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How to diagnose mitochondrial disease

• No reliable and consistent means of diagnosis currently exist. The road to diagnosis is often personalized based on symptoms. Clinicians are working to create diagnostic and treatment standards for mitochondrial medicine.

• Diagnosis can be made by DNA testing and/or muscle biopsy.

• Diagnosis of mitochondrial disease can be invasive, expensive, time-consuming, and labor-intensive. Therefore, evaluation is not taken lightly. Doctors experienced in diagnosing and treating these diseases will take either a step-wise approach to diagnosis or, in some centers, the evaluation takes place over a few days. The evaluation includes a combination of clinical observations and laboratory tests.

• Diagnosis can be made by:

Evaluating the patient’s family history Performing a complete physical examination Performing a neurological examination Performing a metabolic examination that includes blood, urine, and optional cerebral spinal fluid tests Performing other tests, depending on the patient’s specific condition and needs. These tests might include: — Magnetic resonance imaging (MRI) or scan (MRS) if neurological symptoms are present — Retinal exam or electroretinogram if vision symptoms are present — Electrocardiogram (EKG) or echocardiogram if heart disease symptoms are present — Audiogram or BAEP if hearing symptoms are present — Blood test to detect thyroid dysfunction if thyroid problems are present — Blood test to perform genetic DNA testing More invasive tests, such as a skin or muscle biopsy, might be performed as needed.

• Lack of understanding of the disease and misinterpretation of symptoms can lead to misdiagnosis.

• Further progression of symptoms can occur if the symptoms are missed and opportunities for treatment and support are not recognized.

Diagnosis

None of the hallmark symptoms of mitochondrial disease — muscle weakness, exercise intolerance, hearing impairment, ataxia, seizures, learning disabilities, cataracts, heart defects, diabetes, and stunted growth — are unique to mitochondrial disease. However, a combination of these symptoms in one person strongly points to mitochondrial disease, especially when the symptoms involve more than one organ system.

To evaluate the extent of these symptoms, a physician usually begins by taking the patient’s personal medical history (a detailed family history including at least three generations is essential to assess hereditary patterns), and then proceeds with physical and neurological exams. At the bottom of this page is a table that explains in detail these tests and what they are expected to show.

Diagnostic tests in mitochondrial diseases

A physical exam typically includes tests of strength and endurance, such as an exercise test, which can involve activities like repeatedly making a fist, or climbing up and down a small flight of stairs. A neurological exam can include tests of reflexes, vision, speech, and basic cognitive (thinking) skills.

Depending on information found during the medical history intake and exams, a physician might proceed with more specialized tests that can detect abnormalities in muscles, brain, and other organs. 1

The most important of these tests is the muscle biopsy, which involves removing a small sample of muscle tissue to examine. When treated with a dye that stains mitochondria, muscles affected by mitochondrial disease often show ragged red fibers — muscle cells (fibers) that have excessive mitochondria. Other stains can detect the absence of essential mitochondrial enzymes in the muscle. It is also possible to extract mitochondrial proteins from the muscle and measure their activity. In most cases, genetic studies should be obtained before invasive testing such as muscle biopsy, thus, muscle biopsy is suggested when genetic testing cannot confirm the diagnosis or when required to rule out other conditions in the differential diagnosis. The main limitation of muscle biopsy in the diagnosis of mitochondrial myopathies is that it may be normal or show only minimal abnormalities for certain mitochondrial defects.

In addition to the muscle biopsy, noninvasive techniques can be used to examine muscle without taking a tissue sample. For instance, a technique called muscle phosphorus magnetic resonance spectroscopy (MRS) can measure levels of phosphocreatine and ATP (compounds that are often depleted in muscles affected by mitochondrial disease).

CT scans and MRI scans can be used to visually inspect the brain for signs of damage, and surface electrodes placed on the scalp can be used to produce a record of the brain’s activity called an electroencephalogram (EEG).

