The Mitochondrial Disease Report: Progress Towards Overcoming Life’s Energy Crisis The Mitochondrial Disease Report: Progress Towards Overcoming Life’s Energy Crisis

Copyright © 2014 Australian Mitochondrial Disease Foundation Limited. All rights reserved. &RQWHQWV

Foreword 1 Professor Ed Byrne AO

Championing the ‘Mito Fight’ to Overcome Life’s Energy Crisis 3 Dr Doug Lingard

The Call to Action 5

Mitochondrial Disease - The Facts 7

Improving the diagnosis of mitochondrial disease patients: the role of the GP 9 Professor Carolyn Sue

A GP and mother’s plea: Doctors must face up to mito for patients’ sakes 13 Dr Karen Crawley

Technology steps up to aid mito diagnosis 17 Professor David Thorburn

Surviving the diagnostic odyssey of mito 21 Mito families’ stories

Approaches to mitochondrial therapy: the next frontier 25 Professor John Christodoulou AM

Reading the blueprint of the mitochondrial genome 29 Professor Aleksandra Filipovska

Towards prevention of mitochondrial DNA disease 31 Professor Jus St John

Seeking every parent’s wish: a healthy baby 35 Mito families’ stories

Glossary of Terms 39

Further Reading 43

Above: Annaliese Hodge, Joanne Edwards & Patrick Edwards Cover Photo: Jack White 2 mitochondrial genome revealed mutations has advanced because of cooperation in a number of areas that underpinned very between clinicians and basic scientists and as speci¿c neurological diseases. At the same that approach continues further advances will )RUHZRUG time it became increasingly apparent that a undoubtedly occur. number of genetic mitochondrial disorders Professor Ed Byrne AO related to defects in the nuclear genome and This report is a very important document that led to a search over some years which portraying the very personal human impact medicine and in my work in London I had uncovered an increasing family of nuclear of these debilitating and often life threating the fortune to do my doctorate with John gene mutations underpinning mitochondrial conditions on children, adults and their Morgan-Hughes who was one of the key disease. As this story has evolved an families. It is one of the most important ¿gures in the earlier elucidation of this area increasingly wide range of medical disorders, documents in this area to be produced in of human illness. At that time the possibility many but not all of them neurological, have Australia and I commend the Australian of mitochondrial dysfunction had only been been identi¿ed relating to genetic problems Mitochondrial Disease Foundation for their identi¿ed in a handful of very rare cases and in either the intra-mitochondrial or the nuclear work in developing this landmark initiative. there was no understanding that this was genome where mitochondrial protein encoding an important area of human illness. Early genes are affected. Yours sincerely, understanding evolved from the development of muscle histo chemistry as a way of probing This work is very important as relatively rare mitochondrial function in muscle biopsies. conditions continue to be identi¿ed and in This was followed by the application of simple addition it has become increasingly evident technologies looking at biochemical studies that mitochondrial dysfunction could play a Professor Ed Byrne AO again on muscle biopsies and on mitochondria role in some very common conditions. In isolated from muscle biopsy using oxygen our own laboratory years ago we made sensitive electrodes and similar technologies. signi¿cant observations about a decrease This resulted in delineation of a series of in mitochondrial respiratory chain ef¿ciency Professor Ed Byrne is a pioneering biochemically identi¿ed defects in the human in human ageing and with others were able neuroscientist who has combined an respiratory chain. to show mitochondrial dysfunction as a outstanding clinical career with an extensive contribution, if not the main cause in some contribution to basic neurological research neurodegenerative conditions including in Australia and the United Kingdom. He Alzheimer’s disease. In these conditions it is recognised worldwide for research into It has become is likely that non-mitochondrial factors played disorders in the mitochondrial DNA and played increasingly evident a major role but mitochondrial inef¿ciency a role in the discovery of mitochondrial links to

that mitochondrial possibly related to ageing may also contribute. ageing. He was a founding director in 1993 of dysfunction could play a the Melbourne Neuromuscular Research Unit This report is one of role in some very Treatments for mitochondrial respiratory chain and the Centre for Neuroscience. Professor common conditions. the most important disorders are getting ever closer with research “ Byrne is President and Vice-Chancellor of around the world continuing in these important documents in this area to Melbourne’s Monash University and patron areas. Australia has made a particular of the Australian Mitochondrial Disease be produced in Australia contribution in mitochondrial medicine because Foundation. of the predominance of Australian research The discovery of the polymerase chain in early years in basic science related to In the course of my career as a neurologist reaction opened up the modern DNA story mitochondria and the presence of a number of “ and researcher I have seen major advances and mitochondria, because of the relatively groups in Australia that have been working on in our understanding of this important aspect small size of their intra-mitochondrial mitochondrial dysfunction for many decades. of medicine. As a young neurologist, I was genome, represented a great opportunity This area, as much or more than any other, at the birth in some ways of mitochondrial for early genetic studies. Sequencing of the 4 However, there is much to be done and gene mutations responsible for the many progress is at times frustratingly slow. forms of mitochondrial disease, and to educate medical practitioners. &KDPSLRQLQJWKH±0LWR)LJKWWR2YHUFRPH The human mitochondrial genome was ¿rst ‡ Federal and state governments need to sequenced in the 1970s and the Cambridge work together to facilitate and fund faster, /LIHV(QHUJ\&ULVLV Reference Sequence for human mtDNA less expensive diagnoses; this is an was ¿rst published in 191. This led on to Dr Doug Lingard important ¿rst step along the path to better the initiation of the human nuclear genome care and support for all Australians with information available about mito, no support project which was completed in 2003 at a mito, no matter where they live and what network, and almost total lack of awareness cost of around $3 billion. Since then the their ¿nancial circumstances. among GPs; the RACGP ‘bible’ Principles of tangible bene¿ts in the eyes of many have ‡ GPs must continue to become better General Practice contained no mention of mito been surprisingly few. However, the cost and informed and include mito in their at all. Consequently many people, particularly time of DNA sequencing have come down curriculum to facilitate early diagnosis and those with milder forms, were (and still are) considerably, and genomic data have steadily appropriate healthcare. The AMDF urges undiagnosed, misdiagnosed, unknowingly accumulated along with our knowledge and the RACGP to update texts to ensure at risk of passing the disease on to their understanding of how cells work and fail. future medical practitioners are informed children, labelled hypochondriacs or told it was Such an accumulation lays the foundation on the latest developments.

psychosomatic, often for years. for advances in human health, leading a ‡ The AMDF calls on the Australian number of experts to express the feeling government to reconsider its position We now know that mito is too common to be that major breakthroughs could be imminent. against the human embryo research called a rare disease – at least one person in Unfortunately, there are as yet no targeted necessary to develop mitochondrial 200 is at risk – yet paradoxically it was, and treatments for mito, although a few in the replacement techniques. In so doing it can still is, not suf¿ciently well known to attract the pipeline look promising. assist women with maternally inheritable major funding, sponsorship or public support mitochondrial disease to have children

enjoyed by less prevalent conditions such as In publishing this report, the AMDF aims to and subsequent descendants free of this Dr Doug Lingard is chairman and a motor neurone disease or muscular dystrophy. provide a credible resource and reference debilitating and potentially fatal condition. co-founding director of the Australian document, and to promote discussion and Mitochondrial Disease Foundation. He It was in this context that the Australian debate on issues related to mitochondrial The AMDF has made signi¿cant progress in and his wife Margie are the parents of two Mitochondrial Disease Foundation (AMDF) disease, its research, treatment and the ³mito ¿ght´ since 2009 but appreciates children with mitochondrial disease. Doug is was formed in 2009. It aims to provide support prevention. that the work is hardly over. There are funds a radiologist and nuclear physician who has and information, build awareness and raise to be raised for research, support provided been active in public and private medicine funds for research to develop better diagnostic The Mito Report focuses attention on the to the mito community, education to be “ in Australia for more than 30 years. He is a methods and targeted treatments, and to help vital role to be played by a wide range of organised, and many more highs and lows to co-founder of the largest diagnostic imaging discover a cure. stakeholders, including GPs, specialists, withstand before mito is considered treatable, practice in Australia, Pittwater Radiology and funding bodies, researchers and patients who or preferably joins that blessed list of curable Medical Imaging Australasia Ltd. The AMDF has achieved much in just four are championing the ³mito ¿ght´. diseases. years, including funding four PhD scholarships Like the vast majority of Australians, I hadn’t and laboratory equipment at major Australian The Australian Mitochondrial Disease heard of mitochondrial disease when my adult research institutes. It has helped establish an Foundation is part of the solution, but daughter Rose ¿rst developed symptoms six Australia-wide mitochondrial patient database, we cannot do it alone. Concerted and short years ago. She was ¿nally diagnosed and has funded priority access to a new Next- collaborative action is urgently required. We now know mito is too after countless seizures, two induced comas, Generation DNA Sequencing Facility at Royal common to be called a months in hospital and many tests. Her Perth Hospital that will enable faster, cheaper ‡ Governments and funding bodies must diagnosis spurred me to ¿nd out all I could and more accurate diagnoses of mitochondrial increase investment in mito and genetic “rare disease – at least one about the disease but, in so doing, I was disease. research. It remains an urgent priority to person in 2000 is at risk.risk. struck by the huge void. There was so little improve diagnostic methods and identify 6 7KH&DOOWR$FWLRQ

Governments and funding bodies GPs must continue to become must increase investment in mito and better informed and include mito in their curriculum to facilitate early genetic research. diagnosis. It remains an urgent priority to improve diagnostic methods and identify gene mutations responsible for the many forms of mitochondrial disease, and to The AMDF urges the RACGP to update texts to ensure future medical practitioners educate medical practitioners. are informed on the latest developments.

