Medical Info

Until about five years ago, mitochondrial disease (the name, not the disease), did not seem to exist. It is an illness that seems to have suddenly appeared and one that most GPs don’t know about. Therefore, it’s easy to think that it must be rare, unimportant, or even not serious.

However, type ‘Mitochondrial Disease’ into Google and faces appear of people who have it, many are children. Although medicine continues to advance rapidly, why is this illness not being considered, and why do most sufferers remain undiagnosed or misdiagnosed?

Many experts refer to mitochondrial disease as the ‘notorious masquerader’ because it mimics so many different illnesses, affecting both children and adults. Due to its widespread variety and severity of symptoms, diagnosing mitochondrial disease can be extremely difficult.

Recent research demonstrates that mitochondrial mutations are present in at least 1 in 200 people and that at least 1 in 5,000 will develop serious illness. So here’s how we summarise mitochondrial disease…

‘…any organ, any symptom, any age’

Mitochondria perform many functions necessary for cell metabolism, but the energy producing pathways are the most important. These pathways allow us to break down carbohydrate, fat and oxygen to live. This process of burning food to make the energy molecule, adenosine triphosphate (ATP), is called oxidative phosphorylation (OXPHOS). Only mitochondria can do it. This highly efficient manufacturing process requires oxygen and is therefore called aerobic metabolism and produces 90% of the energy needed by the human body.

Mitochondria also play intimate roles in most of the cell’s major metabolic pathways that build, break down, or recycle its molecular building blocks. Cells cannot even make the RNA and DNA they need to grow and function without mitochondria. However for the purpose of this booklet, we will discuss in depth only the mitochondria’s main role in energy production.

Over 70 different polypeptides or proteins interacting on the inner mitochondrial membrane make up the complex mitochondrial respiratory chain and allow OXPHOS to occur. Energy sources such as glucose are initially metabolized in the cytoplasm then imported via proteins at the beginning of the chain. Other proteins in the chain continue the process of catabolism using metabolic pathways such as the Krebs cycle, fatty acid oxidation, and amino acid oxidation.

This produces energy-rich electron donors whose electrons are then passed through an electron transport chain (a series of complex molecules I, II, III, and IV). Cytochrome oxidase or complex IV, passes the electrons to oxygen which is reduced to water. ATP synthase or Complex V then uses the electrochemical proton gradient produced by the electron transport chain to finally make ATP. Although electron transport occurs with great efficiency, a small percentage of electrons are prematurely leaked to oxygen, resulting in the formation of the toxic free-radical superoxide.
Mitochondria take on many different shapes, each being characteristic of the specialised cell in which it resides7, and tailored to meet the needs of that cell. All told, there are about 250 different cell types in the human body, many having their own distinct mitochondria with its own specialised metabolic function4. Most of our body’s nucleated cells contain 500 to 2,000 mitochondria, though some cell types have only a few mitochondria. For example, platelets have only two to six mitochondria whilst red blood cells do not contain any mitochondria, though its cellular precursor, the proerythroblast, is critically dependent on mitochondrial function for differentiation into a mature red blood cell.

The tissues that require lots of energy are the ones most plentiful in mitochondria, and so these highly energy-dependent tissues or organs are the ones most affected in mitochondrial disease. Therefore most damage is to the cells of the muscles, brain, heart, liver, ears and eyes.

Mitochondrial diseases are a clinically heterogeneous group of disorders that result from a dysfunction in the mitochondrial respiratory chain. The first molecular identification of the cause of mitochondrial diseases was not until 1988. Tissues and organs that are highly dependent upon this aerobic metabolism are most likely to be involved in mitochondrial disease. Common clinical features are ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, hypoglycaemia, liver failure, sensorineural deafness, optic atrophy, and pigmentary retinopathy, along with central nervous system findings of fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity.

The ability for an organ to function normally depends partly on whether its energy production meets a minimum threshold for that organ, otherwise dysfunction occurs. The organs that are more highly energy dependent may show symptoms with even a relatively small drop in energy production. For example, the central nervous system has a lower threshold than other organs at which it will start to show evidence of functional impairment.

Some mitochondrial disorders only affect a single organ, such as the eye in Leber hereditary optic neuropathy (LHON), but many involve multiple organ systems and often present with prominent neurologic and myopathic features. Many affected individuals display a cluster of clinical features that fall into a discrete clinical syndrome, such as ‘mitochondrial encephalopathy with lactic acidosis and stroke-like episodes’ (MELAS), or myoclonic epilepsy with ragged-red fibres (MERRF). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category3. There is no consistent correlation between the severity of a particular biochemical defect and the severity of that patient’s presentation.