Similar techniques might be used to examine the functions of other organs and tissues in the body. For example, an electrocardiogram (EKG) can monitor the heart’s activity, and a blood test can detect signs of kidney malfunction.

Finally, a genetic test can determine whether someone has a genetic mutation that causes mitochondrial disease. Ideally, the test is done using genetic material extracted from blood or from a muscle biopsy. It is important to realize that although a positive test result can confirm diagnosis, a negative test result is not necessarily conclusive.

Diagnostic Tests in Mitochondrial Diseases

Clinical exam or oral history of family members

Can sometimes indicate inheritance pattern by noting “soft signs” in unaffected relatives. These include deafness, short stature, migraine headaches, and PEO.

4. Electron microscopy

1. Detects abnormal proliferation of mitochondria and deficiencies in cytochrome c oxidase (COX, which is complex IV in the electron transport chain).

2. Detects presence or absence of specific proteins. Can rule out other diseases or confirm loss of electron transport chain proteins.

3. Measures activities of specific enzymes. A special test called polarography measures oxygen consumption in mitochondria.

4. May confirm abnormal appearance of mitochondria, though not used often today.

Blood enzyme test

1. Lactate and pyruvate levels

2. Serum creatine kinase

1. If elevated, may indicate deficiency in electron transport chain; abnormal ratios may help identify the part of the chain that is blocked.

2. May be slightly elevated in mitochondrial disease but usually only high in cases of mitochondrial DNA depletion.

1. Known mutations

2. Rare or unknown mutations

1. Uses blood sample or muscle sample to screen for known mutations, looking for common mutations first.

2. Can also look for rare or unknown mutations but may require samples from family members; this is more expensive and time-consuming.

·Complete blood count

·Serum creatine kinase (CK) and uric acid

·Serum lactate and pyruvate

·Lactate/pyruvate ratio if serum lactate is elevated

·Serum amino acids (for elevated alanine)

·Serum acylcarnitine (low free carnitine and elevated acyl/free carnitine ratio are suggestive of disrupted fatty acid oxidation)

·Serum and urine 3-methylgluticonic acid

These tests are suggested by the consensus-based expert recommendations for the evaluation and diagnosis of mitochondrial disease published in 2014. 2

Affiliations

  • 1 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 2 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Department of Paediatrics, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 3 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 4 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. Electronic address: [email protected]
  • PMID: 32674947
  • DOI: 10.1016/j.tig.2020.06.009
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Authors

Affiliations

  • 1 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 2 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Department of Paediatrics, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 3 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 4 Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. Electronic address: [email protected]
  • PMID: 32674947
  • DOI: 10.1016/j.tig.2020.06.009

Abstract

Mitochondrial disorders have emerged as a common cause of inherited disease, but are traditionally viewed as being difficult to diagnose clinically, and even more difficult to comprehensively characterize at the molecular level. However, new sequencing approaches, particularly whole-genome sequencing (WGS), have dramatically changed the landscape. The combined analysis of nuclear and mitochondrial DNA (mtDNA) allows rapid diagnosis for the vast majority of patients, but new challenges have emerged. We review recent discoveries that will benefit patients and families, and highlight emerging questions that remain to be resolved.

Keywords: genetic diagnosis; mitochondrial disease; molecular diagnostics; mtDNA mutation; whole-genome sequencing.

How to diagnose mitochondrial disease

Scientists have developed a new strategy for diagnosing mitochondrial diseases and identified the Mrps34 gene as a cause for Leigh syndrome.

Diagnosing mitochondrial diseases is often a hard task, and while genetic screening of a person’s entire genome has helped, additional strategies are in need to identify the most difficult cases.

Now, a team of scientists at the Murdoch Children’s Research Institute (MCRI)В in Australia found a new cause underlying Leigh syndrome, the most common form of childhood mitochondrial disease.

They found mutations in a gene called Mrps34 in six patients with Leigh syndrome from different parts of the world, including Australia, France, and the United States. The findings were only possible with researchers applying a different technique called quantitative proteomics.