The AMDF calls on the Australian Federal and state governments need government to reconsider its position to work together to facilitate and fund against the human embryo research faster, less expensive diagnoses. necessary to develop mitochondrial This is an important first step along the path to better care and support for replacement techniques. all Australians with mito, no matter where they live and what their financial In so doing it can assist women with maternally inheritable mitochondrial disease circumstances. to have children and subsequent descendants free of this debilitating and potentially fatal condition. 8 life-threatening form of mitochondrial disease ‡ Huntington disease (1 in 5000 people), making it the second most ‡ motor neurone disease / amyotrophic lateral commonly diagnosed serious genetic disease sclerosis (ALS) after cystic ¿brosis, which has an incidence of ‡ cardiovascular disease 0LWRFKRQGULDO'LVHDVH7KH)DFWV around 1 in 3500 people. ‡ diabetes ‡ cancer, particularly solid tumours and :KDWLVPLWRFKRQGULDOGLVHDVHDQG Needing to stay in bed to rest and recharge is +RZLVPLWRFKRQGULDOGLVHDVH tumour metastasis (spread to other organs). ZKDWFDXVHVLW" a common outward symptom of mitochondrial GLDJQRVHGDQGWUHDWHG",VWKHUHD Mitochondrial disease (or mito) is a debilitating disease. Inside the body, it’s much more FXUH" Research into mitochondrial medicine therefore Mitochondrial disease is a complex condition genetic disorder that robs the body’s cells of serious and complex: mitochondrial disease offers hope not only to people with primary that is dif¿cult to diagnose due to the energy, causing multiple organ dysfunction may literally cause any symptom in any organ mitochondrial disease (due to a genetic widespread range, type and severity of or failure and potentially death. Most patients at any age. mutation), but also to the millions suffering from symptoms and its varying onset and impact on have a genetic mistake (mutation) in the other major diseases commonly associated with patients’ lives (from none to severe). Multiple mitochondrial or nuclear DNA. The condition :KRLVDIIHFWHGE\PLWRFKRQGULDO ageing. tests may be required to con¿rm mitochondrial can be inherited from the mother, the father or GLVHDVH" disease, including genetic tests, muscle both parents, or can arise as a spontaneous Mitochondrial disease can affect both children Improvements in mitochondrial medicine may biopsies or brain scans (depending on the type genetic mistake at conception. and adults; due to its genetic basis, the disease eventually provide the key to better health and often affects multiple family members. Adult of disease suspected). quality of life in old age for all. :KDWDUHPLWRFKRQGULD" onset is becoming more commonly recognised. There are currently very few effective Mitochondria are the energy source in In many cases, the impaired mitochondrial load :K\KDYHQWZHKHDUGPXFKDERXW treatments and as yet no cure for mitochondrial almost every body cell. Often called the cells’ (cell injury and cell death) increases with age, PLWRFKRQGULDOGLVHDVHEHIRUH" disease. It impacts differently on every patient, Mitochondrial medicine is a newly established powerhouses or generators, mitochondria until organ systems begin to fail and symptoms so doctors can’t predict the progression of and rapidly evolving ¿eld thanks to major transform food to produce 90 per cent of the develop. the disease or symptoms, or the outcome for advances in our understanding of genetics. energy needed by the human body to function, +RZFRPPRQLVPLWRFKRQGULDO patients. It was not until 19 when mutations in sustain life and support growth. Mitochondria GLVHDVH" mitochondrial DNA were discovered to cause are most plentiful in tissues that require a lot Until the 1990s, mitochondrial disease was disease, and not until 1995 when nuclear of energy to function; the disease therefore /LQNVZLWKDJHLQJDQGPDMRUGLVHDVHV thought to be rare (1 in 20,000 people), but Whereas people with mitochondrial disease gene mutations were also found to cause causes most damage to the cells of the brain, it is now recognised as the most common have a genetic mutation that predisposes mitochondrial disease. Since then, more than muscles, heart, liver, inner ear and eye. subgroup of inherited metabolic disorders. their mitochondria to fail early, mitochondrial 100 clinical syndromes and disorders have Recent research shows 1 in 200 people, or +RZDUHVXIIHUHUVDIIHFWHG" dysfunction is thought to be one of the major been recognised as coming under the category more than 100,000 Australians, may carry factors contributing to ageing and the reason of mitochondrial disease. Depending on which parts of their bodies genetic mutations that put them at risk for why humans have a ¿nite lifespan. Over are affected and to what degree, people with developing mitochondrial disease or other a lifetime, our mitochondria slowly suffer mitochondrial disease can: related symptoms such as diabetes, deafness inevitable damage from environmental and ‡ lose their sight or hearing or seizures during their lifetimes. Many of these lifestyle factors and become less effective ‡ suffer muscle weakness and pain people are symptomatic but undiagnosed or at producing the energy our organs need to ‡ be unable to walk, eat, swallow or talk Mitochondrial disease misdiagnosed, some are not yet symptomatic, function properly. normally and others are unknowingly at risk of passing is a debilitating genetic ‡ have strokes or seizures the disease on to their children. Researchers increasingly believe mitochondrial disorder that robs the ‡ develop liver disease or diabetes dysfunction may be a signi¿cant factor in a wide “ ‡ suffer heart, respiratory or digestive body’s cells of energy, Put another way, up to 20 children born in range of major diseases – particularly chronic problems Australia each week are at risk for developing degenerative disorders and those associated causing multiple ‡ experience developmental delays or a mild form of mitochondrial disease, while with ageing – including: organ dysfunction and intellectual disability. one Australian child born each week – or 50 ‡ Parkinson disease potentially death. children every year – will develop a severe or ‡ Alzheimer disease 10 manifest from early in the neonatal period to occasional abdominal bloating. Doctors or late in adulthood. Children often present with patients may overlook these mild symptoms, different clinical features when compared yet a combination of symptoms may point to to adults and thus inheritance patterns may a diagnosis of mitochondrial disease. Thus, it ,PSURYLQJWKHGLDJQRVLVRIPLWRFKRQGULDOGLVHDVH not be obvious on ¿rst review. Children is important for the primary physician to take SDWLHQWVWKHUROHRIWKH*3 typically present with failure to thrive, lactic a detailed history to assess each symptom Professor Carolyn Sue acidosis, motor regression, encephalopathy or individually and be alerted to those signs that seizures. In contrast, adults frequently develop are indicators of mitochondrial disease (refer The diagnosis of mitochondrial disease often hearing loss, muscle weakness, diabetes, to table). involves a long, complex journey for both gastrointestinal dysmotility and fatigue. patient and clinician, but greater understanding Speci¿c clusters of symptoms may alert Although often inherited, mitochondrial disease by doctors and the development of new the clinician to the diagnosis. For example, may follow several different inheritance diagnostic tests provide hope for earlier an affected patient may have migraine-like patterns and may also occur sporadically diagnosis, prompt symptom management and headaches, early onset and mild asymmetrical in the population. This complex pattern of better introduction of supportive treatments hearing loss associated with diabetes and inheritance is because the mitochondria use and preventative strategies.

A key issue to improve the early detection of &OLQLFDOIHDWXUH &KDUDFWHULVWLFVWKDWPLJKWUDLVHWKHVXVSLFLRQ mitochondrial disease requires a high index of RIDPLWRFKRQGULDOGLVHDVH

suspicion and knowledge about this disorder. Early onset Clinicians need to consider mitochondrial Asymmetrical onset disease when speci¿c symptoms cluster within Hearing loss Sudden onset an affected individual. Unfortunately, many Worse after metabolic stress Partial recovery after an auditory insult sufferers remain undiagnosed or misdiagnosed (particularly adults with milder symptoms), Early age of onset Preceded by nausea, vomiting, constipation or drowsiness Professor Carolyn Sue is a neurologist and because of the vast range of symptoms that Non-vascular territory on neuroimaging Stroke-like episodes research scientist with a major interest in can present in affected patients. Because Concomitant basal ganglia calci¿cation understanding the disease processes involved mitochondrial disease is often inherited and Neuroradiological features out of proportion to clinical de¿cit in mitochondrial disorders and developing can follow an unpredictable disease course, Associated focal seizures or status epilepticus diagnostic and treatment options. Professor undiagnosed individuals may unknowingly Status epilepticus of cryptogenic origin Sue runs Australia’s largest clinic specialising pass the disease on to their unborn children Seizures worsened by sodium valproate Seizures in the diagnosis, assessment and treatment or are at risk of developing severe, life- Concomitant basal ganglia calci¿cation of adults with mitochondrial disease and threatening symptoms themselves. Additional features of hearing loss, diabetes or short stature heads a research team at the Kolling Institute Accompanying external ophthalmoplegia or retinal pigmentary changes of Medical Research. She is a professor There are several challenges that the GP faces Ptosis (droopy eyelids) Asymmetrical onset at the University of Sydney, director of the in identifying mitochondrial disease. Slowly progressive with little diurnal variation

Department of Neurogenetics at Royal North Perimacular distribution Shore Hospital and the director of the National Firstly, the ¿eld of mitochondrial medicine is Retinal pigmentary Non-vision threatening Centre for Adult Stem Cell Research (Sydney a newly established, complex and evolving changes No associated drusen Node). Professor Sue is co-founding director of specialty that may not be at the top of the Associated with hearing loss and diabetes the AMDF and a member of its Scienti¿c and clinician’s mind when assessing affected Associated with hearing loss and retinal pigmentary changes Medical Advisory Panel. patients. Originally thought to be a rare No associated diabetic retinopathy/peripheral neuropathy with respect Diabetes disorder affecting predominantly children, it to the length of diabetes onset is now recognised to be the most common Easily controlled with oral hypoglycaemic agents with respect to duration of diabetes inherited form of metabolic disease that may Table: Clinical features suggestive of a mitochondrial disorder