When a cell contains defective mitochondria, it not only becomes deprived of ATP, it also accumulates unused energy molecules and oxygen. The mitochondrial function worsens as these molecules are then used to make ATP by inefficient means, producing potentially harmful by-products such as lactic acid. This ‘lactic acidosis’ is associated with muscle fatigue, and has the potential to damage muscle and nerve tissue. Another harmful by-product, called free radicals or ‘reactive oxygen species’ may also produce oxidative damage.

Therefore, the combined effects of energy deprivation and toxin accumulation in these cells produce the main symptoms of mitochondrial myopathies and encephalomyopathies.

Mitochondria are the only cellular organelles known to have their own DNA (mitochondrial DNA or mtDNA), distinct from the nuclear DNA (nDNA).

Genetic testing (mutation analysis) for mitochondrial diseases is complicated by the complexity of the mitochondrion and mitochondrial respiratory chain itself, encoded by both mtDNA and nDNA. All up it takes about 1,500 genes to make an entire mitochondrion, and mtDNA encodes just 37 of those genes, the rest is encoded by the nDNA. Less than 10% of these 1,500 genes are actually allocated for making ATP with the rest involved in the specialised duties of the differentiated cell.

Defects in nDNA can be inherited from either parent and in a Mendelian pattern, (that is, one copy of each gene comes from each parent). Also, most are autosomal recessive. Due to a quirk in the process of fertilisation, defects in the genes of the mtDNA are only maternally inherited. That’s because during conception, when the sperm fuses with the egg, the sperm’s mitochondria, and its mtDNA, are destroyed.

Each human cell contains thousands of copies of mtDNA which at birth are usually all identical and called homoplasmy. By contrast, individuals with mitochondrial disorders resulting from mtDNA mutations may harbour a mixture of mutant (dysfunctional) and wild-type (normal) mtDNA within each cell and this is called heteroplasmy. The proportion of mutant mtDNA must exceed a critical threshold level, ‘the threshold effect’, before a cell expresses a biochemical abnormality of the mitochondrial respiratory chain10. The percentage level of mutant mtDNA may vary among individuals within the same family, and also among organs and tissues within the same individual11. Simplistically, a child conceived from a ‘mostly healthy’ ovum probably won’t develop the disease, and a child conceived from a ‘mostly mutant’ ovum probably will.

Therefore, the way that mtDNA and nDNA mutations interact with each other and with the environment, can help determine if disease occurs. So the link between genotype and phenotype in mitochondrial diseases has and will always be recognised as complex

Mitochondrial diseases are usually difficult to recognise because patients can have varying presentations due to the multiple organ systems involved, and because the onset may occur from before birth to late adult life. Even within the same family the same disease may affect individuals differently as there is no one identifying feature of mitochondrial disease.

So to begin the diagnostic process, firstly we must consider the possibility of mitochondrial disease. That is when:

1) A ‘common disease’ has atypical features that set it apart from the pack.
2) Three or more organ systems are involved.

3) Recurrent setbacks/flare ups in a chronic disease occurs with infections.4

Mitochondrial disease should therefore be suspected when these unexplained symptoms in the table below occur, especially in combination4. If these symptoms exist, then referral to a mitochondrial specialist would be appropriate to continue to ‘build the case’.

Perhaps the only way to make a diagnosis of a primary mitochondrial disease with absolute certainty at this time is to identify a mtDNA or nDNA abnormality that is known to cause disease. Without that, the best one can do is ‘build a case’ for a diagnosis by using several diagnostic approaches. These diagnostic approaches include:

Findings in any one of these categories is not sufficient to make a diagnosis as abnormalities can occur in other illnesses, or may be a secondary phenomenon reflecting mitochondrial dysfunction in another non-mitochondrial disease. Furthermore, some patients with proven disease may not show any biochemical, histological or imaging abnormalities18.

When a diagnosis is made without absolute certainty, the patient should then be re-evaluated regularly by a geneticist or neurologist who has an interest in mitochondrial disease.

The terminology used to describe mitochondrial disease can be confusing and it is still a struggle to fit many patients into the groups we know. A single syndrome, with a combination of symptoms, may have many different genotypes, while more than one syndrome may have the same genotype. A diagnosis may be named for the cause, such as COX deficiency, or it may be based on the symptoms of the disease such as the following examples:

MELAS: Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes.

