The challenges of recognising mitochondrial diseases

12 minute read

Mitochondrial diseases are a diverse group of disorders affecting cellular energy production and represent the most common form of inherited metabolic disorders

The presentations for mitochondrial diseases is highly variable and diagnosis can be challenging, even for specialist clinicians.

With limited teaching and awareness of mitochondrial diseases, it is important that mitochondrial diseases can be recognised on the frontline.


A 48-year-old lady presents to you describing “missing” parts of her vision with preserved central acuity, which has been gradually getting worse over several months.

Her background history is relevant for type 2 diabetes, diagnosed at the age of 35 with a normal BMI at diagnosis. She is managed with insulin, and has developed mild diabetic nephropathy. There have been no macro vascular complications. She also describes hearing loss, which occurred fairly suddenly in her early 30s, one ear after the other. She wears hearing aids now.

Her other medical history includes gallstone pancreatitis and hypercholesterolemia. She is a non-smoker who does not drink alcohol. She works full time in clerical work, and is married with two adult children. She has a family history of diabetes in her mother, and her maternal aunt and her aunt also has significant hearing impairment.

Examination reveals a lady of short stature, approximately 150cm tall. She is overweight. Her eye examination reveals normal visual acuity of 6/6 in both eyes. However she does have abnormal visual fields, with a doughnut shaped scotoma, sparing central acuity in both eyes. Funduscopy reveals marked retinal pigmentary epithelial atrophy in the perimacular region sparing the fovea. She has a mildly abnormal neurological examination with depressed ankle jerks and difficulty with heel-toe walking.

Her history and examination findings are suspicious for Maternally Inherited Diabetes and Deafness (MIDD), a disorder caused by the most common mitochondrial DNA mutation, m.3243A>G. It is suspected that the visual field loss is due to a maculopathy, often seen in patients with MIDD. DNA sequencing of her mitochondrial DNA confirms the diagnosis.

This case exhibits some of the common findings in mitochondrial disease, but is by no means representative. The spectrum of symptoms, both in type and severity, can be confusing and daunting.

It is always worth reminding oneself that mitochondrial disease can present at any age, in any organ, at any severity. However, there are certain signs that should prompt a search for mitochondrial disease; and there are some constellations of symptoms that point to specific mitochondrial syndromes.

As mitochondria are responsible for ~90% of cellular energy production, mitochondrial disease symptoms often occur in organs with high energy needs, reflecting an inability of impaired mitochondria to keep up with cellular demands.

A non-exhaustive, top-down list of “red flag” symptoms include short stature, stroke-like episodes, cognitive impairment, ataxia, progressive external ophthalmoplegia, ptosis, optic neuropathy, retinal pigmentary abnormalities, hearing loss, cardiomyopathy, cardiac conduction defects, slowed gastric and colonic transit, low weight, diabetes mellitus, proximal myopathy and peripheral neuropathy. (1)

From this list, it becomes apparent that mitochondrial diseases may go unrecognised due to the overlap with more common diseases, although often behave atypically – which in itself is a flag for mitochondrial disease. This is further complicated by variability in clinical presentations (even for the same disorder, and also in the same family), with phenocopies and genocopies common. (2)

Specific syndromes commonly presenting in adult patients include those caused by the common m.3243A>G mutation – Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes (MELAS) or Maternally Inherited Diabetes and Deafness (MIDD). Other characteristic presentations are Leber’s Hereditary Optic Neuropathy (LHON), which typically presents in young men as bilateral, sequential, painless and devastating visual loss. Myoclonic Epilepsy with Ragged Red Fibres (MERRF) presents with myoclonic epilepsy and ataxia. Leigh Syndrome is an early onset disease with multiple causative genetic mutations, and results in psychomotor regression, often with other complex neurological defects and premature death.

These are just some of the numerous distinct mitochondrial disorders. (3)


If a patient presents with suspected mitochondrial disease, based either on characteristic individual features or a constellation of typical features (as outlined above, especially if three or more organ systems are involved, or an atypical presentation of a common disease) and/or family history (which can follow maternal (mitochondrial) or mendelian modes of inheritance), there are some simple and important tests to undertake before referring on for specialist review.

Simple blood tests can exclude (potentially treatable) alternative diagnoses, while also evaluating organ involvement, and should include FBC, UEC, LFTs, Glucose and HbA1c, inflammatory and autoimmune screens, serum protein electrophoresis, B12, folate and thyroid function tests. CK should be checked; it may be elevated in mitochondrial disease, amongst other (mainly muscle) conditions. Lactate may also be elevated, although frequently falsely due to processing.