12 proteins that are encoded by two different individuals may have gene mutations and DNA genomes. genomes: mitochondrial and nuclear DNA. remain asymptomatic until later in life. Because mitochondrial DNA is typically passed Unfortunately there is no single diagnostic New investigations to simplify and improve the on from mother to all children, mitochondrial test that is abnormal in each patient with diagnosis of mitochondrial disease are currently disease caused by mutations in this gene follow mitochondrial disease. Thus, multiple being evaluated. Two recent studies published “ a maternal pattern of inheritance (all children of investigations are often required. Diagnostic by Suomalainen (Lancet Neurology) and Davis an affected mother are potentially at risk of the investigations include blood tests, urinary (Neurology) have reported the promising GPs need to continue to disease, but affected fathers do not pass on the analysis, biochemical and genetic tests. development of a new serum biomarker (serum become more informed disease). Given that other genetic mutations Serum lactate and pyruvate levels, imaging FGF21 levels) that may preclude the need for “about mitochondrial that cause mitochondrial disease are found in studies, and neurophysiological studies a muscle biopsy in most cases and simplify the nuclear DNA, other types of mitochondrial may help to de¿ne the patient’s disease the screening for mitochondrial disease to a disease and consider this disease may be inherited via Mendelian traits syndrome, but are only supportive of the simple blood test. Secondly, new advances in group of disorders as a such as autosomal recessive (both parents diagnosis and are not de¿nitive. Muscle biopsy methods to sequence large amounts of DNA who are asymptomatic of the disease have is the historical gold standard to diagnose (known as massively parallel sequencing diagnostic possibility. to be carriers to have affected children) or mitochondrial disease, but this is invasive or ³next-generation´ sequencing or ³NGS´), autosomal dominant (only one parent has to and may present an additional risk to the have been shown to be effective in detecting be affected to have an affected child) modes of affected patient if performed under general mutations in both mitochondrial and nuclear inheritance. Finally, mutations in mitochondrial anaesthesia. Histological, biochemical and genes. These new sequencing techniques are DNA may arise sporadically and thus there genetic analysis of the muscle tissue can be able to determine the genetic code of millions may be no family history at all. Adding to this performed, but these may have poor sensitivity of bases of DNA both rapidly and cheaply. As a complexity, the range of impact that genetic or have limited availability. Genetic testing is consequence, NGS has increased the diagnostic mutations have on different individuals is highly also not freely available throughout Australia yield and improved the ability of researchers variable, resulting in the fact that even family and can be prohibitively expensive, given that to con¿rm a genetic cause in many cases of members with the same genetic mutation may the responsible genetic mutations may require suspected mitochondrial disease. It is possible have different disease courses and certain analysis of both the mitochondrial and nuclear that using a combination of these new methods to diagnose mitochondrial disease may improve the diagnostic accuracy of mitochondrial disease. Current diagnostic pathway Proposed diagnostic pathway Further evaluation of relatively inexpensive new biomarkers (such as a simple blood test e.g. serum levels of FGF21) to screen for mitochondrial disease will encourage GPs to Clinical evaluation Clinical evaluation order it when mitochondrial disease is suspected, particularly for adults with milder symptoms or for asymptomatic family members. Muscle biopsy (for histological or Blood test for serum FGF21 levels biochemical analysis) GPs need to continue to become more informed about mitochondrial disease and Mitochondrial and nuclear DNA mutations Next generation sequencing of mtDNA, consider this group of disorders as a diagnostic screening analysis whole-exome and/or whole genome possibility. Increased awareness and improved understanding among frontline clinicians, 25-50 genetically con¿rmed diagnosis 70-0 genetically con¿rmed diagnosis combined with improved pathways to diagnosis may assist us to provide earlier and more accurate diagnosis, providing answers and better Figure: Comparison between current and proposed future diagnostic pathways for mitochondrial disease. Note symptom management for more mitochondrial the proposed future diagnostic pathway would avoid muscle biopsy and result in an increased number of patients disease sufferers around the world. receiving a genetically con¿rmed diagnosis of mitochondrial disease. Dion Taprell 14 After Kara turned eight, I found her that doctors can do much more to alleviate,

semiconscious and vomiting in bed. A bad judging by the calls for help I answer. gastro seemed the most obvious to me, not her ¿rst stroke-like episode. The diagnosis Frequent visits to the doctor before a mito $*3DQGPRWKHUVSOHD was quick: a progressive neurodegenerative diagnosis is even considered – sometimes 'RFWRUVPXVWIDFHXSWRPLWRIRUSDWLHQWVVDNHV form of mito called MELAS (Mitochondrial at the behest of a patient who has turned in Encephalomyopathy, Lactic Acidosis and desperation to their own research – may lead

Dr Karen Crawley Stroke-like episodes syndrome). to the patient or caring parent being pre- labelled, which hinders their whole medical (AMDF) Helpline, which I answer in a volunteer My knowledge of mitochondrial disease was care. Patients may be left waiting months or capacity. We not only provide information and zero and my medical textbooks said nothing, years for tests to be performed and results support, but also help empower patients (and so when an internet search revealed what obtained. Some are told “it might be mito, but those who suspect they have mitochondrial she and us as a family were to face…you can it’s too dif¿cult to diagnose´. disease) to take control of their diagnostic “ imagine our devastation. journey, understand their disease, and actively

manage it in partnership with a compassionate Even though there is as yet no cure and very medical practitioner who is determined to few targeted treatments for mito, getting a assist their patient. Knowledge is a powerful diagnosis is a vital step. tool that can ease the path for patients and Despite my medical

families, and for their healthcare providers. Painful as the news was, we are thankful training, I was unaware for Kara’s quick diagnosis because the However, it’s not as simple as it sounds. I am a “anything was seriously insidious, variable, ill-de¿ned and often slow GP myself and mitochondrial diseases were an development of mito unfortunately puts many wrong when my daughter unknown entity at university more than twenty patients – particularly with adult-onset mito – Kara started showing years ago. We were told not to worry about on a long and harrowing diagnostic odyssey what was then considered a ‘rare problem’ signs of mito. Dr Karen Crawley is a GP and the mother affecting only 1 in 20,000 people (recent of three children affected by mitochondrial research shows 1 in 200 people may develop disease. She is dedicated to educating mito in their lifetime). Kara, Braden and Samantha Crawley doctors about mito, raising awareness and empowering patients to manage their Despite my medical training, I was unaware condition, and answers the AMDF’s Helpline: anything was seriously wrong when my elder 1300 977 180. daughter Kara started showing what I now know were signs of mitochondrial disease People often feel powerless and isolated when (mito) when she began school in 2005. dealing with a very sick child or their own illness. This is intensi¿ed when the disease is Her slowness in all tasks, poor balance and so complex and relatively unknown that rounds ever poorer sporting skills made Kara simply of doctors and tests can’t provide answers, seem hard work. The excess body hair, early multiple symptoms remain unexplained, or loss of teeth, repeated spontaneous vomits, patients are labelled as unlucky, ‘dif¿cult’, plummeting percentile bands, awkward malingering or suffering a psychosomatic running style, stiff muscles, ‘stick legs’, illness. stress incontinence, jerky eye movements, poor concentration and a failed occupational This is a common refrain from callers to the therapy assessment should have rung a few Australian Mitochondrial Disease Foundation mitochondrial alarm bells if I had heard of it. 16 The Crawley family Yet while con¿rming mito can be dif¿cult and Information Days at hospitals and research as the number one metabolic disorder in their time consuming and may not change the institutes, and provides literature such as list of differential diagnoses, preferably before eventual outcome, leaving a patient stranded the AMDF’s Medical Information Booklet for they ring the psychiatrist or dismiss the patient without a diagnosis or a way forward is not General Practitioners. The AMDF Helpline as a malingerer or ‘too much hard work’. why I became a doctor. is also for medical practitioners, not just for patients. It’s also past time for an update of the GP’s Even if the exact genetic mutation remains ‘bible’, The Principles of General Practice, to unknown, many patients and carers speak of Slowly but surely, good progress is being made reÀect the latest understanding of mitochondrial the ‘dignity in diagnosis’, of the overwhelming and signi¿cantly increased requests for testing disease and its devastating impact on comfort it is not in their head, they are not are being reported by specialist mito centres at Australians like our family, and ensure future alone, and they or their child/ren have one the Kolling Institute and the Murdoch Childrens doctors are better informed than I was. disease rather than several. When both Research Institute. patient and GP understand mito well, it can In the meantime, we take each day as it comes lead to better quality of life, particularly for But moving ahead on mito requires action with Kara. Early dementia has set in, she’s in adults with debilitating yet non-life threatening from the medical profession too. We know a wheelchair, has a feeding tube and hearing disease. Patients may be able to manage there are many thousands of people in the aids and her eyesight is slowly disappearing. their condition and prevent worsening health community with mito who are undiagnosed or With a few years at most to live, our gorgeous through exercise, diet and medications misdiagnosed, and not receiving the care they girl is disappearing with each stroke. We are or surgery for symptom management in deserve. cautiously hopeful for the future of our younger collaboration with their GP. Referrals to son and daughter, who have also tested specialists like neurologists, cardiologists, As a doctor and a ‘mito mum’ working to help positive for the defective gene but are relatively gastroenterologists, endocrinologists and other affected families, I urge all doctors to healthy. At least we now know what we are ophthalmologists also become easier seek information and consider mito when dealing with. (although specialists also need to be better patients have symptoms that don’t seem to add informed about mito). up; to be prepared to say “I don’t know much about mito, but I’ll ¿nd out´; to remember mito Diagnosis helps relatives who may have been experiencing mito symptoms and/or who are planning to have children, and can now approach their doctor with speci¿c questions.