“A key approach was using quantitative proteomics. This process involves sampling all the proteins in a cell at once to identify any problems with the cellular machinery,” Nicole Lake, a Murdoch PhD studentВ and the study’s first author, said in a press release. “Using this technique, you get a snapshot of what’s happening in cells.”

The MRPS34 is a component of mitochondrial ribosomes, called mitoribosomes, which are the protein synthesis machinery responsible for the production of proteins involved in the mitochondrialВ oxidative phosphorylation (OXPHOS) system. This system, located in the inner membrane of our mitochondria, is where the majority of the energy used by cells is produced.

Researchers performed quantitative proteomics in skin cells extracted from the six patients as well as in healthy skin cells, called controls. They found that the mutations led to a reduction in MRPS34 protein levels. Examining the mitoribosome profile by quantitative proteomics showed that its assembly was impaired, with half of its members falling apart.

These results establish theВ Mrps34 gene as an important cause for mitochondrial diseases and that employing quantitative proteomicsВ could help improve the diagnosis of these fatal diseases.

“This approach will therefore help to end the diagnostic odyssey for families with children suspected of mitochondrial and other inherited diseases,” said Murdoch chief investigator and Prof. David Thorburn, the study’s lead author.

“Early diagnosis improves the chance for early intervention. It can also provide the opportunity to enroll patients withВ mitochondrial diseasesВ into clinical trials to test many new promising therapies that are in the pipeline, but not yet proven,” Thorburn added.

Sean Murray, CEO of the Australian Mitochondrial Disease Foundation (AMDF) said he was thrilled to see “an outcome like this, as it has been partly supported by the hard work of AMDF fund-raisers through activities such as our ‘Bloody Long Walks’ and demonstrates the value of researchers engaging with the patient community.”

Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria – mitochondria that don’t work properly. It can affect energy intensive systems within the body including:

  • liver
  • kidneys
  • pancreas
  • brain
  • digestive tract
  • muscles

It can affect multiple systems in the body including the liver, kidneys, pancreas, brain and digestive tract. The eyes, inner ear, muscles and blood may also be affected. Click here to view an illustration.

There are currently over 300 illnesses associated with mitochondrial dysfunction, and the list is growing. Every 30 minutes, a child is born with mitochondrial disease and about 1 in 4,000 people has the disease.

Each condition is the result of a genetic mutation – a specific change in the genetic material of the mitochondria. The mutations occur in the mitochondrial DNA (mtDNA) or nuclear genes (nDNA) and cause the mitochondria to fail. At least 1 in 200 individuals harbor a mitochondrial mutation.

Healthy mitochondria convert oxygen and the sugar, fat and protein from the foods we eat into energy-rich molecules called ATP (adenosine triphosphate). Energy from ATP is needed to carry out vital functions that our bodies need to survive and thrive. The mitochondrion is very susceptible to damage. When mitochondria are not functioning properly, their impacts on the body can be devastating. To view the body system affected by the primary mitochondrial disease, click here.

During the production of ATP, your mitochondria produce waste called free radicals. This toxic waste can cause specific changes (mutations) in the genetic material of the mitochondria that damage the mitochondrion itself and can cause cell dysfunction and disease. Mitochondrial disease results when the production of cellular energy is defective.

Primary mitochondrial disease (PMD) is genetically inherited and diagnosed by identifying mutations on mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that result in mitochondrial dysfunction. PMDs can occur due to germline mutations mtDNA and/or nDNA genes encoding ETC proteins. Point mutations can occur in any of the mtDNA’s 37 genes encoding 13 proteins or the 1,000 nDNA genes, which are essential for optimal ETC function. Some common primary mitochondrial diseases include:

  • MELAS
  • NARP
  • Leigh’s Syndrome
  • MERRF
  • LHON
  • Kern-Sayre Syndrome
  • MNGIE
  • Aplers

How to diagnose mitochondrial disease

We estimate that over 10,000 Canadian’s suffer from primary mitochondrial diseases – most are yet to be diagnosed.