Simple cardiac evaluation with electrocardiogram, holter monitor and echocardiogram is important if there is a high suspicion for mitochondrial disease, as both cardiomyopathy and conduction defects are associated with mitochondrial diseases and can be life-threatening and treatable.

Arranging for the patient to have their eyes checked, including retinal photography, in addition to macular and optic nerve optical coherence tomography, can provide valuable diagnostic clues also.

An audiogram is also easily arranged and high frequency sensorineural impairment, particularly prematurely, can be suggestive of mitochondrial disease.

If there are muscle symptoms, requesting nerve conduction studies with electromyography when referring for specialist review can also provide useful diagnostic information. Similarly, if there is any suspicion the patient might have seizures, referring for electroencephalogram can also provide important supportive information. If migraines are prominent or there have been “stroke-like” episodes, ensure brain imaging with magnetic resonance imaging has been done.

Where to refer can also be challenging; as diagnosis is often difficult, expertise in mitochondrial disease is beneficial.

For children, a paediatric neurologist or metabolic physician is best placed to evaluate for mitochondrial disease, but many general paediatricians will also be comfortable progressing this question and considering important differentials.

For adults, a neurologist is best placed to evaluate and diagnose mitochondrial disease; ideally one with specific expertise in mitochondrial disease (most states now have one or two) or neurogenetics.

When eye manifestations predominate, a neuro-ophthalmologist or ophthalmologist can also be an appropriate first point of referral, usually in conjunction with a neurologist.

Diagnosis is often challenging, requiring a stepwise approach, and the patient may require multiple tests from multiple medical specialties (as outlined above).

A synthesis of clinical features and associated tests (biochemical and imaging) can be indicative of mitochondrial disease, however definitive diagnosis generally requires identification of a genetic cause.

As >1200 genes are associated with mitochondrial structure and function (4) and mutations in around 300 of these genes have been associated with mitochondrial diseases to date, (3) the genetic landscape for diagnosis is vast.

Despite this, definitive genetic diagnosis remains elusive in around half of patients. The patient should be made aware that diagnosis can be challenging and can take substantial time, possibly years. (5)


Unfortunately, there is no cure yet for mitochondrial disease (although treatments for some specific disorders do exist), and management is largely supportive.

As the disease has many forms, specific organ system screening and management, including cardiac, respiratory, hearing, vision, cognitive and gastrointestinal function will be guided by the specialist team(s), while the GP is key for co-ordination and oversight, and there are some common and important general themes.

Maintaining good general health is key; ensuring adequate and appropriate nutrition is vital and can slow progression of disease. Often, this requires frequent small meals (due to slowed gastrointestinal transit), and unintentional weight loss or low body weight should prompt dietitian review.

Equally, ensuring what goes in also comes out is important, and aperients are typically required. Movicol is preferred, whilst bulking agents can exacerbate the problem and are best avoided.

Managing fatigue, which is frequently prominent, is achieved through measured activity while ensuring adequate rest and sleep; a trial of a mitochondrial supplement (such as ATP support from Bioceuticals) can sometimes improve this symptom.

Consider a sleep study if there are flags, as both central and obstructive sleep apnoea can occur.

Maintenance of physical function is essential while avoiding excessive physical activity or exhaustion, which can precipitate or exacerbate symptoms.

Regular exercise can simultaneously improve stamina and mitochondrial function, noting that exercise should be low intensity, aerobic and gradually incremented.

It is suggested that initially five minutes of aerobic activity with target HR 70% of max [(220-age)*0.7] should be carried out three to five times weekly, and then each workout incremented by a minute every week. An appropriately experienced physiotherapist or exercise physiologist can help guide and support.

Many vitamins and cofactors are postulated to benefit, albeit with little supportive evidence, and a trial of mitochondrial supplements (either individually or in combination, such as ATP support) with evaluation for symptomatic benefit is reasonable.

Smoking, nicotine and alcohol can hasten progression and should be avoided, while nicotine, including nicotine replacement therapy, can also damage mitochondria.

Avoiding metabolic stress (including infections) is important, as the increased energy demand of acute illness can exacerbate mitochondrial disease, with prominent fatigue and prolonged recovery, and at times may be life threatening.

Vaccinations should be kept up-to-date (including seasonal influenza) and early antibiotic treatment should be considered.

If the patient becomes acutely unwell, early escalation of care is appropriate.

Stroke-like episodes (the most severe neurological manifestations) may be precipitated by metabolic stressors (sleep deprivation, infection, significant emotional stress) and may be preceded by a clinical prodrome including nausea, vomiting and headache, with fever, drowsiness and/or seizures.