The overwhelming and unnecessary cost Moving ahead to Medicare also needs to be considered. If on mito requires mitochondrial disease is not considered as a real possibility by a patient’s doctor, they action from the medical and other affected relatives remain on the profession… many diagnostic government-funded merry-go- round, with thousands of dollars being spent thousands of people in on unnecessary investigations. the community are not

Given the pivotal role of GPs in diagnosing receiving the care they mito and managing patients’ health, the deserve. AMDF engages with GPs through General Practitioner Conference & Exhibition (GPCE) educational events and Mitochondrial 18 of copies in each cell and is inherited only genetics and cost of DNA testing means that from our mother. This makes the genetics this has typically been limited to testing for of mitochondrial disorders particularly a small number of mutations, mostly in the 7HFKQRORJ\VWHSVXSWRDLGPLWRGLDJQRVLV complicated. Recently, thanks to work by mtDNA. Hence only a minority of patients Professor Carolyn Sue in Sydney and two are diagnosed quickly and easily by DNA Professor David Thorburn research groups in the UK, we have realised testing on a blood sample. The next step for that at least 1 in 200 people carry a change most patients has been a muscle biopsy. The Laboratory is the Australasian referral centre in their mtDNA that can cause disease. Only mitochondrial energy pathway consists of ¿ve for diagnosis of mitochondrial disease in about 1 in 50 of these carriers is currently major components or enzymes, known as children. He is a member of the AMDF board being diagnosed with mtDNA disease. Complexes I to V. Muscle biopsies are usually and its Scienti¿c and Medical Advisory Panel. While some may be healthy, it is likely that a tested for how much of these complexes are substantial number of these individuals have present and how well they work. Finding a Even at rest, humans need to constantly symptoms caused by their mtDNA mutation de¿ciency of one or more of these Complexes generate about 100 Watts of energy, the same but they are not being investigated properly can be diagnostic. Sometimes the combination amount as a bright light globe. This allows and not being diagnosed with mtDNA disease. of the patient’s clinical and enzyme ¿ndings our neurons to send messages, our heart to suggest one or two obvious genes that should pump and our other organs to perform their So how do we diagnose mitochondrial be tested. Other combinations, such as roles. To do this, we must be able to ef¿ciently disorders? For over 10 years, genetic testing Leigh Syndrome with Complex I de¿ciency use fuels such as fats, sugars and proteins has been available in Australia for some may still leave more than 20 different genes to make a small molecule called ATP, which DNA mutations. However, the complicated and several different types of inheritance as is our chemical energy store. Mitochondria are our cellular power plants, responsible for generating the majority of energy required for 1XPEHURIGLVHDVHJHQHVLGHQWLILHG cellular function and survival. Each day we generate and consume about 65 kilograms of Professor David Thorburn is an NHMRC ATP, emphasising how much we rely on our Principal Research Fellow and Director mitochondrial power plants! of the Genetics Research Theme at the Murdoch Childrens Research Institute at Mitochondrial disorders pose great challenges the Royal Children’s Hospital, Melbourne. in diagnosis and treatment. Most patients He holds honorary appointments with the suffer from mitochondrial disease because Department of Paediatrics, University of one of the 1500 or so genes needed to make Melbourne, and Genetic Health Services healthy mitochondria is not working properly. Victoria, and chairs one of four working Over 150 of these are already known to be parties of the Royal College of Pathologists “disease´ genes with perhaps another 100 of Australasia developing guidelines for or more awaiting identi¿cation. Most of these Next-Generation DNA Sequencing in clinical genes are the regular nuclear genes that practice. Professor Thorburn has a particular are present in two copies, one inherited from interest in understanding how mitochondrial our mother and the other from our father. DNA mutations are passed from mothers to However, mitochondrial disorders are unique children, and translating this into approaches since they can also be caused by mutations for genetic counselling, prenatal diagnosis and (changes in the genetic coding sequence) in prevention; he also studies nuclear genes. the mitochondrial DNA (mtDNA). The mtDNA Professor Thorburn’s Mitochondrial Research is a small genome present in thousands mtDNA nuclear genes (traditional) nuclear genes (MPS) 20 plausible. Genetic diagnosis is often a slow mtDNA or in 7 nuclear genes previously linked couples on their risk of having further affected process and most centres can only afford to mitochondrial disease. We also identi¿ed children and allows them access to effective to test a handful of genes so many patients 15 novel “candidate´ genes not previously reproductive options. Finally it is important to and families remain on a diagnostic odyssey linked to mitochondrial disease with mutations understanding the true incidence and impact without a clear answer to the genetic cause of and showed that at least two of these 15 of mitochondrial disorders, both of which are their symptoms. candidate genes were true novel disease likely to be highly underestimated. genes. We have subsequently shown that at The game changer in genetic diagnosis is least another 5 of these candidates are true So what do we still need to do? A number of the emergence of new technologies called novel disease genes. This illustrates that we challenges remain in improving its sensitivity “Next-Generation´ or “Massively Parallel´ DNA still have plenty to learn about which genes so that we can detect and interpret virtually sequencing. Instead of having to decide on the can cause mitochondrial disease and that all DNA changes that cause mitochondrial most likely handful of genes that we can afford these approaches will identify many more such disorders. On average, each individual has to sequence, we can now sequence panels of genes in the next few years. The US National about 20,000 DNA sequence differences in 100 genes, 1,000 genes or all 20,000 different Institutes of Health kindly chose this study as their 20,000 genes when compared to anyone genes at once. The latter is called “Whole one of 12 “Genome Advances of the Month´ else. Finding the needle in the haystack Exome Sequencing´ and cost a few million for 2012 (www.genome.gov/27547295). remains an issue. Hence we may still need dollars in 2007 but can now be done for a few to do muscle biopsies on most patients for thousand dollars. “ a few years in order to help interpret all the DNA variants that we ¿nd. This technology In theory this means we should be able to requires additional investment in equipment, sequence blood ¿rst and sift through the The game changer in informatics, data storage, training of the sequencing data to pull out the genetic cause genetic diagnosis is scienti¿c workforce and education of medical without needing to do a muscle biopsy. This the emergence of new practitioners. At present there is no direct approach is starting to be used more widely “ government funding for these techniques so and should be the reality for most patients technologies called “Next- costs are usually coming either from research within a few years’ time. It has been made Generation” or “Massively budgets or families’ hip pockets. By working possible by the extraordinary fall in DNA together, scientists, clinicians, the AMDF and sequencing costs in the last 6 years and Parallel” DNA sequencing. professional bodies like HGSA and the RCPA advances in bioinformatic analyses of the will seek to develop a standardised approach data. However, it is still transitioning from for diagnosing mitochondrial disorders to being a research tool into routine diagnostic ensure faster, less expensive diagnosis and use. The AMDF has been active in supporting better care and support for all Australians, the use of this technology in Australia, by no matter where they live and what their supporting a PhD student in my laboratory and ¿nancial circumstances. AMDF members by funding use of the technology in Perth. What are the incentives to develop this and professionals will also need to lobby technology when we don’t yet have effective governments to achieve this outcome. The power of massively parallel sequencing treatments for most patients? Firstly, a is demonstrated by a study we published diagnosis can end the diagnostic odyssey and last year on 42 infants with de¿cient activity provide dignity in diagnosis. In some cases of one or more of the mitochondrial enzyme an accurate diagnosis does guide treatment complexes. In conjunction with Prof. Vamsi options and in others it can aid access to Mootha’s group in Boston, we sequenced additional bene¿ts and support. It can also over 1000 genes encoding all the known enable patients to proactively manage mitochondrial proteins in each patient. We health to manage disease progression and identi¿ed genetic diagnoses in 10 children in quality of life. It provides precise estimates to Martine and Tom Martin 22 Annaliese with brother Patrick & sister Bethany 6XUYLYLQJWKHGLDJQRVWLFRG\VVH\RIPLWR

Despite the often poor outlook, receiving a a new paediatrician and geneticists still couldn’t diagnosis of mitochondrial disease can be a relief help. for patients and their families. Personal stories abound of years of tests, countless medical “As a parent I got to the point where I felt I appointments, various diagnoses and signi¿cant was looking for something that didn’t exist and ¿nancial costs, heartache and uncertainty. couldn’t understand how a child could be so impacted by this condition and the doctors not be

$QQDOLHVH able to ¿nd anything.´ Annaliese Hodge and her family endured a The breakthrough came when, just before her twelve-year diagnostic odyssey before she 17th birthday, Annaliese was sent for further was diagnosed with mitochondrial disease at blood tests following yet another neurological 17 thanks to advances in genetic testing. Her review. mother, Joanne Edwards, who now runs the Melbourne support group of the Australian “Finally, after 12 years and thousands of dollars,