Secondary mitochondrial dysfunction (SMD) can be caused by genes encoding neither function nor production of specific proteins, oxidative stress, drug toxicity or environmental factors. Distinguishing whether mitochondrial dysfunction is inherited or acquired is extremely challenging. The best method for making this distinction is still poorly understood. One of the most reliable (but not all-encompassing) tools is comprehensive molecular testing (genome sequencing) of both mDNA and nDNA which, at least in some cases, can ultimately distinguish between PMD and SMD.

Unfortunately, there is no single test that can determine whether you do or do not have mitochondrial disease.

Mitochondrial disease is difficult to diagnose because it affects different people in different ways. It is estimated millions of Canadians suffer from diseases in which mitochondrial dysfunction is involved. These include diabetes, diseases of the heart, kidney and liver, Alzheimer’s, ALS, Parkinson’s, autism, cancer, blindness, deafness, chronic fatigue, infertility and more. There is no cure for mitochondrial disease – yet.

MitoCanada is transforming the outlook for people with mitochondrial disease by raising awareness, offering knowledge and support to patients, families and caregivers and, funding transformational research.

Who is at risk?
The more energy a cell needs, the more mitochondria they have. Because our brain, heart, liver, kidneys, digestive tract and muscles need the most energy, they are the most susceptible to mitochondrial disease.

General Rule: If three or more organ systems are involved, mitochondrial disease may be suspected.

What to expect, how to manage it and where to find support.

A diagnosis of mitochondrial disease can be unexpected, confusing and frightening. Initially, you may feel overwhelmed by a wave of emotion, from fear to worry to incredible sadness, despair and grief. However, the immediate reaction may also be one of numbness – frozen by the shock of the news. Some other common emotional reactions to diagnosis include:

  • Anger – a feeling of ‘why now’, or ‘why me / my child’.
  • Fear or anxiety about what this might mean for the future.
  • Grief – in response to the loss of the life you thought you might have, or the life you expected for your loved one.
  • Feeling powerless, or ruminating on all of the worst things that might happen.
  • Regret or guilt – feeling that you could have done something to change the situation, even if that wasn’t possible.
  • Denial – being unable to accept the diagnosis or that something is wrong.
  • Changes to your sense of self – a feeling that you are no longer ‘you’, or that your diagnosis is now part of you in some way.

There is no right or wrong way to be feeling in response to a diagnosis. People may have different emotions at different times, and not everyone will show their feelings in the same way. For this reason, it’s important not to have expectations about how others should respond. Someone might not express their emotions in the same way as you, but that doesn’t mean they don’t feel upset by the news. They may be coping with it in their own way, and in their own time.

Because everyone’s experience is different, it is hard to say with certainty what will be helpful. Here are some general guidance that might be helpful following diagnosis.

If you or someone in your care has received a diagnosis

  • Try not to question your emotional experience or fight your feelings. Allow yourself the space to feel your emotions as they arrive. Not doing can result in increased stress and anxiety.

Be patient with the pace of information. You are bound to have a lot of questions, and it can feel like you want all the answers right away. While it’s natural to feel this way, try to remember that your doctors and consultants are doing all they can to help you, and be patient with them while they find out the next steps to help you manage symptoms and plan for the future.

Avoid information overload. It can be tempting to google your condition and read about everything all at once, however not all the information you find online will be inaccurate or relevant to your diagnosis. Instead, use reliable sources of information such as your medical specialists, mito charities or support groups who have real experience of the condition.

Connect with others in your situation. Receiving a diagnosis can be an isolating experience, and at first you might find it difficult to talk about it with others. But connecting with an online support group or attending a patient day will put you in touch with others who understand what you’re going through, have lived through it, and who can offer you emotional and practical support. Many people who are affected by mitochondrial disease say that connecting with others in their situation made a huge difference.