Gastrointestinal disease may manifest as vomiting and pseudo-obstruction, which may require admission for supportive care although non-surgical management is recommended.

Ensuring psychological health and support is critical. Adjusting to a chronic incurable disease with many and varied symptoms can be daunting, particularly when the diseases are little known, and depression is a common exacerbating feature.

In children, learning and behavioural problems are common, and educational support with a tailored plan should be facilitated.

Mitochondrial diseases are typically progressive, and ensuring good social support networks, financial security, and facilitating appropriate disability support early can significantly improve quality of life for those affected.

Most patients should qualify for NDIS support encompassing many aspects of their disease.


Various medications can negatively affect mitochondria: antiretroviral medications, including azidothymidine and other nucleosides, are mitochondrial toxins and should be avoided, as should doxorubicin (a chemotherapeutic), as it can induce a mitochondrial cardiomyopathy.

Metformin should be avoided as it can cause lactic acidosis, and statins may deplete Coenzyme Q10 so benefits should be carefully weighed.

Aminoglycoside antibiotics can induce mitochondrial hearing loss and alternatives should be used. Erythromycin and amphotericin are also best avoided. Furthermore, sodium valproate can be catastrophic in certain mitochondrial diseases (e.g. POLG-related disease) and should be avoided where possible until a more definitive diagnosis can be obtained.

There is a general consensus that mitochondrial disease patients are more susceptible to surgical complications. Due to the physiological stress imposed and the fact that most anaesthetic compounds inhibit mitochondrial function directly or indirectly, surgery should be carefully considered. (6)

If surgery is required, appropriately informed anaesthetic management is important. The anaesthetist should be advised well in advance, and in conjunction with a mitochondrial disease specialist, should make an appropriate perioperative plan.

This would often encompass appropriate anaesthetic and/or sedative agents, anticipating prolonged perioperative observation and care that minimises metabolic fluctuation (i.e. minimising fasting).


Mitochondrial diseases can be challenging to recognise. The sheer variability of disease types, presentations and disease progression means that diagnosis and management are often complex.

Despite the complexity, red flags, clinical constellations and basic tests can support a suspicion of mitochondrial disease. As mitochondrial diseases overlap with a myriad of other diseases, it is important to perform basic tests that support referral to specialist mitochondrial disease clinics.

In the absence of a cure, clinical management prioritises supportive care and prevention of complications, and general healthy behaviours can benefit mitochondrial health.

Certain aspects of care are contraindicated for patients with mitochondrial diseases and can have variable outcomes from worsening disease to catastrophic.

The importance of frontline clinicians to recognise potential mitochondrial disease patients and co-ordinate initial workups and cross-specialty care is paramount to timely diagnosis, appropriate management, improved disease progression and better patient outcomes.


  1. Davis RL, Liang, C, Sue CM. (2018) Chapter 10 – Mitochondrial Diseases. Handbook of Clinical Neurology 147: 125-141
  2. Gorman GS et al. (2016) Mitochondrial Diseases. Nature Reviews Disease Primers 2: 16080
  3. Chinnery PF. (2014) Mitochondrial Disorders Overview. GeneReviews®
  • Frameworks for Sick Mito Patient plans and protocols for when mitochondrial disease patients become ill can be found at

Dr Eloise Watson is an advanced neurology trainee in the Department of Neurology, Royal North Shore Hospital, Sydney and a Neurological Foundation of New Zealand Chapman Fellow.

Dr Kate Ahmad is a consultant neurologist in the Department of Neurology, Royal North Shore Hospital, Sydney, with sub-specialty expertise in neuro ophthalmology.

Dr Ryan Davis is a NSW Health EMC research fellow in the Department of Neurogenetics at the Kolling Institute, University of Sydney and Royal North Shore Hospital, Sydney.


  1. Gorman GS, Chinnery PF, DiMauro S, et al. Mitochondrial diseases. Nature Reviews Disease Primers 2016;2:16080.
  2. Davis RL, Liang C, Sue CM. Mitochondrial diseases. Handbook of Clinical Neurology 2018;147:125-41.
  3. Martikainen MH, Chinnery PF. Mitochondrial disease: mimics and chameleons. Practical Neurology 2015;15:424-35.
  4. Calvo SE, Clauser KR, Mootha VK. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Research 2016;44:D1251-7.
  5. Grier J, Hirano M, Karaa A, Shepard E, Thompson JLP. Diagnostic odyssey of patients with mitochondrial disease: Results of a survey. Neurology Genetics 2018;4:e230.
  6. Niezgoda J, Morgan PG. Anesthetic considerations in patients with mitochondrial defects. Pediatric Anaesthesia 2013;23:785-93.




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