Mitochondrial Disease Foundation, says while we got a diagnosis of mitochondrial disease. I’m it was obvious something was wrong with told we have advances in medical research and Annaliese, doctors were unable to ¿nd the cause genetic testing to thank. of her symptoms and the family had no answers on how to help their daughter. Although the diagnosis doesn’t open up doorways to targeted treatments or a cure, at “We noticed from a young age that Annaliese least we know Annaliese’s form of mitochondrial was intellectually delayed and had tremors in her disease is not life-threatening and that it’s “ hands. At age ¿ve, a paediatrician diagnosed her maternally inherited.´ with ADHD and put her on Ritalin, but this didn’t help,´ says Joanne. Tests showed Joanne’s older daughter and son also have the genetic mutation that puts “During primary school, academic testing showed them at risk of mitochondrial disease like their Annaliese was functioning four to ¿ve years If you don’t know what’s sister’s: MERRF syndrome (Myoclonic Epilepsy behind her age group. Her tremors got worse with Ragged Red Fibres, the latter being wrong, you can’t be and it became harder for her to do day-to-day characteristic microscopic abnormalities seen on confident you’re doing the tasks such as eating, doing up buttons and shoe muscle biopsy in some mito patients). right thing for your child… laces, writing and reading. It also affected her “ speech and her limbs, making her extremely Finally, after 12 years and “Thankfully my other children are not clumsy. And because she was different, she had symptomatic, but we know the onset can occur in thousands of dollars, we very few friends, which was upsetting. adulthood and symptoms can differ among family got a diagnosis of mito. members. Because their mitochondrial disease “If you don’t know what’s wrong, you can’t be is maternally inherited, my daughters are at risk con¿dent you’re doing the right thing for your of passing it on to their children, but now at least child, so we persevered in trying to ¿nd answers. they can make informed decisions.´ However, neurologists, movement specialists, Annaliese Hodge 24 Miranda Kirk with her aunt Lucy 0LUDQGD “She got the feeding device in December 2012 Brian Kirk and his wife endured a similar four- and put on a stone over eight months, which year ordeal of misdiagnoses, hospital stays, has really improved her strength and stamina multiple tests and worry with their daughter, and possibly slowed her deterioration. Miranda, before she was ¿nally diagnosed with mitochondrial disease at the age of ¿ve. “It’s made such a difference that we do wonder whether an earlier diagnosis, and therefore “We suspected something was wrong when getting this nutrition earlier, could have Miranda was a baby – she had developmental improved her physical development when she delays, was failing to thrive and didn’t seem to was younger and reduced the severity of her feel pain. She didn’t start walking and talking problems.´ until she was four,´ says Brian.

Now aged seven, Miranda’s muscles don’t During what Brian describes as a ‘horri¿c’ properly support her and she uses a walking diagnostic journey, doctors variously thought frame as well as a wheelchair for longer Miranda might have colon cancer or epilepsy activities and stability in the schoolyard. She or even that she was ‘just small’ and the Kirks has retinal dystrophy and is losing her sight, were imagining her symptoms. Their distress and wears hearing aids; cochlear implants may

at the lack of answers was compounded by the be necessary in a couple of years. fact they lost their ¿rst child at the age of nine months to a diaphragmatic hernia. “Miranda’s future quality of life is uncertain, but for now she’s a happy little girl who’s making After years of tests including invasive muscle, the most of life.´ liver and skin biopsies, Miranda was eventually diagnosed with mitochondrial Complex I disease, which is damaging her intellect, “ muscles, eyes and ears. Conventional genetic testing has not identi¿ed the gene responsible for Miranda’s disease but this has not yet included next-generation DNA sequencing, which will be performed in the next year and will …we do wonder whether hopefully provide the answer. an earlier diagnosis… could have improved her “Although there are no targeted treatments for “ physical development and mitochondrial disease, it was some comfort to get a diagnosis because it enabled us to access reduced the severity of her support, specialist counselling and treatment.´ problems.

After years of struggling to put on weight, Miranda had a breakthrough after being ¿tted with a feeding pump that delivers her a high-fat concentrate solution for one-and-a-half hours each night. 26

A number of such supplements, including In some cases, a ketogenic diet (high fat/low vitamin C and vitamin E, have been trialled carbohydrate) has been shown to be of bene¿t with some appearing to have bene¿cial effects for patients with dif¿cult-to-control seizures, $SSURDFKHVWRPLWRFKRQGULDOWKHUDS\ in some mitochondrial disease patients. and this has been considered to be safe even WKHQH[WIURQWLHU Coenzyme Q10 is also popular, based on for children with mitochondrial disorders. suggestions that it is able to reduce free Professor John Christodoulou AM radicals, and so is creatine, based on its ability Altering the balance between mutated and to function as an alternate energy source. normal mtDNA understanding of mitochondrial disease and its However, there is a lack of objective studies For those MRCDs that are due to a primary impact have increased over the past decade, demonstrating therapeutic bene¿t in using mtDNA mutation, altering the balance between this has not yet translated into treatments. these supplements, either on their own or in mtDNA with and without the mutation could Once diagnosed, there are no curative combination. potentially improve mitochondrial function. therapies and very few effective treatments New drug- or gene-based technologies are for patients with mitochondrial disease; these On the other hand, there is a body of currently being developed with this aim in represent the next frontier for researchers. evidence supporting the use of the amino mind, but none have translated into clinical acid L-arginine in patients with MELAS trials yet. Research is underway around the world, (Mitochondrial Encephalopathy, Lactic Acidosis including Australia. Most efforts are focused on and Stroke-like episodes syndrome) by Exercise as a therapy improving patients’ quality of life and on early decreasing the frequency and the severity of While drug and gene-based technologies are identi¿cation and management of secondary acute stroke-like episodes, and more recently, still under development, there is a growing side effects. Some treatment approaches it has been suggested that L-citrulline may be body of research literature showing that include the use of nutriceuticals (nutritional of better therapeutic value than L-arginine in carefully supervised exercise training can type products) in an attempt to improve the MELAS. result in muscle regeneration with an improved ef¿ciency of cells’ energy production through ratio of normal to mutated mtDNA, and this metabolic manipulation, while others attempt leads to improved exercise tolerance and to improve energy production by altering the capacity. Professor John Christodoulou is a senior balance between mutated and normal working geneticist based at The Children’s Hospital versions of mitochondrial DNA (mtDNA), by Many Mitochondria Inside A Cell at Westmead, where he is Director of the enzyme replacement therapy, or by the use of Western Sydney Genetics Program, one of speci¿c gene activators. the few integrated clinical and laboratory Mitochondria are found in most cells of diagnostic genetics services in Australia. He Metabolic manipulation the body, with each cell having tens to is also Professor, Disciplines of Paediatrics Abnormalities in the mitochondrial energy hundreds of mitochondria. They are the and Child Health and Genetic Medicine, in the production pathways in our cells can lead to an Inside The Mitochondrion powerhouses of the cell, using fat and Sydney Medical School at the University of accumulation of free radicals, which potentially Fat & Sugar sugars in our diet to convert them into “Intermediaries´ Sydney, and a board member of the Australian have damaging effects on a number of key energy (ATP), through a complex set of Mitochondrial DNA ¿nely regulated biochemical reactions.

Mitochondrial Disease Foundation and its cell processes, and are believed to contribute

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Scienti¿c and Medical Advisory Panel. to disease progression in many cases. By a The ¿nal common pathway, generating h

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Oxidation P Mitochondrial disease – or, more speci¿cally, patient’s diet through supplementation with T mitochondrial respiratory chain, which A

in is physically located within the inner mitochondrial respiratory chain disorders vitamins and co-factors, it is hoped that such a ATP Citric Acid h Cycle C rt membrane of the mitochondrion. (MRCDs) – can encompass a wide array of metabolic manipulation may reduce the o ATP p s n ATP health problems, and require a methodical accumulation of free radicals. a r The ATP which is generated by oxidative T n o and rigorous approach to testing to establish tr (Energy) c phosphorylation can then be used by the le the diagnosis with certainty. Although our E cell for a multitude of essential purposes. 28 Enzyme replacement New therapies under evaluation Mitochondrial-Neuro-Gastro-Intestinal A chemically modi¿ed form of Coenzyme Q10 Encephalopathy (MNGIE) is a form of called idebenone is believed to penetrate key mitochondrial disease caused by loss organs such as the brain more effectively, of activity of the enzyme thymidine and there is some evidence to suggest it is of phosphorylase (TPase). There is early some bene¿t in mitochondrial diseases such evidence to suggest that restoration of TPase as MELAS, Leber Hereditary Optic Neuropathy ...it is hoped [further activity may be of bene¿t, using either a (characterised by sudden, profound loss research] will give gene therapy approach (based on studies of central vision) and Friedreich ataxia rise to new and in a mouse model), or by bone marrow (progressive nervous system degeneration). “ transplantation (this form of therapy has been powerful therapeutic applied to a number of human patients). Another synthetic analogue of Coenzyme agents that prove However, the long term bene¿t of this Q10, EP1-743, is believed to be even more their value... and approach remains to be demonstrated. potent and safer. Studies have shown EPI-743 eventually provide to be of bene¿t in patients with a number of Regulation of speci¿c gene activators MRCDs. A Phase 2B randomised, placebo- significant benefits Some therapies are focused on increasing the controlled, double blind clinical trial is currently for patients.

