Genetic Health (BLC)

Researching neurogenetics, and in particular, Friedreich ataxia and Huntington disease, haemochromatosis and community genetics.

The Bruce Lefroy Centre (BLC) for Genetic Health Research is a research group within the Murdoch Children's Research Institute, made possible by the generosity of the Lefroy family and friends.

The centre benefits from the synergy between the Murdoch Children's and Victorian Clinical Genetics Services, the major provider of clinical genetics services to Victoria and Tasmania.

We study genetic diseases of the nervous system including Friedreich ataxia, Parkinson's 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 and screening for conditions that can affect the health of the screened individual including haemochromatosis.

Our projects

Haemochromatosis research

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

Friedreich ataxia

Friedreich ataxia (FRDA) is the most commonly 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.

• Australian Friedreich Ataxia Stem Cell and Gene Therapy Consortium

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 several 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 annually 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 is revised every two years. FARA (USA) has partially funded this study.

A functional magnetic resonance imaging (fMRI) study addressing cognitive function in individuals with Friedreich Ataxia

The team is undertaking a four-year longitudinal study to investigate the clinical, neurocognitive, behavioural (motor/cognitive), and neurobiological profile of Friedreich ataxia. The National Health and Medical Research Council (NHMRC) funds this study.

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. The National Ataxia Foundation (USA) funds this study.

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 and several biochemical biomarkers.

Pre-symptomatic genetic testing for Friedreich ataxia

Pre-symptomatic testing of children for adult-onset genetic conditions is not recommended as it's considered that the child should be able to decide whether 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 percent 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 people 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 many 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.

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 seeks empirical data 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

Featured publications

• A family study implicates GBE1 in the etiology of autism spectrum disorder. 2021
  
  
• Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations. 2021
  
  
• Rapid Diagnosis of Spinocerebellar Ataxia 36 in a three-Generation Family Using Short-Read Whole-Genome Sequencing Data. 2020
  
  
• Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype. 2020
  
  
• 'Is it better not to know certain things?': views of women who have undergone non-invasive prenatal testing on its possible future applications. 2019