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Each year, thousands of Australians are diagnosed with an inherited condition that affects their nervous system. Neurogenetic disease is an umbrella term to describe these conditions, which

are primarily caused by an alteration – or mutation – in our DNA. Affecting both the young and the elderly, these disorders are typically chronic and debilitating. In some cases, they are

degenerative and life-limiting. Neurogenetic disease has an enormous impact on Australia’s health services and economy. The direct burden on the health system from diseases of the brain was

approximately A$11 billion in 2009-2010. MONOGENETIC OR COMPLEX? Diseases with a mutation in a single gene are referred to as “monogenetic diseases”. These include Huntington’s disease,

myotonic dystrophy, Rett syndrome and fragile X syndrome. In these cases, the single-gene mutation causes certain neurons in the central and/or peripheral nervous system to develop

abnormally and/or function poorly. Some neurogenetic diseases are referred to as “complex diseases”, since multiple genes and environmental factors can contribute to the development of the

disease. These include Parkinson’s disease and Alzheimer’s disease. HOW DO THEY AFFECT THE BODY AND BRAIN? Much like a computer, the nervous system is comprised of central and peripheral

networks. The central nervous system is the central processing unit and includes the brain and spinal cord. The peripheral nervous system – made up of the sensory and motor nerve cells

(called neurons) – acts like a broadband network to relay information to and from the central nervous system. When a computer malfunctions or the broadband network is disrupted, it can have

compounding effects on the entire operating system. This leads to poor communication or intermittent service – and a lot of frustration. Similarly, when things go awry in the nervous system,

it can have devastating consequences on the entire body. It’s unclear exactly how many neurons make up the brain; estimates range from one billion to 100 billion. These neurons form an

intricate, interconnected network, which communicates using small chemicals called neurotransmitters. Precision functioning of this complex neural network is needed for all of the daily

activities we take for granted – walking, talking, thinking and feeling. Neurogenetic disease can lead to neuronal “misfiring”, irreversible degeneration of specific neurons and/or neuronal

cell death. Even though only certain types of neurons may be affected in different neurogenetic diseases, the global impact on the nervous system can often lead to similar clinical symptoms,

making diagnosis difficult. DIAGNOSIS AND MANAGEMENT A diagnosis of neurogenetic disease can mean a person will face years, potentially decades, living with a severe – and often progressive

– disability. In degenerative neurogenetic conditions, as disease develops, the ability to move freely can decrease, impacting an individual’s independence and quality of life. Often, it’s

more devastating when cognitive function also declines, which affects the ability to reason, to understand situations and remember friends, family and past events. Until the 1980s,

neurogenetic disease could be diagnosed but little could be done to prevent its onset or progression. Since then, our understanding of the genetic basis has led to more accurate diagnosis

and the ability to predict who will or won’t develop the familial disorder. Before a diagnosis, parents can often sense when something’s not quite right with their child. They may somehow

behave differently or perhaps seem “clumsier” than usual – a stumble here, tripping over there. But it takes an assessment by a clinical neurologist, and sometimes a battery of tests, to

know for sure. As the genetic mutations responsible for neurogenetic diseases are identified, diagnosis shifts from clinical assessment alone to including a blood sample that can be used in

a definitive genetic test in a diagnostic laboratory. Following diagnosis, people generally receive care from a multidisciplinary team, which may include a neurologist, physiotherapist,

occupational therapist, speech pathologist and social worker. The aim of treatment is to maximise function and minimise complications. Clinicians may prescribe various medications to treat

symptoms such as seizures, spasticity (stiffness) and depression. But none provide a cure. The patient and family may be referred for genetic counselling to identify the exact genetic basis

of the condition, learn of the risk for other family members and for those who wish to know, or genetic testing to predict whether an asymptomatic family member will go on to develop the

condition. FUTURE TREATMENT Two of the most promising areas for treatment of neurogenetic disease are pharmacological intervention and gene therapy. The development of pharmacological agents

to slow disease progression can occur in two ways: researchers can identify new applications for current medications or discover novel compounds. The diabetes drug metformin, for example,

has shown promise in reducing the risk of Parkinson’s disease. Several clinical trials have shown that the novel drug “EPI-743” is safe for human use. The US Food and Drug Administration has

recently fast-tracked this compound as a treatment for the devastating neurodegenerative disease Friedreich’s ataxia. Gene therapy is the introduction of new genetic material to cells to

replace missing or malfunctioning genes. While previously considered to be in the realms of popular science fiction (think of Rise of the Planet of the Apes), gene therapy has now reached

the clinic with promising results in neurological disease (in Parkinson’s disease, for example). For those whose lives are touched by neurogenetic disease, scientific research provides hope

for the future. In the “omics” era (genomics, epigenomics, proteomics), we have an enormous capacity to obtain large amounts of information on the many different factors that can influence

clinical outcome in neurogenetic disease. Understanding the genome, the DNA sequence, provides vital genetic information in the context of disease. We can also profile the epigenome, which

includes the chemical “tags” on DNA and how tightly it is packaged. Changes to either the genome or the epigenome can alter the proteome – the proteins in cells and tissues. Profiling such

disease-related changes can provide greater insight into disease mechanism. In parallel, there have been remarkable developments in our understanding and utilisation of biomarkers. These

unique signatures of disease can be used for early detection, predicting disease trajectory and outcome, and for monitoring novel therapies during clinical trials. This means we can now zoom

out to see the “bigger picture” and potentially use this molecular insight to develop personalised medicine, with therapies tailored to the affected individual. The hope that stem cells

will provide an effective treatment remains a long way off, with many challenges still to overcome. For now, stem cells are a critical tool in understanding neurogenetic disease and provide

a valuable resource for research.