number of healthy mitochondria. It is possible underway into EPI-743 as a treatment for to increase the level of a transcriptional children with Leigh Syndrome, the most coactivator protein PGC-1Į (peroxisome commonly recognised mitochondrial disease proliferator activated receptor gamma co- of childhood (http://clinicaltrials.gov/ct2/show/ activator 1 alpha), which is a key player NCT01642056). in promoting increases in the number of Despite these advances, there are many

mitochondria. Exercise, especially endurance people with mitochondrial disease for whom exercise, and speci¿c drugs such as no effective treatment is currently available. beza¿brate and resveratrol can increase PGC- For them it remains an incurable, debilitating 1Į levels. and potentially life-threatening disorder. Prenatal diagnosis to prevent recurrences in future generations is an important option that “ should be explored. This can be an option for most families where a nuclear DNA mutation has been identi¿ed, but only for a minority Once diagnosed, there of families with mtDNA mutations. Similarly, are no curative therapies pre-implantation genetic diagnosis is also an “and very few effective option for families with nuclear DNA mutations. but only for some families with mtDNA treatments for patients… mutations. these represent the next There is therefore an urgent need for frontier for researchers. further research focusing on improving our understanding of the cellular and molecular biology of these disorders. Such research, it is hoped, will give rise to new and powerful therapeutic agents that prove their value in extensive clinical trials and will eventually provide signi¿cant bene¿ts for patients. Dion Taprell 30 team at the University of Western Australia indicate that RNA-binding proteins play a central role in the lifecycle of the mitochondrial genetic blueprint. The basic components and 5HDGLQJWKHEOXHSULQWRIWKHPLWRFKRQGULDOJHQRPH mechanisms of RNA regulation have recently been discovered; however, the ¿ne-tuning of Professor Aleksandra Filipovska mitochondrial gene expression at the level of RNA remains a worthy pursuit for our future neurodegeneration, muscle defects and research endeavours and will provide new exercise intolerance. To understand these avenues for therapeutic interventions for conditions better and identify therapeutic mitochondrial diseases. targets it is necessary to understand how gene expression is regulated within mitochondria, as some of the most signi¿cant gaps in our knowledge of mitochondrial function and disease are in the regulation of mitochondrial gene expression. In all living things genes provide the blueprints for cells and our bodies. When genes are turned on they make RNA, which acts as instructions to make the protein building blocks of the cells. These processes ...recent new and are well understood for most of the genes exciting findings... in the cell, however the small set of genes indicate that RNA-binding which reside in mitochondria follow different proteins play a central rules, which are only now beginning to be role in the lifecycle of the Professor Aleksandra Filipovska is an ARC understood. mitochondrial genetic Future Fellow at the Western Australian blueprint. Institute for Medical Research and the In a recent collaboration with Professor John University of Western Australia in Perth, Mattick’s team (Garvan Institute, Sydney) and established her research group in we performed the ¿rst comprehensive Mitochondrial Medicine and Biology in census of all the RNA instructions in human 2006. Her research focuses on studying mitochondria. We discovered an unanticipated mitochondrial gene regulation and function in variety of different RNAs, many of which had health and mitochondrial disease. Professor never been observed before. These RNAs are Filipovska’s group has made advances in very dynamic and vary dramatically depending the development of methods for studying on the energy demands of the cell. For mitochondrial gene function and developing example, we found that mitochondrial RNAs therapeutics for inherited mitochondrial were far more abundant in tissues with high diseases. She is a member of the AMDF’s energy demands, such as the heart and brain, Scienti¿c and Medical Advisory Panel. compared to those that require less energy, RNA is one of the essential macromolecules for life; such as the skin. it regulates how genes are turned on and made into Mitochondria play a fundamental role in cell proteins. RNA is present in all cells and in organelles and energy metabolism and consequently Although little is known about how the levels within cells such as mitochondria. Defects in RNAs or mitochondrial dysfunction can lead to severe of mitochondrial RNAs are controlled in cells, the regulation of RNAs can cause or contribute to many multi-system disorders with a wide range of recent new and exciting ¿ndings emerging important human diseases including mitochondrial clinical presentations that commonly include from groups around the world including our diseases. 32 Maternal spindle transfer

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Professor Jus St John The challenge for a woman who is a carrier of mitochondrial DNA disease and wants to have children is that each of her eggs will have different amounts of damaged or mutated mitochondrial DNA. As one egg is ovulated at each menstrual cycle, she will not know if that egg has high or low levels of mutated mtDNA. Furthermore, current genetic tests do not allow us to predict whether the egg has high or low REMOVAL of MII FUSION of patient’s FERTILISATION of FORMATION OF levels of mutated mitochondrial DNA and then Spindle from patient chromosomes to reconstructed oocyte ZYGOTE, which and donor oocytes donor oocyte by partner’s sperm developes into an allow the woman to proceed with her egg to embryo make a child. However, recent developments using in vitro fertilisation (IVF) technologies are now opening up new research avenues Metaphase II spindle - patient oocyte that could prevent mitochondrial DNA disease Metaphase II spindle - donor oocyte from being transmitted from the mother to her Female pronucleus children. Male pronucleus Professor Jus St John is Director of the Centre Two approaches have been proposed that Mutated mtDNA for Genetic Diseases at the Monash Institute Images reproduced with permission of would prevent children from inheriting these Wild type (healthy) mtDNA Justin C St. John. of Medical Research in Melbourne. The severe forms of mitochondrial DNA disease. overall aim of Professor St John’s research One of the techniques, known as Maternal is to understand how maternally inherited Spindle Transfer (M-ST), enables the mother’s mitochondrial DNA is transmitted, segregated chromosomes to be transferred from one of before the parents’ chromosomes, which are produced from a single adult cell introduced and replicated. His current research her eggs into an egg from a donor. In this case, contained within each of the pronuclei, are into an egg. However, through M-ST and PNT, focuses on de¿ning key mitochondrial DNA the donor egg retains its healthy mitochondrial transferred into a healthy donor egg. These the baby will have three genetic parents. S/ replication events and how they inÀuence the DNA but has had its chromosomes removed. fertilised oocytes can then develop into he will inherit his or her chromosomes from transmission of mutant mitochondrial DNA from The eggs are fertilised with her partner’s embryos and be transferred to the mother to the mother and father, as is normal following one generation to the next. Professor St John sperm, as is normal during IVF treatment, and establish a pregnancy. natural fertilisation and IVF. However, the ‘third is currently developing models of mitochondrial then allowed to develop into an embryo in the parent’ is the mitochondrial DNA mother who DNA diseases and testing the safety and laboratory. After a few days, the developing Debate on ethics of such treatments donated the egg. ef¿cacy of maternal spindle transfer. He embryo is transferred to the mother. Normally, Admittedly, there is controversy associated has advised the UK government, parliament it would then implant into her womb and a with these techniques. Some people regard Whilst some groups regard these procedures and the Royal College of Obstetricians and pregnancy is established. these techniques as cloning. Although they as unacceptable, others believe that Gynaecologists on policy related to stem cells use the technology that produced ‘Dolly the the signi¿cant bene¿ts outweigh the and reproduction, and also advised the Human The other technique is known as Pronuclear Sheep’, they do not produce an identical unacceptability. This is because there is the Fertilisation and Embryology Authority on stem Transfer (PNT). It is similar to M-ST except individual as s/he is produced from the potential to eradicate these terrible diseases. cells and embryo policy. that the partner’s sperm fertilises the egg mother’s and father’s chromosomes. Dolly was Indeed, there have been two important reports 34

Pronuclear transfer These reservations are very important. If met, so, scientists in the USA would operate under they will ensure that no mutant mitochondrial the jurisdiction of the FDA, which regulates all DNA is transferred with the chromosomes into medical and drug procedures. the donor egg. This will ensure that there is no risk of even low levels of mutant mtDNA being Looking ahead for Australian families preferentially replicated and the baby suffering If mitochondrial DNA disease is to be from mitochondrial disease. Furthermore, they eradicated in Australia then Australian law

will ensure that the baby would not suffer from will need to embrace these technologies. The any harmful side effects of the technology. Australian Mitochondrial Disease Foundation’s recently released position statement Scientists are not proposing to conduct any welcoming further research adds to the weight of these approaches without the appropriate of support from many scientists as well as

regulations in place. Firstly, scientists are people affected by mitochondrial disease, who proposing to do the work in animal models to advocate for the opportunity to develop safe demonstrate that they are absolutely safe. and effective methods to prevent transmission of the disease.

FERTILISATION of REMOVAL of pronuclei FUSION of patient RECONSTRUCTED Nevertheless, signi¿cant progress will need to patient and donor from zygotes. Patient pronuclei to donor ZYGOTE, which “ oocytes pronulcei are retained; zygote develops into an be made in order to determine the safety and donor pronuclei are embryo Recent developments effectiveness of these technologies and they discarded using IVF technologies require extensive validation. Once validated, they could prevent mitochondrial disease from “are now opening up being passed from the mother to her children Metaphase II spindle - patient oocyte new research avenues and to subsequent generations. The female children will not have to undergo the dilemma Metaphase II spindle - donor oocyte that could prevent that current carriers do. Female pronucleus mitochondrial DNA disease Male pronucleus from being transmitted Female pronucleus - donor zygote from the mother Male pronucleus - donor zygote to her children. Mutated mtDNA Wild type (healthy) mtDNA

that support these procedures. However, they The other key statement came from the They will not demonstrate this in just one insisted that some important reservations UK’s regulator of all fertility procedures, the animal model but several and in those that were implemented before the techniques Human Fertilisation and Embryology Authority have the most relevance to humans. Just as are used to produce children. Firstly, the (HFEA), which was commissioned by the important, they are working with governments UK’s Nuf¿eld Council on Bioethics stated: Secretary of State for Health to seek public to ensure that any procedures performed “If further research shows these techniques opinion. This year, it reported that: “... there in the human are under the control of the to be suf¿ciently safe and effective, we think is general support for permitting mitochondria respective regulators. For example, in the UK, it would be ethical for families to use them replacement in the UK, so long as it is safe scientists have been working with Government if they wished to, provided they receive an enough to offer in a treatment setting and is to legalise these procedures. This will ensure appropriate level of information and support.´ done so within a regulatory framework.´ that they are regulated by the HFEA. Equally 36