  • Recognise that change is difficult. Adjusting to life changing news is incredibly hard and takes times to digest. During this period, it’s really important to focus on self-care. This means ensuring you have adequate sleep, nutrition and hydration, and exercise where possible. Try and maintain healthy habits and routines where possible, as these will directly contribute your emotional and physical wellbeing and help you through this very difficult time.
  • If a family member or loved one has received a diagnosis

    • Offer your support. Be present and be there, in whatever way you might be needed. Try and maintain this over time, as often people experience lots of offers of support in the short-term, which then fades away over time. This is especially true for longer-term health conditions like mitochondrial disease.
    • Listen. Simply by listening, you will be helping the person to process and come to terms with their feelings. You might feel like you’re not much use, or like you want to ‘fix’ the problem for them, so remember that just by listening you are giving their feelings somewhere to be. Try to resist the urge to say things like ‘everything will be fine’ or ‘I know how you feel’, and don’t compare their situation to someone else’s. Everyone’s experience is unique.

    Get informed. Finding out all can about the condition will help the person feel less isolated and you’ll be better placed to help them. Make sure you use reliable sources of information (e.g. a charity, medical consultant or support group) and avoid giving the person specific medical advice or guidance that has not come from their specialist practitioner.

  • Don’t try too hard. Sometimes, the affected person might not want to talk about it. Remember to give them space, and don’t take it personally if they reject your offer of help, or if they get angry or upset. If they seem to be managing, avoid telling them that they should talk.
  • Need help?

    If you or a loved one have recently been diagnosed with a mitochondrial disease, support is available through The Lily Foundation. Talking to someone who understands your situation can bring a sense of relief and clarity, and help you to plan a way forward. We can also give you useful information about support groups, specialist services, patient days etc.

    To get in touch call 0300 400 1234 or email [email protected] . All conversations are private and confidential, and we respect your right to decide what’s best for you.

    How to diagnose mitochondrial disease

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    DIAGNOSTIC SERVICES FOR MITOCHONDRIAL DISORDERS
    & METABOLIC MYOPATHIES

    How to diagnose mitochondrial diseaseThe Columbia University Department of Neurology is world-renowned for many pioneering studies on mitochondrial and metabolic myopathies.

    We provide comprehensive biochemical, morphological and DNA analyses to diagnose mitochondrial diseases, and to detect glycogenoses and disorders of lipid metabolism.

    The laboratory is under the supervision of Salvatore DiMauro, MD, a recognized leader in the field. The Laboratory Director is Ali Naini, PhD, and the Medical Director is Michio Hirano, MD.

    We provide personalized service and consultation, in order to help you decide on the most appropriate tests to order and to help you understand and interpret the results.

    Find out more about glycogenoses and disorders of lipid metabolism and the services we provide

    Please note, our address has changed to:
    Laboratory of Personalized Genomic Medicine
    Department of Pathology and Cell Biology
    Columbia University Medical Center
    630 West 168th Street, P&S 17th Floor, Room 401
    New York, NY 10032

    Tel. 212-305-9706
    Fax: 212-342-0420

    Affiliations

    • 1 Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK. [email protected]
    • 2 Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK.
    • PMID: 26759002
    • DOI: 10.1007/s12098-015-1932-y
    • Search in PubMed
    • Search in NLM Catalog
    • Add to Search

    Authors

    Affiliations

    • 1 Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK. [email protected]
    • 2 Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK.
    • PMID: 26759002
    • DOI: 10.1007/s12098-015-1932-y

    Abstract

    Disorders of the mitochondrial respiratory chain are an exceedingly diverse group. The clinical features can affect any tissue or organ and occur at any age, with any mode of inheritance. The diagnosis of mitochondrial disorders requires knowledge of the clinical phenotypes and access to a wide range of laboratory techniques. A few syndromes are associated with a specific genetic defect and in these cases it is appropriate to proceed directly to an appropriate test of blood or urine. In most cases, however, the best strategy starts with biochemical and histochemical studies on a muscle biopsy. Appropriate molecular genetic studies can then be chosen, based on these results and the clinical picture. Unfortunately, there is currently limited availability of respiratory chain studies in India. Exome sequencing is undertaken increasingly often; without preceding mitochondrial studies, this can lead to misleading results.