This is the most common type of mitochondrial encephalopathy.
Onset: Usually between 2 to 40 years of age, mean is 10 years, but can be any age.
Disease characteristics: Hallmark sign is the ‘MELAS’ attack. General characteristics are exercise intolerance, seizures, dementia, muscle weakness, hearing loss, blindness, migraine-type headaches, myopathy, gastric dysmotility, polyneuropathy, ptosis, cardiomyopathy, diabetes, renal failure and short stature.
Inheritance: Maternal

MERRF: Myoclonic Epilepsy with Ragged-Red Fibres

Onset: Usually late adolescence to adulthood; variable progression.
Disease characteristics: Myoclonic epilepsy, proximal myopathy, sensorineural deafness, ataxia, pigmentary retinopathy, coordination loss, dementia, distal sensory loss and optic atrophy.
Inheritance: Sporadic or maternal

KSS: Kearns-Sayre Syndrome

Onset: Before age 20
Disease characteristics: Progressive External Ophthalmoplegia (PEO), ptosis, pigmentary degeneration of retina, heart block, myopathy, dysphagia most commonly associated with cricopharyngeal achalasia, hearing loss, ataxia, and dementia.
Inheritance: Sporadic

Leigh syndrome: Subacute necrotizing encephalomyopathy

Onset: Infancy and progression can be fast or slow. Death often occurs within two years of onset.
Disease characteristics: Vomiting, ataxia, hypotonia or spasticity, seizures, feeding and speech difficulties, hearing loss, nystagmus, visual loss, choreoathetosis, peripheral neuropathy, hyperventilation, motor and intellectual regression.
Inheritance: Mendelian or maternal

MNGIE: Mitochondrial Neuro-GastroIntestinal Encephalopathy

Onset: Often before age 20, range five months to 55yrs
Disease characteristics: External ophthalmoplegia, ptosis, digestive tract disorders due to visceral neuropathy with weight loss, retinal degeneration, neuropathy, short stature, myopathy, loss of coordination, leukoencephalopathy and hearing loss.
Inheritance: Mendelian

NARP: Neuropathy, Ataxia and Retinitis Pigmentosa

Onset: Infancy or childhood
Disease characteristics: Retinitis Pigmentosa causing visual loss, lack of coordination, ataxia, weakness, dementia, seizures and developmental delay. This syndrome may represent a less severe form of MILS (Maternally Inherited Leigh Syndrome).
Inheritance: Maternal

PEO: Progressive External Ophthalmoplegia

Onset: Usually in adolescence or early adulthood; slow progression.
Disease characteristics: Gaze limited in all directions, slow eye movements, bilateral, associated with ptosis, slowly progressive, and usually associated with muscle weakness and fatigue.
Inheritance: Maternal, Sporadic, and Mendelian. Often occurs in conjunction with other mitochondrial syndromes.

LHON: Leber Hereditary Optic Neuropathy

Onset: Male predominance, usually 30yr, range one to 70yr
Disease characteristics: Visual loss, pre-excitation cardiac conduction syndromes, spasticity, dystonia, ‘multiple sclerosis-like’ disorder and encephalopathy.
Inheritance: Maternal

The management of mitochondrial disease is largely supportive14, as there is no way of simply increasing the capacity of the cell to generate energy21. Treatment therefore involves optimising energy production, reducing energy losses, meeting lifestyle needs such as education, and monitoring for complications

OPTIMISING ENERGY PRODUCTION

1. Adequate nutrition. Adequate calories and nutrition can dramatically improve a patient’s overall clinical state and slow the progression of the illness21. Special diets may benefit some patients, such as high fat diets with restriction of simple carbohydrates, fructose restriction, and/or high complex carbohydrate intake4. Eating smaller meals more regularly and avoidance of fasting, particularly prolonged fasting is also extremely important in optimizing mitochondrial function.

2. Adequate sleep. Improving sleep is a correctable component of fatigue. Therefore, issues like sleep apnoea need to be managed. Central sleep apnoea can occur in more advanced disease, whereas obstructive sleep apnoea (due to muscle hypotonia or weakness) is more common21.

3. Promoting activity. Regular exercise not only improves stamina it also improves mitochondrial function25,26. To maximise energy production, mitochondrial patients must remain active, though exhaustion should be avoided and achieving a ‘normal’ level of endurance is unrealistic21.

4. Supplementation with certain vitamins and cofactors. It is considered standard care to use a cocktail of vitamin and co-factor supplementation for patients with mitochondrial disorders, although there are a large variety of studies with even a larger variety of answers regarding their efficacy. At present, there are no cures for these disorders except in very rare and specific disorders such as primary carnitine deficiency or primary coenzyme Q10 deficiency4. The goals of supplementation are to improve symptoms and to halt the progression of the illness. The effectiveness of treatment varies with each patient but it will not reverse any damage that has already occurred23.