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The ¿rst Rhonda Murray’s family knew of of ill health, early deaths, miscarriages and still mitochondrial disease was when her brother births. Rhonda’s mother died in 2011, aged 70, Peter became progressively ill from his mid- after having a serious stroke-like episode; she thirties with fatigue, vagueness, hearing loss started going deaf in her forties and became and eye problems. Following his diagnosis, tired very easily. Now 47, Rhonda is also losing tests showed Rhonda, her two sisters, her hearing and has fatigue, which raises the her brother and their mother also had the spectre of whether her health will decline like genetic defect that causes a debilitating and her mother and Peter, who died in 2009. potentially fatal form of maternally inheritable Clockwise from top left: Warren, Levi, Dion Taprell mitochondrial disease called MELAS “Both our daughters are currently well, but Tracy, Bree and Erin Taprell (Mitochondrial Encephalomyopathy, Lactic there’s an added level of anxiety when they Acidosis and Stroke-like episodes syndrome). seem tired or get sick… I think, is this the ¿rst Currently, for women at risk of maternally “Dion wasn’t growing or putting on weight, was sign of mitochondrial disease?´ inheritable mitochondrial disease, the only lethargic, often had vomiting and diarrhoea “I was pregnant with our eldest daughter Annie, reproductive options to have a healthy and eventually just couldn’t eat at all without who’s now 14, not long after Peter had his ¿rst “Being able to bear a healthy child is something child are donor egg donation or, in some medical intervention,´ says Tracy. stroke-like episode. We had Annie’s cord blood most Australian women take for granted, cases where the exact gene mutation is tested and hoped for the best, but our baby had so I hope for my daughters’ sakes that IVF known, prenatal diagnosis or IVF using “We cried rivers of tears when we ¿nally got the defective gene too,´ says Rhonda. technology becomes available that enables pre-implantation genetic diagnosis (PGD). the diagnosis after an MRI showed lesions in them to have children free of mitochondrial However, these options are not available to Dion’s brain, and then 12 weeks of waiting on “Later, my husband and I agonised about disease. many women at risk because most of their muscle, liver and skin biopsies to con¿rm he having a second child. Mito affects every eggs may be carrying substantial amounts of had a fatal form of mitochondrial disease.´ individual differently, from no health problems “Mitochondrial disease is a dark cloud hanging a mitochondrial DNA mutation. Also, PGD can to severe illness, so we ¿nally decided to go over our family, so preventing mito being only reduce and does not eliminate the risk of Tracy and Warren eventually decided to try ahead and had our daughter Cassie, who’s now passed to future generations is a prospect mitochondrial disease in the resulting child, or for another baby, a brother or sister for their 12. We’ll discuss testing with her when she’s we welcome with open arms. We hope the of her passing the disease to her children. daughter Erin, thankfully unaffected by mito. older.´ Australian government follows the lead of the Tracy became pregnant naturally in 2010, UK and moves to support and legalise research A further issue is that mitochondrial disease but genetic tests showed the foetus had the The Murray family diagnoses were an eye- to make this technology a safe and effective is so often undiagnosed or misdiagnosed that genetic defect and they made the dif¿cult opener that seemed to explain a family history reality for families like ours.´ many people unknowingly pass the disease on decision to terminate the pregnancy. to their children. “Having IVF using pre-implantation genetic Tracy and Warren Taprell’s son Dion died in diagnosis was our only alternative to taking June 2009 just after his third birthday, having another chance with a normal conception. been diagnosed at 20 months with a severe form of mitochondrial disease called Leigh “Thanks to advances in mitochondrial disease syndrome, which affects the central nervous research – and the legacy of Dion’s diagnosis system. and biopsy samples – scientists could identify the speci¿c gene mutation responsible. Annie Hawes Annie Hawes, Rhonda Murray & Cassie Hawes 38 Specialists were then able to test the embryos for a defective copy of the gene.´ Jack White

This accurate identi¿cation was vital because mitochondrial disease can be caused by multiple genetic defects (at least 26 are known for Leigh syndrome), may involve mutations in the nuclear and/or mitochondrial DNA, and can have different inheritance patterns.

On 1 November 2011, Tracy gave birth to a healthy little boy named Levi. And, on 9 August 2013, the family welcomed a new baby, Bree, also conceived using PGD.

“I know PGD isn’t an option for many women who carry mitochondrial disease. We are just so grateful to have been able to have two more children who are healthy and have their whole lives ahead of them.´ 40 '<63+$6,$ '(0(17,$ Lack of coordination in speech, and failure Loss of cognition and mental functions due to to arrange words in an understandable way; a disease or disease process. due to brain lesion. Aphasia is the complete *ORVVDU\RIWHUPV or near complete absence of speech, and is '1$ used to describe a more severe situation than Deoxyribonucleic acid; a two-stranded dysphasia. $&,'26,6 molecule that contain the genes that provide Elevated amounts of organic acids in the &2(1=<0(4 (Ubiquinone): A vitamin cofactor responsible the blueprint for all of the structures and (/(&752175$163257&+$,1 blood, which accumulate when food is not functions of a living being. Most human DNA is properly metabolised. for transferring electrons in the oxidative See respiratory chain. phosphorylation system. nDNA, which is a huge molecule that is folded $'3 tightly and stored in the nucleus of the cell. (1&(3+$/23$7+< MtDNA is a much smaller molecule stored in Adenosine diphosphate; the low energy &203/(;,The ¿rst component of Any disease of the brain. oxidative phosphorylation, which transfers the mitochondria. product produced when ATP releases energy (1=<0( to the cell. electrons from NADH to Coenzyme Q. PW'1$ A protein that speeds up a chemical reaction $3+$6,$ &203/(;,, Mitochondrial DNA contain the genes that or causes a chemical change in another code for some of the enzymes and some of Impaired or absent language function, usually (Succinate dehydrogenase). The third substance. Enzymes do their work without the necessary molecules needed to make referring to speech; which results from component of oxidative phosphorylation, being changed or used up in the process. those enzymes of the respiratory chain. an injury to brain structures usually in the which transfers electrons from succinate to Mitochondria are the only part of the body *(1( dominant hemisphere (the side of the brain Coenzyme Q. cell with their own separate and unique DNA. The fundamental unit of heredity. Genes are that controls language function is usually the Regardless, most of the mitochondria and the located on strands of DNA found in the cells side opposite to the handedness of the person &203/(;,,, respiratory chain are coded by nDNA. MtDNA and mitochondria. and is referred to as the dominant hemisphere the third component of oxidative is inherited only from the mother. by de¿nition). phosphorylation, which transfers electrons from Coenzyme Q to cytochrome c. +<32721,$ Poor muscle tone, such as seen in “Àoppy $7$;,$ Q'1$ Nuclear DNA; located in the nucleus of the babies´. Un-coordination; inability to coordinate the &203/(;,9 cell, this DNA contains the blueprints for cells muscles in voluntary movement. (Cytochrome c oxidase, COX). The fourth component of oxidative phosphorylation, which make up the body. /$&7$7(RU/$&7,&$&,' A chemical that is formed when sugars are $73 which transfers electrons from cytochrome c to broken down for energy without the presence Adenosine triphosphate; cellular energy oxygen. 51$ Ribonucleic acid (RNA) is one of the essential of adequate oxygen. Lactic acid cannot be is stored in the third phosphate bond. ATP macromolecules for life; it regulates how used by the body and will accumulate in blood is formed from ADP and phosphate in the &203/(;9 genes are turned on and made into proteins. and urine. Lactic acid causes the muscle pain process known as oxidative phosphorylation. (ATP synthase). The ¿nal component of oxidative phosphorylation, which uses the RNA is present in all cells and organelles when one runs too fast for too long. In people %(7$2;,'$7,21 proton gradient generated by Complexes I, III within cells such as mitochondria. Defects in with mitochondrial disorders, lactic acid forms A series of metabolic reactions necessary for and IV to convert ADP to ATP. RNAs or the regulation of RNAs can cause or when the oxidative capacity (ability to burn burning fatty acids (fats) contribute to many important human diseases foods using oxidative phosphorylation) of the &2; including mitochondrial diseases. person is impaired. &$51,7,1( Cytochrome c oxidase (Complex IV). Responsible for the transport of long chain '586(1 /(,*+',6($6(256<1'520( fatty acids into mitochondria. &3(2 Tiny yellow or white accumulations of Subacute Necrotizing Encephalomyelopathy; Chronic Progressive External Ophthalmoplegia extracellular material that build up in the eye. a form of mitochondrial disease associated &/2186 Syndrome; the combination of ptosis and with neurodegeneration, usually with onset in An abnormal movement characterised by rapid restricted eye movements is referred to as infancy. contraction and relaxation of muscles. opthalmoplegia. 42 /+21 087$7,21 nerves); tingling, numbness, pain, usually in of fear. Partial seizures are classi¿ed as Leber Hereditary Optic Neuropathy; a form A change in the DNA sequence, which can the hands or feet (sensory nerves); abnormal either simple or complex. In simple partial of mitochondrial disease associated with disrupt the normal function of a gene. blood pressure and heart rate, reduced ability seizures, there is no loss of consciousness. blindness, usually with onset in adulthood. to perspire, constipation, bladder dysfunction In partial complex seizures, consciousness 0<2&/2186 (autonomic nerves). is impaired. 0(/$6 A single spasm or twitching of a muscle. ‡ Petit-mal: Now called generalised absence Mitochondrial Encephalomyopathy Lactic Myoclonus can be a single event (twitch) or 32,17087$7,21 seizures. These are characterised by 5 to Acidosis and Stroke-like episodes; a form of repeated events. Myoclonus can be a normal The substitution of one nucleotide for another 15 second lapses in consciousness. During mitochondrial disease. event (the jerks that occur when we fall nucleotide in a gene. This can result in an absence seizure, the child appears to asleep) or an abnormal event (those that occur changing the amino acid sequence of the be staring into space and the eyes may roll 0(55) while awake, or those associated with seizures protein encoded by a gene or affect the upwards. Absence seizures typically occur Myoclonic Epilepsy and Ragged-Red Fibre or mitochondrial diseases). Clonus is the expression of the gene. in childhood and resolve in adolescence. disease; a form of mitochondrial disease. repeated spasms of muscles, due to a seizure Absence seizures are rare in adults. or increased muscle tone. 3726,6 0(7$%2/,60 Droopy eyelids. The process of cells burning food to produce 0<23$7+< 62',809$/352$7( energy. This is similar to a car’s engine (the Any abnormal conditions or disease of the 5(63,5$725< &+$,1 Anticonvulsant drug. cell’s mitochondria) burning petrol (the food we muscle tissues, which include the muscles Also known as Electron Transport Chain: eat) to produce the energy or torque that turns over our bones (skeletal muscle) and the heart The mitochondrial enzymes (also known as 67$786(3,/(37,&86 A life-threatening condition in which the brain the drive train that spins the car’s wheels (the (cardiac muscle). complexes I, II, III and IV) that are needed to energy we need to move and think). generate the electron and proton “gradient´ is in a state of persistent seizure for longer 1$53 across the mitochondrial inner membrane. than ¿ve minutes. 0,72&+21'5,$ Neuropathy, Ataxia and Retinitis Pigmentosa; A part of the cell (organelle) that is responsible a form of mitochondrial disease 5(7,123$7+< 8%,48,121( for energy production. The organelle consists Persistent or acute damage to the blood Coenzyme Q. of two sets of membranes: a smooth 1<67$*086 vessels inside the retina, causing vision loss continuous outer coat and an inner membrane Involuntary, erratic eye movements and blindness. arranged in tubules or in folds that form plate-like double membranes (cristae). The 23+7+$/023/(*,$ 6(,=85(6 principal energy source of the cell, containing A paralysis or weakness of one or more of the Disturbances of brain function, manifested as the cytochrome enzymes of terminal electron muscles that control eye movement. episodic impairment or loss of consciousness, transport and the enzymes of the citric acid abnormal movement, or sensory disturbances. 2;,'$7,9(3+263+25