    Keywords: Exome sequencing; Histochemistry; Lactic acid; Muscle biopsy; Neurodegeneration; mtDNA.

    • Find this author on Google Scholar
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    • For correspondence: [email protected]

    Key points

    Mitochondrial DNA disorders are a common cause of inherited disease, affecting 1 in 5,000 of the UK population 1

    They should be considered in any complex multisystem disorder, especially those disorders in which neurological, ocular or endocrine features predominate

    Many patients will fit neatly into defined classic syndromes, but significant numbers are oligosymptomatic, or have an overlapping, poorly defined, phenotype

    If a mitochondrial disorder is suspected, it is vital to assess fully the clinical phenotype in the patient and their relatives with symptoms, paying particular attention to the non-neurological manifestations, because these can often be effectively managed

    Counselling depends on the underlying molecular basis of disease and might necessitate discussion with specialist centres

    There are currently no treatments known to modify the underlying disease process

    Investigation of mitochondrial disorders can be complex and might necessitate referral to one of the three commissioned groups forming the Rare Mitochondrial Disorders Service for Adults and Children (in Newcastle, Oxford and London)

    Numerous mitochondria are present in every nucleated cell in the body. They have a diverse role in cellular metabolism and are the principal source of adenosine triphosphate (ATP). ATP is produced through oxidative phosphorylation (OXPHOS) by the mitochondrial respiratory chain. Impairment of OXPHOS leads to cellular dysfunction and, eventually, cell death. As a result, mitochondrial disorders primarily affect tissues that have a high metabolic demand, such as the neural, muscular, cardiac, ocular and endocrine systems.

    Mitochondrial function is dependent on the interplay of mitochondrial DNA and the nuclear genome. 2 Mitochondria contain their own DNA (mtDNA), which comprises 16,569 base pairs (bp) and encodes only 37 genes (compared with the 3.3 billion bp in, and thousands of genes encoded by, the nuclear genome). However, most of the approximately 1,500 mitochondrial proteins are coded by nuclear DNA and synthesised on cytoplasmic ribosomes. 3 Therefore, abnormalities of mitochondrial proteins can result from defects in both mtDNA and nuclear DNA, and so cause maternally inherited, Mendelian (autosomal dominant, recessive or X-linked), or sporadic diseases (owing to de novo mutations, or recessive inheritance).

    How to spot mitochondrial disease

    Although mitochondrial disease can present with a heterogeneous array of symptoms, there are certain key neurological clinical features that suggest the possibility of such disease (Fig 1; Table 1). Occasionally, these features form a ‘classic mitochondrial syndrome’ (Table 2). Although some patients fall neatly into a defined syndrome, many patients will be so-called ‘oligosymptomatic’, having one or two components of a syndrome (such as a young individual with an occipital stroke-like lesion, or mild nonfatigable ptosis without ophthalmoplegia), and are more problematic to reach a diagnosis for. These patients often also have several other features that, if present, further support evidence of a mitochondrial disease. A clinician should look and test for these additional feature if suspecting the diagnosis (Table 3). Non-neurological involvement in a patient with unexplained multisystem neurological disease is a ‘red flag’ for mitochondrial disease. Finally, and perhaps most challenging, are patients presenting with ‘non-specific presentations’ (such as epilepsy, diabetes or sensorineural deafness), who often have a multisystem disease that does not fit neatly into any particular category. In these circumstances, the diagnosis of a mitochondrial disorder is often only made in a tertiary referral centre with direct access to specialist laboratory investigations.