There is no standard vitamin cocktail, commonly known as the ‘mito cocktail’. Ideally, vitamins should be started one at a time to allow observation of any benefit or adverse reaction.

The following table lists substances often suggested as clinically effective in the literature or for which the literature contains reports on a case-by-case basis of potential positive treatment effects for mitochondriopathies (17,22,23). But please note that a Cochrane Review concluded there was no proven efficacy for any of these substances

REDUCING ENERGY LOSSES

1. Prevention of infections. Patients with mitochondrial disease frequently do not tolerate infections well and they may cause prolonged, debilitating fatigue and weakness, and possibly even death. As a result, their vaccinations should be kept up-to-date including the seasonal vaccinations (e.g., influenza), and antibiotics should be considered early in any infective illness.

2. Avoiding excessive physical activity. ‘Overdoing it’ produces no benefit and can leave a patient exhausted, in pain, nauseous, and miserable.

3. Treating emotional distress. Frequent or persistent anxiety, depression, or obsessive-compulsive behaviours are very energy-demanding.

4. Maintaining a suitable ambient temperature. Patients with mitochondrial disease often don’t tolerate extremes of temperature.

EDUCATIONAL NEEDS

The majority of children with mitochondrial disease show learning and/or behavioural problems that are typically unique to each child, so an educational plan should be tailored to each child, not based on his/her diagnosis. However, a medical plan is frequently needed as well to create an optimal learning environment.
Points to consider include:

Pacing the child to match their fatigability
Never forget they have ‘good and bad’ days
A comfortable classroom temperature
Avoidance of infective illnesses
Avoidance of unnecessary emotional distress21.

MONITORING COMPLICATIONS

The caring physician must have a thorough knowledge of the potential complications of mitochondrial disorders in order to prevent unnecessary morbidity and mortality. This includes the early diagnosis and/or management of diabetes mellitus, seizures, cardiac pacing, ptosis correction, and intraocular lens replacement for cataracts.

Unless a patient has a very specific disease with a predictable phenotype, routine monitoring of the following organs is generally on a 1-2 year schedule:

Blood and urine testing

1. Bone marrow involvement – FBC, WBC differential, platelets
2. Liver involvement – AST, ALT, bilirubin
3. Kidney involvement – Blood urea nitrogen (BUN), creatinine (blood), urinalysis, urine amino acids (quantitative)
4. Muscle involvement – CK
5. Endocrine involvement – thyroid functions, calcium, phosphorus. Adrenal insufficiency is also a possibility.
6. Metabolic status – lactate and pyruvate, carnitine and acylcarnitines, leukocyte coenzyme Q10, urine organic acid analysis.

Other testing

1. Ophthalmological evaluation and especially screening for visual function if concerned
2. Audiology testing
3. Cardiac evaluation, including ECG, echocardiogram
4. Developmental or neuropsychological testing according to the patient’s needs

Although research into mitochondrial genetic manipulation is well on the way around the world, particularly in the UK, there are many ethical and medical obstacles to overcome before it can truly be considered a viable form of mitochondrial disease prevention.

At present there is no known cure and it is not possible to predict the future of a person with mitochondrial disease, as the expression of the illness in each individual is extremely variable and difficult to assess. The disease might progress quickly or slowly over decades, or it might appear stable for years. Research so far has helped some of the affected children and adults to live fairly normal lives but at the opposite end of the spectrum, many are severely affected, and some children do not survive to their teenage years.

Even when mitochondrial dysfunction is confirmed by sophisticated biochemical testing, it can be difficult to know whether the cause is primarily genetic (and directly impacting the mitochondrial respiratory chain), or if it is secondary to another unrelated genetic or environmental cause. For instance, mitochondrial dysfunction may be seen when the primary defect occurs in another energy-related metabolic pathway, such as fatty acid oxidation or amino acid metabolism. Mitochondrial dysfunction has also been shown to occur in vitro in disorders such as copper-metabolism disorders (Wilson disease and Menkes disease), some lysosomal disorders, and neonatal haemochromatosis, to name a few. In addition, decreased activities of ‘electron transport chain’ complexes in skeletal muscle may be seen in malnourished children, with correction to normal levels after improved nutrition13.

Researchers are also studying mitochondrial diseases looking for clues to other conditions such as cancer, Parkinson’s disease, Alzheimer’s, and heart disease. Damage to the mitochondria is thought to be involved with all of these conditions, and a lifetime of mitochondrial damage may also be part of the aging process.