D. Martinelli, M. Catteruccia, F. Piemonte, A. Pastore, G. Tozzi, C. Dionisi-Vici, G. Pontrelli, T. Corsetti, S. Livadiotti, V. Kheifets, A. Hinman, W.D. Shrader, M. Thoolen, M.B. Klein, E. Bertini, G. Miller, EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically de¿ned )XUWKHUUHDGLQJ Leigh Syndrome, Molecular genetics and metabolism, 107 (2012) 33-3

S. Ahola-Erkkila, C.J. Carroll, K. Peltola-Mjosund, V. Tulkki, I. Mattila, T. Seppanen-Laakso, M. E.A. Schon, S. DiMauro, M. Hirano, R.W. Gilkerson, Therapeutic prospects for mitochondrial Oresic, H. Tyynismaa, A. Suomalainen, Ketogenic diet slows down mitochondrial myopathy disease, Trends in molecular medicine, 16 (2010) 26-276. progression in mice, Human molecular genetics, 19 (2010) 1974-194. C.M. Sue. Mitochondrial disease: recognizing more than just the tip of the iceberg. Med J Aust. R. Davis, C.M. Sue. Genetics of mitochondrial disease. Seminars in Neurology. 2011; 2010; 193(4):195-6. Nov;31(5):519-30. Epub 2012 Jan 21. T. Taivassalo, R.G. Haller, Exercise and training in mitochondrial myopathies, Medicine and R.L. Davis, C. Liang, F. Edema-Hildebrand, C. Riley, M. Needham, C.M. Sue. Fibroblast Growth science in sports and exercise, 37 (2005) 2094-2101. Factor-21 is a sensitive biomarker of mitochondrial disease. Neurology 2013 in press (November M.A. Tarnopolsky, The mitochondrial cocktail: rationale for combined nutraceutical therapy in 19th issue) mitochondrial cytopathies, Advanced drug delivery reviews, 60 (200) 1561-1567.

S. Dimauro, P. Rustin, A critical approach to the therapy of mitochondrial respiratory chain and J. Torres-Torronteras, A. Gomez, H. Eixarch, L. Palenzuela, G. Pizzorno, M. Hirano, A.L. Andreu, oxidative phosphorylation diseases, Biochimica et biophysica acta, 1792 (2009) 1159-1167. J. Barquinero, R. Marti, Hematopoietic gene therapy restores thymidine phosphorylase activity in a A.W. El-Hattab, J.W. Hsu, L.T. Emrick, L.J. Wong, W.J. Craigen, F. Jahoor, F. Scaglia, cell culture and a murine model of MNGIE, Gene therapy, 1 (2011) 795-06. Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation, Molecular genetics and metabolism, 105 (2012) 607-614.  :HEVLWHV G.M. Enns, S.L. Kinsman, S.L. Perlman, K.M. Spicer, J.E. Abdenur, B.H. Cohen, A. Amagata, A. Barnes, V. Kheifets, W.D. Shrader, M. Thoolen, F. Blankenberg, G. Miller, Initial experience in the Australian Mitochondrial Disease Foundation: www.amdf.org.au treatment of inherited mitochondrial disease with EPI-743, Molecular genetics and metabolism, United Mitochondrial Disease Foundation: www.umdf.org 105 (2012) 91-102. Association of Genetic Support of Australasia: www.agsa-geneticsupport.org.au R. Horvath, G. Gorman, P.F. Chinnery, How can we treat mitochondrial encephalomyopathies? Approaches to therapy, Neurotherapeutics : the journal of the American Society for Experimental ClinicalTrials.gov (worldwide registry and results database): www.clinicaltrials.gov NeuroTherapeutics, 5 (200) 55-56. Genetics Home Reference (US National Library of Medicine): ghr.nlm.nih.gov T.D. Jeppesen, M. Schwartz, D.B. Olsen, F. Wibrand, T. Krag, M. Duno, S. Hauerslev, J. Vissing, Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy, Human Genome Organisation: www.hugo-international.org Brain : a journal of neurology, 129 (2006) 3402-3412. Mitochondria Research Society: www.mitoresearch.org H.C. Kang, H.S. Lee, S.J. You, C. Kang du, T.S. Ko, H.D. Kim, Use of a modi¿ed Atkins diet in MITOMAP human mitochondrial genome database: www.mitomap.org intractable childhood epilepsy, Epilepsia, 4 (2007) 12-16. OMIM (Online Mendelian Inheritance in Man - catalog of human genes and genetic disorders): S. Koene, J. Smeitink, Metabolic manipulators: a well-founded strategy to combat mitochondrial www.omim.org dysfunction, J Inherit Metab Dis, 34 (2011) 315-325. Rare Mitochondrial Disease Service for Adults and Children: www.mitochondrialncg.nhs.uk Y. Koga, Y. Akita, J. Nishioka, S. Yatsuga, N. Povalko, Y. Tanabe, S. Fujimoto, T. Matsuishi, L-arginine improves the symptoms of strokelike episodes in MELAS, Neurology, 64 (2005) 710- 712.

C Liang, C.M. Sue. How to treat mitochondrial disease. Australian Doctor. 2011 Mar 25:27-34. $FNQRZOHGJHPHQWV

The Mitochondrial Disease Report: Progress Towards Overcoming Life’s Energy Crisis is published by the Australian Mitochondrial Disease Foundation (AMDF) in the interests of promoting greater awareness and understanding of mitochondrial disease.

The AMDF gratefully acknowledges the involvement of the AMDF board and its Scienti¿c and Medical Advisory Panel of eminent clinicians and researchers, some of whom have generously contributed to this report. They include: t
3URIHVVRU-RKQ&KULVWRGRXORX Director, Western Sydney Genetics Program t
'U-RKQ'XOH\ an expert on metabolic diseases and pharmacogenetics at the University of Queensland t
3URIHVVRU$OHNVDQGUD)LOLSRYVND, an Australian Research Council Future Fellow at the University of Western Australia t
$VVRFLDWH3URIHVVRU3KLOOLSD/DPRQW neurologist and neurogeneticist at Royal Perth Hospital t
'U'RXJ/LQJDUG, radiologist and nuclear physician t
3URIHVVRU0LNH5\DQ, Head, Department of Biochemistry, La Trobe Institute for Molecular Science t
3URIHVVRU&DURO\Q6XH, Director, Department of Neurogenetics at Royal North Shore Hospital t
3URIHVVRU'DYLG7KRUEXUQ'LUHFWRU, Genetics Research Theme at the Murdoch Childrens Research Institute.

The AMDF also appreciates the contributions of: t
3URIHVVRU(G%\UQH, Vice Chancellor and President Monash University and AMDF Patron t
3URIHVVRU-XV6W-RKQ, Director of the Centre for Genetic Diseases at the Monash Institute of Medical Research t
'U.DUHQ&UDZOH\, a GP who is also the founder and operator of the AMDF Helpline t
2WKHULQGLYLGXDOVDQGIDPLOLHVaffected by mitochondrial disease who have shared their stories and photographs. Copyright © 2014 Australian Mitochondrial Disease Foundation Limited. All rights reserved. This work is copyright. You may download, display, print and reproduce this material in unaltered form only for your personal, non-commercial use or use within your organisation. Requests and enquiries concerning reproduction and rights should be addressed to the chief executive, AMDF. This report has been prepared for general information only and should not be relied on for decisions regarding medical care. Australian Mitochondrial Disease Foundation Suite 4, Level 6 9-13 Young Street Sydney NSW 2000

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