying the impact of lifestyle on clinical features of this disorder using the same questionnaire as the original study.

Haemochromatosis research

Haemochromatosis causes the body to absorb more iron than usual from food, which can eventually lead to organ damange.

Mi-Iron - Moderately increased iron - is reducing iron overload necessary?
This NHMRC-funded project is examining whether treatment of moderate iron overload in HFE-related hereditary haemochromatosis is necessary. Individuals who are HFE C282Y homozygous with moderate iron overload (serum ferritin between 300 and 1000µg/L) are randomised to have their iron levels reduced or to have sham treatment. Questionnaires and objective markers of liver wellbeing and oxidative stress are administered prior to and following treatment. The outcomes have the potential to have major impacts on the diagnosis and treatment of this common disorder.  More information can be found at www.mi-iron.com.au.

Community genetic and ethics research

Community genetics research
This research examines the impact of screening for carrier status of autosomal recessive and X-linked recessive conditions.  This work is of great importance as screening becomes available for multiple conditions for less and less cost.

Ethics research
Our team examines ethical issues in clinical genetics and obtains empirical data to try to resolve appropriate clinical pathways. Examples of areas that this work is examining include predictive testing in minors and selection for a genetic condition such as deafness.

Funding: 
  • National Health and Medical Research Council
  • Friedreich Ataxia Research Alliance (USA) – Bronya Keats International Research Collaboration Award
  • National Ataxia Foundation (USA)
  • Psychology-Monash Biomedical Imaging (Monash University)
  • European Huntington Disease Network
Collaborations: 

Friedreich ataxia clinical research

  • Andrew Churchyard (Monash Health)
  • Roger Peverill (Monash Heart)
  • Nellie Georgiou Karistianis (Monash University)
  • Gary Rance (University of Melbourne)
  • Grace Yoon (Hospital for Sick Children, Toronto)
  • David Lynch (CHOP)
  • Kimberley Lin (CHOP)
  • Megan Keage (University of Melbourne)
  • Darren Hocking (Latrobe University)
  • Gary Egan (Monash University)
  • Joanne Fielding (Monash University)
  • Phillip Cremer (Royal North Shore Hospital)
  • Owen White (Royal Melbourne Hospital)
  • Elsdon Storey (Monash University)
  • Massimo Pandolfo (Université Libre de Bruxelles)
  • Jorg Schulz (University Hospital Aachen)
  • George Wilmot (Emory University)
  • Susan Perlman (UCLA)
  • Kevin Croft (University of Western Australia)
  • Barbara Scheiber-Mojdehkar (Medical University of Vienna)
  • Monique Ryan (RCH).

Friedreich ataxia laboratory research

  • Beverly Davidson (University of Iowa)
  • Arthur Nienhuis (St. Jude Children’s Research Hospital)
  • Alice Pebay (Centre for Eye Research Australia)
  • Mirella Dottori (Centre for Neural Engineering)
  • Ian Alexander (Westmead Childrens Hospital)
  • David Thorburn (MCRI)
  • Matthew Burton (MCRI)
  • Dong Zhang (MCRI)
  • Don Newgreen (MCRI)
  • Christopher Gomez (University of Chicago)
  • FRDA Clinical Research Network USA
  • Clinical Research Collaborative in Spinocerebellar Ataxia
  • Elsdon Storey (Monash University)
  • John Hopper (University of Melbourne)
  • Minh Bui (University of Melbourne)
  • Charles Galea (Monash Institute of Pharmaceutical Sciences)
  • Andrew Webb (WEHI)
  • Anthony Hannan (Florey Neurosciences Institute)
  • Marnie Blewitt (WEHI)
  • Richard Saffery (MCRI)
  • David Lynch (CHOP)

Huntington disease research

  • Andrew Churchyard (Monash Health)
  • Lisette Curnow (VCGS)
  • Aad Tibben (Leiden University)
  • Rhona Macleod (St Mary’s Hospital, Manchester)
  • Sharon Lewis (MCRI).

Haemochromatosis research

  • Lawrie Powell (QIMR)
  • John Olynyk (Fremantle Hospital)
  • Amanda Nicoll (Royal Melbourne Hospital)
  • Lyle Gurrin (University of Melbourne)
  • Darrell Crawford (University of Queensland)
  • Katie Allen (MCRI)
  • Greg Anderson (QIMR)
  • Grant Ramm (QIMR)
  • Erica Wood (Monash University)

Community genetic and ethics research

  • John Massie (RCH)
  • Julian Savulescu (Oxford University)
  • Loane Skene (University of Melbourne)
  • Clara Gaff (University of Melbourne)
  • Sylvia Metcalfe (MCRI)
  • Sharon Lewis (MCRI)
  • Jane Halliday (MCRI)
  • Jan Hodgson (MCRI).