1. Population prevalence of the MELAS A3243G mutation. Manwaring N, Jones MM, Wang JJ, Rochtchina E, Howard C, Mitchell P, Sue CM. Mitochondrion, 2007 May; 7(3):230-3.

2. Pathogenic mitochondrial DNA mutations are common in the general population. Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. American Journal of Human Genetics, 2008 Aug;83(2):254-60.

3. Mitochondrial disorders overview Patrick F Chinnery, MBBS, PhD, MRCP. GeneReviews, Initial Posting: June 8, 2000. Last Update: February 21, 2006.

4. A Primary Care Physician’s Guide, the Spectrum of Mitochondrial Disease. Robert K. Naviaux, MD, PhD. United Mitochondrial Disease Foundation at www.umdf.org.

5. Prevalence of mitochondrial 1555ARG mutation in adults of European descent. Vandebona, H. et al. N. Engl. J. Med. 360, 642–644 (2009).

6. Prevalence of mitochondrial 1555ARG mutation in European children. Bitner-Glindzicz, M. et al. N. Engl. J. Med. 360, 640–642 (2009).

7. Slides of the various shapes of mitochondria. Exceptional Parent, June 1997, pp. 40-42.

8. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Holt IJ, Harding AE, Morgan-Hughes JA. Nature. 1988; 331: 717–9.

9. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. Am J Hum Genet. 1990; 46: 428–33.

10. Mitochondrial DNA mutations and pathogenesis. Schon EA, Bonilla E, DiMauro S. J. Bioenerg Biomembr. 1997; 29: 131–49.

11. Variable distribution of mutant mitochondrial DNAs (tRNA(Leu[3243])) in tissues of symptomatic relatives with MELAS: the role of mitotic segregation. Macmillan C, Lach B, Shoubridge EA. Neurology. 1993; 43: 1586–90.

12. Vibration treatment for genetic disease. In press, “www.news.com.au” August 13, 2009 4:45AM

13. Mitochondrial disease: a practical approach for primary care physicians. Haas R. Et al. Pediatrics 120:1326-33 (2007).

14. Epidemiology and treatment of mitochondrial disorders. Chinnery PF, Turnbull DM. Am J Med Genet. 2001; 106: 94–101.

15. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Lyndsey Craven et al. Nature Letters 08958

16. Mitochondrial disease. Anthony H V Schapira. The Lancet; Jul 1-Jul 7, 2006; 368, 9529

17. United Mitochondrial Disease Foundation www.umdf.org

18. Mitoaction www.mitoaction.org.

19. Muscular Dystrophy Association www.mda.org

20. The Mitochondria Research Society www.mitoresearch.org

21. A Clinician’s Guide to the management of Mitochondrial Disease: A manual for primary care providers developed by Margaret Klehm, Mark Korson, and mitoaction.org, 2008: www.mitoaction.org

22. Guidelines issued by the Working Group on Paediatric Metabolic Disorders; Diagnostic and Treatment Approaches to Mitochondriopathies in Children and Adolescents; Results of Three Conferences of Experts Current status of the guideline development: Development stage 1 Prof. Dr. Wolfgang Sperl, et al. March 2008.

23. Diagnosis and Treatment of Childhood Mitochondrial Diseases. Andrea L. Gropman, MD. Current Neurology and Neuroscience Reports 2001, 1:185–194

24. Effect of Idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary study. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, et al. Lancet 1999, 354:477–479.

25. Mahoney, 2002: A Clinician’s Guide to the management of Mitochondrial Disease: A manual for primary care providers developed by Margaret Klehm, Mark Korson, and mitoaction.org, 2008: www.mitoaction.org

26. Jeppesen 2006: A Clinician’s Guide to the management of Mitochondrial Disease: A manual for primary care providers developed by Margaret Klehm, Mark Korson, and mitoaction.org, 2008: www.mitoaction.org

27. Treatment for mitochondrial disorders. Chinnery P, Majamaa K, Turnbull D, Thorburn D. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004426.

28. Mitochondrial Disease Information Booklet for Medical Practitioners. Crawley K, MBBS FRACGP, Sue C MBBS PhD FRACP, Cristodoulou J MB BS PhD FRACP FRCPA FHGSA, Thorburn D BSc(Hons) PhD FHGSA FFS (RCPA) Mito Foundation May 2014

The Mito Foundation would like to give a very special thanks to the UMDF, Mitoaction, the Muscular Dystrophy Association and the Mitochondrial Research Society for encouraging and supporting us in the establishment of our foundation, and by allowing us to resource the invaluable material in their websites.